Fight 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.

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."

Link: http://www.bristol.ac.uk/news/2017/march/blood-cells.html

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.

Link: https://www.portal.uni-koeln.de/9015.html?&L=1&tx_news_pi1%5Bnews%5D=4521&tx_news_pi1%5Bcontroller%5D=News&tx_news_pi1%5Baction%5D=detail

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.

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.

Link: https://unews.utah.edu/pain-in-the-neck/

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.

Link: https://doi.org/10.3389/fonc.2017.00055

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.

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.

Link: http://www.utsouthwestern.edu/newsroom/news-releases/year-2017/apr/nano-cancer-therapy.html

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.

Link: https://www.eurekalert.org/pub_releases/2017-04/acs-nct042117.php

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.

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.

Link: http://www.fredhutch.org/en/news/center-news/2017/04/dissolving-implant-could-bring-immunotherapy-to-solid-tumors.html

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.

Link: https://www.eurekalert.org/pub_releases/2017-04/b-aar041917.php

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.

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.

Link: https://dx.doi.org/10.3389/fimmu.2017.00356

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.

Link: http://www.uhn.ca/corporate/News/PressReleases/Pages/when_liver_immune_cells_turn_bad.aspx

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.

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.

Link: https://doi.org/10.3389/fnagi.2017.00083

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.

Link: http://onlinelibrary.wiley.com/doi/10.1002/jcsm.12204/full

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.

The Lifespan.io 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 Lifespan.io 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.

Link: https://www.lifespan.io/campaigns/join-us-become-a-lifespan-hero/

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.

Link: http://www.ebiomedicine.com/article/S2352-3964(17)30154-8/fulltext

A growing collection of studies and projects have emerged from parabiosis experiments in which the circulatory systems of a young and an old individual are joined. The old individual experiences a modest reduction in the impact of aging, in measures such as regeneration, stem cell activity, and more. This has prompted researchers to search for proteins in young blood that might act as signals to improve function when delivered to old tissues, though the field is young enough and complex enough that there is considerable uncertainty over whether or not youthful signals are in fact the mechanism of interest. There is good evidence for the effects to result from a dilution of harmful factors in old blood instead, for example, which might explain past failures to obtain benefits from transfusion of young blood - though human trials are still ongoing on that front. The paper noted below stands somewhat in opposition to this position, in that the researchers involved have identified another candidate factor in young blood that appears to improve health in old animals. Young fields of research are usually characterized by this sort of apparently incompatible evidence.

Considering the bigger picture, the teams involved in this area of research are essentially engaged in a process of cataloging the differences in types and amounts of proteins found in young blood versus old blood. They are carrying out transfusion experiments and building other interventions to try to pin down which of these proteins are involved in age-related decline or in maintaining youthful function - a matter of needles in haystacks. It is plausible that in the years ahead this might be an alternative road to capturing some of the benefits of present stem cell therapies, those that largely work though signals produced by the transplanted cells, and a way to adjust the behavior of native cell populations. It would override cellular reactions to the rising damage of aging, and push cells into a more youthful pattern of behavior. This carries risk, as damaged cells working harder raises the possibility of cancer. That stem cell therapies can be made to work with a minimal cancer risk should give us hope on that front, however.

As the research results below suggest, there are other possibilities beyond that of enhancing regeneration. Improvements in faltering neurogenesis and synaptic plasticity in the brain are a possibility, for example, with the potential to provide greater resilience to cognitive decline in old age. All of these things will likely operate within the same bounds of the possible and the plausible as are observed for stem cell therapies: it is a road to improvements, not to a reversal of aging. Forcing youthful behavior doesn't remove the underlying damage that has caused age-related changes in cellular behavior, and that damage will still win if not repaired. Methods of enhanced regeneration and neural plasticity may still be beneficial enough to spend time on, however. We shall see.

Young human blood makes old mice smarter

For decades, researchers have studied the effects of young blood on ageing in mice through a technique called parabiosis, in which an old mouse is sewn together with a younger one so that they share a circulatory system. Until now, the rejuvenating properties of young blood had only been demonstrated in mouse-to-mouse transfers. Nevertheless, the work has inspired ongoing clinical trials by at least two companies in which elderly people are infused with blood from younger adult donors and then tested for physical improvements. In one of the clinical trials researchers have started testing plasma collected from the umbilical cords of newborn babies. Their goal is to find out how very young human blood might affect the symptoms of ageing.

Infusing this human plasma into the veins of elderly mice, they found, improved the animals' ability to navigate mazes and to learn to avoid areas of their cages that deliver painful electrical shocks. When the researchers dissected the animals' brains, they found that cells in the hippocampus - the region associated with learning and memory - expressed genes that caused neurons to form more connections in the brain. This didn't happen in mice treated with blood from older human donors.

The researchers then compared a slate of 66 proteins found in umbilical cord plasma to the proteins in plasma from older people, and to proteins identified in the mouse parabiosis experiments. They found several potential candidates, and injected them, one at a time, into the veins of old mice. The team then ran the animals through the memory experiments. Only one of these proteins, TIMP2, improved the animals' performance. It did not, however, result in regeneration of brain cells that are lost during normal ageing. Injections of human umbilical cord plasma lacking TIMP2 had no effect on memory. The researchers don't yet know how TIMP2, which is known to be involved in maintaining cell and tissue structure, exerts its effect on memory. And although it is expressed in the brains of young mice, TIMP2 has never before been linked to learning or memory. Researchers suspect that the protein functions as a 'master regulator' of genes involved in the growth of cells and blood vessels, and that increasing its levels affects many pathways simultaneously.

Human umbilical cord plasma proteins revitalize hippocampal function in aged mice

Ageing drives changes in neuronal and cognitive function, the decline of which is a major feature of many neurological disorders. The hippocampus, a brain region subserving roles of spatial and episodic memory and learning, is sensitive to the detrimental effects of ageing at morphological and molecular levels. With advancing age, synapses in various hippocampal subfields exhibit impaired long-term potentiation, an electrophysiological correlate of learning and memory. At the molecular level, immediate early genes are among the synaptic plasticity genes that are both induced by long-term potentiation and downregulated in the aged brain. In addition to revitalizing other aged tissues, exposure to factors in young blood counteracts age-related changes in these central nervous system parameters, although the identities of specific cognition-promoting factors or whether such activity exists in human plasma remains unknown.

We hypothesized that plasma of an early developmental stage, namely umbilical cord plasma, provides a reservoir of plasticity-promoting proteins. Here we show that human cord plasma treatment revitalizes the hippocampus and improves cognitive function in aged mice. Tissue inhibitor of metalloproteinases 2 (TIMP2), a blood-borne factor enriched in human cord plasma, young mouse plasma, and young mouse hippocampi, appears in the brain after systemic administration and increases synaptic plasticity and hippocampal-dependent cognition in aged mice. Depletion experiments in aged mice revealed TIMP2 to be necessary for the cognitive benefits conferred by cord plasma. We find that systemic pools of TIMP2 are necessary for spatial memory in young mice, while treatment of brain slices with TIMP2 antibody prevents long-term potentiation, arguing for previously unknown roles for TIMP2 in normal hippocampal function. Our findings reveal that human cord plasma contains plasticity-enhancing proteins of high translational value for targeting ageing- or disease-associated hippocampal dysfunction.

The Life Extension Advocacy Foundation volunteers here interview Alex Zhavoronkov of Insilico Medicine. This company is focused on analysis of aging and discovery of drugs that might modestly slow aging rather than interventions after the SENS rejuvenation research model. If continuing along much the same road in the future, I predict that that the most important contribution to the field arising from this work will likely be a range of novel biomarkers to help determine the effectiveness of therapies that aim to treat aging. I have never been all that enthused by efforts to produce or repurpose drugs that tinker with the operation of metabolism to slightly slow aging, such as calorie restriction mimetics and the like. The plausible outcomes resulting from such efforts look marginal at best, and these research projects are at least as expensive as initiatives that aim at actual rejuvenation, while that rejuvenation has a far greater predicted outcome on health and longevity. On this topic, Zhavoronkov and I clearly differ in our expectations.

Your work focuses on computational medicine, how would you explain this relatively new field of science to our readers?

Computational biomedicine is a very broad field of research, where computational methods and tools are applied for diagnosis, treatment and research. The field has been around since the invention of electronic analytical equipment, but in recent years it got a major boost due to the availability in Big Data, increases in computing power, breakthroughs in machine learning and convergence of the many fields of science and technology.

You are the CEO of Insilico Medicine. What are the main goals of the company for the next 5 years? Can we expect breakthroughs in personalised medicine?

Our long-term goal is to continuously improve human performance and prevent and cure the age-related diseases. In 5 years we want to build a comprehensive system to model and monitor the human health status and rapidly correct any deviations from the ideal healthy state with lifestyle or therapeutic interventions. Considering what we already have, I hope that we will be able to do it sooner than in 5 years. One reason why we can manage over 170 projects is because we use agile development practices and approach every project as a software development project. We treat aging as a salami, constantly "cutting" thin slices and I think we are halfway through.

In 5 years you can definitely expect breakthroughs in personalized medicine and we are not the only company working in the field, so there will be many breakthroughs on the many fronts. The main breakthroughs I can promise from Insilico are in the area of multi-modal biomarkers of aging, where we take as much data available for an individual from simple pictures and regular blood tests to very expensive molecular and imaging data and turn it into a model, which can be used to make a broad range of predictions, recommendations and treatments. We are entering the era of personalized drug discovery and regenerative medicine.

One of our major contributions to the field was the application of deep neural networks for predicting the age of the person. People are very different and have different diseases. But if you want to find just one feature, which is biologically relevant and can be predicted using many data types - it is the person's date of birth. So we build all kinds of predictors of chronological age and then look at what features and at what levels are most important and can be used to infer causality and be targeted with interventions. I think that this approach is novel and will result in many breakthroughs.

How do you decide what projects to get involved in?

The way we prioritize projects at Insilico Medicine is by looking at the number of quality-adjusted life years (QALY) each project can generate. Most pharmaceutical companies, governments, and philanthropists do not realize that aging research generates the maximum number of QALY per dollar spent. It is the most altruistic cause and the most effective investment. If you add just one year of life to everyone on the planet, you generate over 7 billion QALY. The average reasonable cost per QALY is around $50,000. So it is possible to generate several hundred trillion dollars by extending life of everyone on the planet with a simple intervention.

What is your estimate, when we could expect the first powerful treatment to slow down aging appear on the market?

I think that there are several very powerful treatments that are already available on the market and to get the extra 10-20 years or even more we just need to devise a way to turn these into therapeutic regimens. I think that a comprehensive regimen involving metformin, targeted rapalogs, senolytics, anti-inflamatory agents, aspirin, NAC, ACE inhibitors, beta-blockers, PDE5, PCSK9 inhibitors, NAD+ activators and precursors in combination with the regenerative medicine procedures and also a set of cosmetic and lifestyle interventions could easily add 20 years to our life span. And I am sure that some people are already trying these interventions on themselves. Unfortunately, nobody is tracking this data.

Link: http://www.leafscience.org/a-i-versus-aging/

The primary goal of longevity science is to extend healthy life span. A secondary, less important goal is to reduce the time spent in ill health and declining function at the end of life. That secondary goal receives more attention for largely political reasons, however; it is what researchers talk about when they want to avoid talking about extension of life span. It is unfortunate that this is still a subject that is avoided by many in the research community. People should be more open when it comes to the fact the goal of treating aging as a medical condition is ultimately to extend healthy life indefinitely, to greatly extend the present all too short human life span. Trying to hide that away just makes everything harder.

The merits of a potential approach to treating aging should be judged primarily by the degree to which it can extend healthy life span. It is quite reasonable to expect some classes of treatment to also extend the period of decline in late life. Aging is caused by an accumulation of metabolic waste and molecular damage. A method that slows the pace of damage accumulation should both extend health and extend frailty. A method that periodically repairs damage should extend health and may or may not extend frailty, depending on the details. A method that improves resistance to damage or some of its consequences might fail to extend health while extending the period of frailty. All of these are possible outcomes, and the research community should aim for the most desirable of them, taking into account the size of the effect. A large extension to health span followed by a large extension to the period of frailty is a good deal better than a small gain in health span that does not extend the period of frailty.

Caenorhabditis elegans has been an invaluable experimental organism for the discovery and characterization of conserved pathways that extend lifespan. In particular, reduced signaling through the stress and nutrient-sensing insulin/insulin-like growth factor 1 (IGF-1) pathway was first shown to double the lifespan of C. elegans and was later found to increase the longevity of other species, including mammals. C. elegans with partial loss-of-function mutations in daf-2, the C. elegans insulin/IGF-1-receptor gene, not only live longer but also maintain more youthful characteristics, such as active movement, neuronal function, and memory, indicating an extension of healthspan as well as lifespan. However, a recent study followed the functional ability of daf-2 mutants and found that the daf-2 healthspan, although chronologically longer than that of the wild-type, did not scale with lifespan, resulting in a disproportionately extended period of age-related decrepitude. This report was disconcerting because such an outcome would be undesirable in a human society, where population aging has already increased healthcare costs substantially. It also brought into question the validity of C. elegans as a model organism to study healthy life extension.

In this study, we set out to accomplish three goals: to undertake a quantitative large-scale analysis to corroborate the reported disproportionately extended end-of-life decrepitude in a daf-2 mutant, to determine whether this phenotype could be due to behavioral particularities of the specific daf-2 allele that was examined, and, if not, to elucidate the cause of this apparently undesirable phenotype. We found that two very different daf-2 mutants both remain active longer and age more slowly than the wild-type, at least through mid-life, but then go on to stay alive but decrepit for a long time. We wanted to understand what might cause this extended decrepitude. Theoretically, eliminating a cause of death that kills relatively young individuals would result in a population's growing older and frailer.

We wondered whether resistance to bacterial toxicity might play a role. We measured bacterial colonization of a daf-2 mutant. Colonization of the upper digestive tract was delayed and never reached the same maximum as in the wild-type. This finding is consistent with the idea that resistance to colonization allows daf-2 mutants to survive into old age. Why bacterial colonization occurs in old C. elegans and how exactly it causes death remains unknown. Decreased immune function with age could contribute to bacterial accumulation and proliferation, and daf-2 mutants have higher expression of some antimicrobial genes that curtail the rate of bacterial proliferation in the intestine. If reduced risk of death due to bacterial colonization allows daf-2 mutants to live long enough to become decrepit, then eliminating bacterial colonization as a cause of "premature" death should allow wild-type worms, too, to live long enough to enter a state of end-of-life decrepitude. To test this hypothesis, we fed wild-type animals bacteria killed by gentamicin from the time of hatching. Using killed bacteria as a food source extended the wild-type lifespan by 40%. Eliminating bacterial colonization as a cause of death in wild-type worms copied the extended period of decrepitude seen in daf-2 mutants.

In summary, we find that the level of bacterial colonization predicts wild-type lifespan. The extent of colonization is significantly greater in the wild-type than in daf-2 mutants, and eliminating colonization in wild-type animals allows them to avoid an early death; instead, they remain alive for a longer time in a decrepit, aged state, just like daf-2 mutants. Therefore, we conclude that a beneficial trait (resistance to bacterial colonization) can explain the extended end-of-life frailty of daf-2 mutants. Surviving the hazard from bacterial colonization allows these mutants to grow biologically older and more decrepit than end-of-life wild-type animals. Together, these findings support the argument that C. elegans daf-2 mutants are valuable for studying healthy lifespan extension. daf-2 mutants live longer because of a two-part mechanism: a slower rate of aging (leading to extension of healthspan) and an increased ability to resist death due to bacterial colonization (leading to extension of decrepitude). More generally, the results presented here show how the healthspan of an organism can be affected in opposite ways at different times of life by an intervention that both decreases the rate of aging and also mitigates a disease that kills old individuals. This is important to keep in mind when seeking to develop interventions that act by different demographic mechanisms to increase human lifespan.

Link: http://www.cell.com/cell-reports/fulltext/S2211-1247(17)30423-0

In recent years, researchers interested in the mechanisms of regeneration have explored the changing landscape of signals in the blood, both in the short term following injury and over the long term during the aging process. A number of interesting findings have emerged, especially in the course of parabiosis studies in which the circulatory systems of old and young individuals are joined. The field is still evolving fairly rapidly, and some results from just a few years ago now look more uncertain in the face of later evidence. Nonetheless, new mechanisms and areas of focus continue to emerge, such as that described in the open access paper I'll note today. The researchers involved have identified hepatocyte growth factor activator (HGFA) as a key signal in the regenerative process, and a possible path to enhance regeneration in mammals.

As we all know only too well, regeneration falters with advancing age. Our stem cells, the cell populations responsible for turning out new cells to replace those lost to injury or required to rebuild damaged structures, decline over the course of aging. In older individuals, stem cells are ever less active, spending more time quiescent, or the population size is reduced. This may be in part a fairly direct result of the molecular damage that causes aging, but in the most studied stem cell populations, such as those in muscle tissue, it appears that aged stem cells are still quite capable if give the right signals. In older tissues those signals are not present to the necessary degree, or are overridden by other signals that are a reaction to damage in the surrounding environment.

It is thought that the decline in stem cell activity, and consequent failure and frailty of tissues, is part of an evolved balance between death by cancer and death through lack of tissue maintenance - too much cellular activity by damaged cells will ultimately produce cancerous cells. On the other hand, the progress of the stem cell therapy industry to date suggests that the evolved balance has some room for adjustment in favor of more regeneration in the old. Further, we should expect the cancer research community to continue to make progress of its own: greater regeneration in the old can advance hand in hand with a greater ability to effectively treat cancer. Looking beyond that partnership, true rejuvenation therapies, those that repair the molecular damage that is the root cause of aging, should reactivate stem cells and restore regenerative prowess without any further downside.

Alerting stem cells to hurry up and heal

This recent study builds upon a previous finding that when one part of the body suffers an injury, adult stem cells in uninjured areas throughout the body enter a primed or "alert" state. Alert stem cells have an enhanced potential to repair tissue damage. In this new study, researchers identified a signal that alerts stem cells and showed how it could serve as a therapy to improve healing. Searching for a signal that could alert stem cells, the researchers focused their attention on the blood. They injected blood from an injured mouse into an uninjured mouse. In the uninjured mouse, this caused stem cells to adopt an alert state. The researchers identified the critical signal in blood that alerted stem cells: an enzyme called Hepatocyte Growth Factor Activator (HGFA). In normal conditions, HGFA is abundant in the blood, but inactive. Injury activates HGFA, so HGFA signaling can alert stem cells to be ready to heal.

Leveraging this discovery, the researchers asked the question: What happens if HGFA alerts stem cells before an injury occurs? Does this improve the repair response? They injected active HGFA into mice that received either a muscle or skin injury a couple of days later. The mice healed faster, began running on their wheels sooner and even regrew their fur better than mice that did not receive the HGFA booster. These findings indicate that HGFA can alert many different types of stem cells, rousing them from their normal resting or "quiescent" state, and preparing them to respond quickly and efficiently to injury. "This work shows that there are factors in the blood that control our ability to heal. We are looking at how HGFA might explain declines in healing, and how we can use HGFA to restore normal healing."

HGFA Is an Injury-Regulated Systemic Factor that Induces the Transition of Stem Cells into GAlert

Tissue damage induces the activation of quiescent stem cells, initiating a cascade in which stem cells enter the cell cycle, divide, and proliferate to generate the cells required to repair or regenerate damaged tissue. Stem cell activation is a limiting step in the process of tissue repair. In many stem cell pools, the first cell division following activation is slow and can take many days to complete, whereas subsequent cell divisions are much more rapid. Defects in stem cell activation, such as a lengthening in the time of first cell division or a failure in stem cells to activate, can result in significant impairments in the healing process. Little is known about the biologic regulation of stem cell quiescence and activation. Approaches to accelerate the rate-limiting step of stem cell activation could have broad therapeutic applications in regenerative medicine.

We previously reported an acceleration of the activation properties of quiescent stem cells in response to a prior injury, distant from the tissue in which the stem cells were residing. We described this regulation as a transitioning of stem cells from the G0 to the GAlert state of quiescence, where GAlert stem cells are poised to activate quickly in response to injury and to repair tissue damage more effectively. Because of the enhanced functional properties of GAlert stem cells, there may be clinical applications for factors that induce the GAlert state. However, the endogenous signals that stimulate the G0-to-GAlert transition of stem cells in response to distant injuries have not been previously described. Here, we show that a single systemic factor, hepatocyte growth factor activator (HGFA), is sufficient to induce the transition of multiple pools of stem cells into GAlert and that administration of HGFA to animals, prior to an injury, improves the subsequent kinetics of tissue repair.

It is known that the cellular housekeeping process of autophagy declines with aging, and it is also known that the metabolic waste known as lipofuscin builds up in long-lived cells at the same time. In the SENS view of aging, this lipofuscin accumulation is one of the causes of failing autophagy, as it accumulates in the recycling structures called lysosomes, degrading their function. Definitively proving this direction of causation, versus it being the other way around, is ever a challenge, however. The most effective way to do that is to clear out lipofuscin in old tissues and then observe the results, but at present this can only be achieved for a few of the many constituent compounds that make up this form of waste.

Autophagy is a self-degradative, highly regulated process that involves the non-specific degradation of cytoplasmic macromolecules and organelles via the lysosomal system. There are three different autophagic pathways based on the mechanisms for delivery of cargo to lysosomes: macroautophagy, microautophagy and chaperone-mediated autophagy (CMA). Macroautophagy (herein referred to as autophagy) is the major lysosomal pathway for the turnover of cytoplasmic components. Emerging evidence indicates that autophagy protects cells by removing long-lived proteins, aggregated protein complexes, and excess or damaged organelles. Defects in autophagy, therefore, are associated to various pathological conditions within organisms, including tumorigenesis, defects in developmental programs and the build-up of toxic, protein aggregates involved in neurodegeneration such as Amyloid precursor protein (APP). It has been recently suggested that the progressive age-related decline of autophagic and lysosomal activity may also be responsible for the continuous intraneuronal accumulation of lipofuscin, or "age pigment".

For this study, we aimed to investigate the expression of autophagic markers and the accumulation of pathologic proteins such as APP and lipofuscin in aged bovine brains. Microscopic findings in the brains of our aged bovines are similar to those previously described in old animals of other species as well as in cattle. In this study, the age-dependent intraneuronal accumulation of lipofuscin is one of the most striking features of aged brains. This finding is not actually new, as it has been described for more than 150 years. In the past, lipofuscin was generally thought to be an innocent end product of oxidation which has no significant influence on cellular activities, but in the last decade several authors have investigated about the possible detrimental and pathogenic potential of this material.

The so-called "mitochondrial-lysosomal axis theory of aging" tries to explain the possible relationship between lipofuscin accumulation, decreased autophagy, increased Reactive Oxygen Species (ROS) production, and mitochondrial damage in senescent long-lived postmitotic cells. According to this theory, in senescent cells lysosomal enzymes are directed towards the plentiful lipofuscin-rich lysosomes and, subsequently, they are lost for effective autophagic degradation because lipofuscin remains non-degradable. The consequences are a progressive impairment of autophagy and the gradual accumulation of damaged mitochondria, other organelles and misfolded proteins that lead to neurodegeneration. Unfortunately, our results cannot support a direct association between lipofuscin accumulation and autophagy impairment in aged bovine brains. According to recent scientific literature, we can only hypothesize that progressive and severe lipofuscin accumulation may irreversibly lead to functional decline and death of neurons by diminishing lysosomal degradative capacity and by preventing lysosomal enzymes from targeting to functional autophagosomes.

Further studies are indeed necessary to better understand how lipofuscin accumulation can influence the neuronal autophagic and apoptotic pathways in bovine brains. It would be interesting to perform double-staining techniques in order to show whether lipofuscin is directly related to autophagic and apoptosis markers and/or to pathologic protein deposition. Unfortunately, to our knowledge, a specific antibody for lipofuscin is not available since this complex substance is mainly composed of cross-linked protein and lipid residues. Alternatively, combined histochemical and immunohistochemical staining protocols can be performed to simultaneously localize lipofuscin and the antigen of interest. However, since lipofuscin progressively accumulates throughout the life of neurons, this combined immunohistochemical/histochemical protocol is not perfectly indicated to investigate the mechanism and relative timing of intraneuronal lipofuscin accumulation and the deposition of other proteins. Primary cultured neuronal cells exhibit, in vitro, a variety of features that are frequently observed in physiologically aged neurons in vivo, including lipofuscin accumulation. Thus, long-term aging culture of primary cultured neurons would be a remarkable model to unravel, at least in part, the molecular mechanisms behind lipofuscin accumulation and its pathological effects on neuronal cells.

Link: https://dx.doi.org/10.1186/s12917-017-1028-1

Expression of the cell surface marker CD47 helps to protect cells from destruction by the immune system. It is abused by a variety of cancers, and thus blocking CD47 is the basis for a line of research into cancer therapies that might be broadly effective. Other researchers have found that this same approach might help to reduce the size of atherosclerotic plaques, so it seems that it isn't just cancerous cells in which excess CD47 is preventing beneficial destruction. Here, researchers discover that the cells making up the scar tissue of fibrosis are similarly protecting themselves with CD47, and blocking its activity causes the immune system to remove this scarring. Fibrosis is a damaging process, an age-related malfunction in the the normal progression of regeneration, and the scarring it causes in organs such as the heart and kidney degrade their proper function, contributing to decline and disease in later life. There is no effective treatment for fibrosis at the present time, which makes this research particularly exciting.

Researchers have identified a pathway that, when mutated, drives fibrosis in many organs of the body. The pathway underlies what have been considered somewhat disparate conditions, including scleroderma, idiopathic pulmonary fibrosis, liver cirrhosis, kidney fibrosis and more, the researchers found. These diseases are often incurable and life-threatening. Importantly, the researchers were able to reverse lung fibrosis in mice by administering an antibody called anti-CD47 now being tested as an anti-cancer treatment. "The variety of diseases caused by overproduction of fibroblasts has made finding a common root cause very challenging, in part because there has been no good animal model of these conditions. Now we've shown that activating a single signaling pathway in mice causes fibrosis in nearly all tissues. Blocking the CD-47 signal, which protects cancer cells from the immune system, can also ameliorate these fibrotic diseases even in the most extreme cases."

Fibrosis occurs when the body's normal response to injury goes astray. An overenthusiastic or inappropriately timed proliferation of cells called fibroblasts, which make up the connective tissue surrounding and supporting all of our organs, can lead to many devastating diseases. In a mouse model she developed, researchers found that fibroblasts were producing unusually high levels of an important signaling molecule called c-Jun. C-Jun is a transcription factor that drives the production of many proteins involved in critical cellular processes. It's been implicated in many types of human cancer. In the current study, researchers investigated c-Jun expression levels in 454 biopsied tissue samples from patients with a variety of fibrotic diseases. They found that in every case the fibroblasts from the patients with fibrosis expressed higher levels of c-Jun than did control fibroblasts collected from people with nonfibrotic conditions.

Blocking the expression of c-Jun in laboratory-grown lung fibroblasts collected from people with idiopathic pulmonary fibrosis substantially decreased the proliferation of these cells, but not of lung fibroblasts collected from people without fibrosis. Furthermore, mice genetically engineered to overexpress c-Jun in all their body's tissues developed fibrosis in nearly every organ, including lung, liver, skin and bone marrow. "We found that c-Jun overexpression and over-activation is a unifying mechanism in many types of fibrosis. But an even more exciting part of the story is the fact that we observed that the diseased, c-Jun-expressing fibroblasts are surrounded by immune cells called macrophages. This is reminiscent of what's often seen in human cancers." Over the past eight years, researchers have shown that many human cancers evade the immune system by expressing high levels of a protein called CD47 on their surfaces. Blocking this protein with an anti-CD47 antibody restores the ability of the macrophages to gobble the cancer and has proven to be a promising treatment in animal models of the disease. Anti-CD47 antibody is currently undergoing a phase-1 clinical trial in humans with advanced solid tumors.

When researchers treated mice with c-Jun-induced lung fibrosis with daily injections of anti-CD47 antibody, the animals exhibited significantly better lung function, lived longer than their peers and cleared the fibrosis. The researchers plan to investigate whether any patients in the phase-1 trial of the anti-CD47 antibody also suffered from any fibrotic conditions. If so, they are eager to learn whether they experienced any relief as a result of participating in the trial. "We have hit upon something unique in this study. We identified a highly activated pathway that causes fibrosis in many tissues in mice, and we've showed that treating the animals with an anti-CD47 antibody reverses the fibrosis. We're hopeful that this could be a potential treatment for people with many types of fibrotic conditions."

Link: http://med.stanford.edu/news/all-news/2017/04/fibrosis-reversed-when-dont-eat-me-signal-blocked.html

Armed with better tools, such as lightweight accelerometers, and given much more data to work with, epidemiologists are nowadays trying to quantify the degree to which specific forms of exercise are better or worse then others. Other teams are trying to put rigorous numbers to the dose-response curve for exercise: where is the optimal point when it comes to health and longevity? It is a given that regular moderate aerobic exercise is good for you, and the evidence for that is overwhelming. Sedentary people suffer shorter lives and a greater burden of age-related disease. But once we start to ask how much exercise is most advantageous, or whether one form of exercise is better than another, then the answers become much less certain. They depend far more upon interpretations of data and the limitations of specific data sets, the details of which can be quite complex - and will thus never appear in the popular press when specific research projects are discussed.

The only useful way to look at this sort of research is in aggregate, summed over many studies. At this point there are simply too few papers comparing different forms of exercise to say more than that it is an interesting topic: I would say that many more years of work are needed to assemble a good consensus for human data, and even then that consensus will be fuzzy around the edges, numbers subject to opinion on various scientific factions and their methodologies. Thus attempting to optimize lifestyle for health and longevity strikes me as a pleasant hobby to maintain, but no matter how much effort you put into it, you'll likely never find out whether you are in fact doing any better than the 80/20 level achieved with far less work.

Given that the future of our health will be increasingly determined by progress in medicine as we age, I would argue that we should direct our extra time and effort towards supporting research into therapies to treat the causes of aging, as opposed to chasing the mirage of a perfectly optimal lifestyle. Good enough is comparatively easy to achieve when it comes to personal health, while significantly more than that is a next to impossible goal. Meanwhile, absent new technologies based on the SENS rejuvenation research programs, even the healthiest of us in mid-life today have but a small chance of making it to 100, and we'll be very frail indeed should we manage to hold out to that point. Technology should be the focus.

An Hour of Running May Add 7 Hours to Your Life

Resarchers found that, compared to nonrunners, runners tended to live about three additional years, even if they run slowly or sporadically and smoke, drink or are overweight. No other form of exercise that researchers looked at showed comparable impacts on life span. The findings come as a follow-up to a study done three years ago, in which a group of distinguished exercise scientists scrutinized data from a large trove of medical and fitness tests. That analysis found that as little as five minutes of daily running was associated with prolonged life spans.

Over all, this new review reinforced the findings of the earlier research, the scientists determined. Cumulatively, the data indicated that running, whatever someone's pace or mileage, dropped a person's risk of premature death by almost 40 percent, a benefit that held true even when the researchers controlled for smoking, drinking and a history of health problems such as hypertension or obesity. Perhaps most interesting, the researchers calculated that, hour for hour, running statistically returns more time to people's lives than it consumes. Figuring two hours per week of training, since that was the average reported by runners in the earlier study, the researchers estimated that a typical runner would spend less than six months actually running over the course of almost 40 years, but could expect an increase in life expectancy of 3.2 years, for a net gain of about 2.8 years. In concrete terms, an hour of running statistically lengthens life expectancy by seven hours, the researchers report.

The gains in life expectancy are capped at around three extra years, however much people run. The good news is that prolonged running does not seem to become counterproductive for longevity, according to the data. Improvements in life expectancy generally plateaued at about four hours of running per week, but they did not decline. Meanwhile, other kinds of exercise also reliably benefited life expectancy, the researchers found, but not to the same degree as running. Walking, cycling and other activities, even if they required the same exertion as running, typically dropped the risk of premature death by about 12 percent. Why running should be so uniquely potent against early mortality remains uncertain, but it raises aerobic fitness, and high aerobic fitness is one of the best-known indicators of an individual's long-term health.

Running as a Key Lifestyle Medicine for Longevity

Running is a popular and convenient leisure-time physical activity (PA) with a significant impact on longevity. In general, runners have a 25-40% reduced risk of premature mortality and live approximately 3 years longer than non-runners. Recently, specific questions have emerged regarding the extent of the health benefits of running versus other types of PA, and perhaps more critically, whether there are diminishing returns on health and mortality outcomes with higher amounts of running. This review details the findings surrounding the impact of running on various health outcomes and premature mortality, highlights plausible underlying mechanisms linking running with chronic disease prevention and longevity, identifies the estimated additional life expectancy among runners and other active individuals, and discusses whether there is adequate evidence to suggest that longevity benefits are attenuated with higher doses of running.

By way of following up on a brace of papers on biomarkers of aging that arrived over the past few weeks, here is an open access review on the topic. It is an important topic, it has to be said. The development of therapies to treat the causes of aging - and thereby significantly extend healthy life spans - is made expensive and slow by the lack of efficient ways to assess outcomes. It is easy enough to see whether a given therapy achieves what it intended to achieve in the short term, that genes are suppressed or unwanted cells are removed, for example, but at present the only way to then link that to increased long-term health and life span is to wait and see. Waiting to see carries a million dollar price tag and several years of effort for studies in mice, and the equivalent situation in humans is obviously impractical. The research community needs a generally agreed upon, robust, low-cost assessment of biological age, an assay that can run immediately before and immediately after a potential rejuvenation therapy to assess its effect on the state of aging in the patient, and does so in a way that is independent of the mechanism of the therapy itself.

Chronological age is a major risk factor for functional impairments, chronic diseases and mortality. However, there is still great heterogeneity in the health outcomes of older individuals. Some individuals appear frail and require assistance in daily routines already in their 70s whereas others remain independent of assistance and seem to escape major physiological deterioration until very extreme ages. In keeping with the unprecedented growth rate of the world's aging population, there is a clear need for a better understanding of the biological aging process and the determinants of healthy aging. Towards this aim, a quest for (biological) markers that track the state of biophysiological aging and ideally lend insights to the underlying mechanisms has been embarked upon.

During the past decades, extensive effort has been made to identify such aging biomarkers that, according to the stage-setting definition, are "biological parameters of an organism that either alone or in some multivariate composite will, in the absence of disease, better predict functional capability at some late age, than will chronological age". Later on, the American Federation for Aging Research (AFAR) formulated the criteria for aging biomarkers as follows: (1) It must predict the rate of aging. In other words, it would tell exactly where a person is in their total life span. It must be a better predictor of life span than chronological age. (2) It must monitor a basic process that underlies the aging process, not the effects of disease. (3) It must be able to be tested repeatedly without harming the person. For example, a blood test or an imaging technique. (4) It must be something that works in humans and in laboratory animals, such as mice. This is so that it can be tested in lab animals before being validated in humans.

However, to date, no such marker or marker combination has emerged. Moreover, the existence of such markers has been questioned, because the effects of many chronic diseases are inseparable from normal aging. The rate of biological aging can also vary across different tissues, and hence it may not be feasible to assume a measurable overall rate. Recently, however, several new biomarkers for biological aging have come into play. They can be separated into molecular (based on DNA, RNA, etc.) or phenotypic biomarkers of aging (clinical measures such as blood pressure, grip strength, lipids, etc.), although we include both types. The focus of this review is on novel biological age predictors, and we define them as markers that predict chronological age, or at least can separate "young" from "old". They should also be associated with a normal aging phenotype or a non-communicable age-related disease independent of chronological age in humans. Promising developments consider multiple combinations of these various types of predictors, which may shed light on the aging process and provide further understanding of what contributes to healthy aging. Thus far, the most promising new biological age predictor is the epigenetic clock; however its true value as a biomarker of aging requires longitudinal confirmation.

Link: http://dx.doi.org/10.1016/j.ebiom.2017.03.046

An ortholog is a gene in one species that serves the same purpose as its equivalent in another species, a pairing that usually implies common ancestry. In the case of humans and nematode worms such as Caenorhabditis elegans, that is a very distant common ancestry, but nonetheless even between such widely diverse species many cellular mechanisms are surprisingly similar. The basic pattern for cellular life is very ancient, and came into being in the earliest stages of evolution, long before the existence of complex organisms. Here, researchers make a list of nematode orthologs of a number of human genes that are known to vary in gene expression levels as aging progresses, and find that more than half of them affect nematode life span if their activity is suppressed. All in all it is an interesting approach to narrowing the scope of further research into the way in which specific human genes impact the pace of aging.

This is characteristic of the approach to aging taken by much of the research community, in aiming first to completely understand how exactly aging progresses, at the detail level, with all of the influences mapped. Where intervention is the goal, that intervention takes the form of adjusting the operation of cells in order to modestly slow the progression of aging. It is far from the most effective path forward, being slow, costly, and producing only limited benefits, but it is the one that dovetails best with the culture of science and funding of science, which seeks greater understanding of biological processes. This is unfortunate, as far better approaches exist if the goal is longer, healthier lives as soon as possible. Aging is an accumulation of damage, and aiming to repair that damage is far better and more cost-effective than aiming to understand exactly how the damage then causes further problems.

Understanding which molecular processes contribute to aging is critical to developing interventions capable of extending healthy human lifespan and delaying onset of age-associated diseases. A key step in this process is building a comprehensive model encompassing the range of genetic and environmental factors that influence lifespan and describing the complex interaction between these factors in an aging organism. Directly screening interventions for lifespan phenotypes in mammals is limited by long lifespans. Despite evolutionary distance and orders-of-magnitude differences in lifespan, processes that contribute to aging are sufficiently conserved that mechanistic knowledge gleaned from short-lived invertebrates can be beneficially applied to mammalian systems. Genetic screens in the nematode, Caenorhabditis elegans, have identified hundreds of genes capable of influencing lifespan.

An approach that is tractable in humans is to characterize systemic changes that occur during normal aging. This approach identifies traits that change with age or during age-associated disease and employs targeted studies to determine which play a causative role in aging. Early applications focused on easily measurable physiological traits, such as body weight or circulating molecules, but has now expanded into the '-omics' realm to provide systems-level insight into molecular changes that occur with age. As part of the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium, we published a large meta-analysis of gene expression in human peripheral blood from 14,983 individuals representing ages across the adult lifespan. This study identified 1,497 genes with significantly different expression at different ages. Gene sets with a defined age-associated expression pattern provide information about molecular processes with altered activity during aging and provide a valuable diagnostic tool for determining individual biological rate of aging and predicting risk of age-associated disease, as demonstrated in follow-up analyses. On a gene-by-gene basis, differential expression alone is insufficient to distinguish between genes that play a causative role in aging and genes that merely respond to the altered physiological environment in an aging organism.

In this study, we selected the human genes with the most significant differential expression with age from the CHARGE meta-analysis and used RNAi to screen C. elegans orthologs for lifespan phenotypes. This selection criterion ensured that every gene identified in the lifespan screen was already of interest in the context of human aging. The short lifespan of C. elegans allowed genes capable of directly influencing lifespan to be rapidly identified and characterized. The resulting C. elegans candidate list was substantially enriched in genes for which knockdown extends lifespan. The five genes with the greatest impact on lifespan (more than 20% extension) encode the enzyme kynureninase (kynu-1), a neuronal leucine-rich repeat protein (iglr-1), a tetraspanin (tsp-3), a regulator of calcineurin (rcan-1), and a voltage-gated calcium channel subunit (unc-36). Knockdown of each gene extended healthspan without impairing reproduction. Each gene displayed a distinct pattern of interaction with known aging pathways. In the context of published work, kynu-1, tsp-3, and rcan-1 are of particular interest for immediate follow-up. kynu-1 is an understudied member of the kynurenine metabolic pathway with a mechanistically distinct impact on lifespan. Our data suggest that tsp-3 is a novel modulator of hypoxic signaling and rcan-1 is a context-specific calcineurin regulator.

Link: http://onlinelibrary.wiley.com/doi/10.1111/acel.12595/full

Today I noticed a recent paper in which the researchers tested a senolytic drug in the course of working on mechanisms relevant to the development of osteoporosis. Once they realized that cellular senescence might be involved in the development of osteoporosis, they put the drug to work in order to clear out senescent cells and see if that improved the picture. This is something we'll be seeing a lot more of in future research papers, whether in cell cultures or in animal models, and it certainly makes a great deal of difference to the quality of the evidence produced by a study. When researchers can address a specific cause of aging in a narrowly targeted way, rather than simply observing it, then it becomes a great deal easier to (a) show that the mechanism is in fact causing age-related disease, and (b) map the size of its effect.

The weakening of bone known as osteoporosis affects every older individual. It is, at root, an imbalance between the constantly ongoing activities of bone creation and absorption: too few osteoblasts creating bone and too many osteoclasts removing it. Any therapy that can reliably and safely tilt back the balance of activity towards creation should be helpful, but none of the approaches to date address the root causes. Instead, as is usually the case in modern medicine, researchers focus on proximate causes, trying to force cellular behavior back towards a more youthful pattern of activity without addressing the reasons why that pattern has changed. This is usually going to be hard to do well - as is any attempt to keep a damaged engine running without fixing the damage - which is why most present treatments for most age-related diseases are marginal at best.

Senescent cells accumulate with age, a lingering tiny minority of all such cells, the few that manage to evade destruction via programmed cell death or the immune system. They might be few in number, but those numbers grow over time and they cause great harm. These cells behave badly, generating signals that spur chronic inflammation, destructively remodel the extracellular matrix, and change the behavior of nearby cells for the worse as well. This adds up to produce failing organ function and disruption of vital processes such as tissue regeneration. Researchers have shown that removing senescent cells can fairly rapidly remove their malign influence as well, to some degree restoring tissue function and to some degree turning back the clock on measures of aging. Linking osteoporosis to increased numbers of senescent cells offers the hope of a better class of therapy for this condition, one that will arrive in clinics within the next few years. Numerous research groups and companies are presently involved in producing the means to selectively destroy these unwanted, harmful cells.

DNA damage and senescence in osteoprogenitors expressing Osx1 may cause their decrease with age

Old age is, by far, the most important risk factor for the development of osteoporosis. In bone biopsies from elderly men and women, the age-related loss of both cancellous and cortical bone is associated with decreased mean wall thickness - the histomorphometric hallmark of decreased bone formation. Loss of bone mass in aged rodents is associated with a decline in the number of osteoblasts, the cells responsible for the synthesis and mineralization of the bone matrix. Because osteoblasts are postmitotic cells with a short lifespan, they need to be constantly replaced with new ones. Osteoblasts arise from progenitors of mesenchymal origin, which express the transcription factors Runx2 and Osterix1 (Osx1).

The decline in the regenerative capacity of most tissues with old age has led to the idea that aging is due, at least in part, to increased cell senescence causing the loss of functional adult stem/progenitor cells. Cellular senescence is a process in which cells stop dividing and initiate a gene expression pattern known as the senescence-associated secretory phenotype (SASP). Several stimuli associated with aging promote senescence. Because the number of senescent cells increases in multiple tissues with aging, it has been widely assumed that senescence contributes to aging. Importantly, ablation of senescent cells using genetically modified mice prolongs lifespan and delays age-related pathologies in naturally aged mice or progeria models. We have recently shown that senescent cells induced by normal aging or ionizing radiation (IR) can be eliminated by administration of ABT263, a drug that kills senescent cells selectively; and clearance of senescent cells rejuvenates aged tissue stem and progenitor cells.

In both humans and rodents, the reduced osteoblast number in the aging skeleton has been attributed to changes in bone marrow-derived mesenchymal progenitors, including a decrease in the number of mesenchymal stem cells, defective proliferation/differentiation of progenitor cells, increased apoptosis, or increased senescence. However, it remains unclear whether the number of senescent osteoblast progenitors increases with old age. Moreover, the contribution of the decline in osteoblast progenitor number to the decrease in bone formation with age remains unknown because of the lack of methods to specifically identify and isolate mesenchymal progenitors. Therefore, the molecular mechanisms responsible for the decline in osteoblast number have remained elusive. To overcome these limitations, we generated a mouse model in which osteoblast progenitors are labeled with a red fluorescent protein (TdRFP) to facilitate their isolation by fluorescence-activated cell sorting (FACS) and examination of the effects of aging in freshly isolated cells. We present evidence that the decline in bone formation with age can be accounted for by a decrease in the number of osteoprogenitors due to DNA damage-induced cell senescence.

We report that the number of TdRFP-Osx1 cells, freshly isolated from the bone marrow, declines by more than 50% between 6 and 24 months of age in both female and male mice. Moreover, TdRFP-Osx1 cells from old mice exhibited markers of DNA damage and senescence. Bone marrow stromal cells from old mice also exhibited elevated expression of SASP genes, including several pro-osteoclastogenic cytokines, and increased capacity to support osteoclast formation. These changes were greatly attenuated by the senolytic drug ABT263. Together, these findings suggest that the decline in bone mass with age is the result of intrinsic defects in osteoprogenitor cells, leading to decreased osteoblast numbers and increased support of osteoclast formation.

Many of the better known age-related neurodegenerative conditions involve aggregates of damaged or misfolded proteins, but there are other similarities as well. This is too be expected, given that aging is at root caused by a small variety of forms of molecular damage. This damage spirals out into a much larger set of secondary and later consequences, ultimately leading to the wide variety of age-related diseases. Simple processes acting in a complex system, such as human biochemistry, tend to produce complex outcomes. Thus if starting at the point of any two age-related diseases, dig far enough back into their roots and you will arrive at shared origins. Somewhat in that vein, this open access review paper looks over some of the commonalities in Alzheimer's disease and Parkinson's disease:

Alzheimer's disease and Parkinson's disease are two common neurodegenerative diseases of the elderly people that have devastating effects in terms of morbidity and mortality. The predominant form of the disease in either case is sporadic with uncertain etiology. The clinical features of Parkinson's disease are primarily motor deficits, while the patients of Alzheimer's disease present with dementia and cognitive impairment. Though neuronal death is a common element in both the disorders, the postmortem histopathology of the brain is very characteristic in each case and different from each other. In terms of molecular pathogenesis, however, both the diseases have a significant commonality, and proteinopathy (abnormal accumulation of misfolded proteins), mitochondrial dysfunction and oxidative stress are the cardinal features in either case.

These three damage mechanisms work in concert, reinforcing each other to drive the pathology in the aging brain for both the diseases; very interestingly, the nature of interactions among these three damage mechanisms is very similar in both the diseases. In the case of Alzheimer's disease, the peptide amyloid beta (Aβ) is responsible for the proteinopathy, while α-synuclein plays a similar role in Parkinson's disease. The expression levels of these two proteins and their aggregation processes are modulated by reactive oxygen radicals and transition metal ions in a similar manner. In turn, these proteins - as oligomers or in aggregated forms - cause mitochondrial impairment by apparently following similar mechanisms. Understanding the common nature of these interactions may, therefore, help us to identify putative neuroprotective strategies that would be beneficial in both the clinical conditions.

Link: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5358994/

Researchers here find a way to stabilize the fatty plaques that form in blood vessels as a part of atherosclerosis. On its own this is a pretty poor treatment option, better than nothing, but worse than any approach that removes plaques or prevents them from forming. It will probably be a useful adjunct to any form of removal or reduction of plaque, however, helping to avoid rupture of larger sections of plaque during that process. It is the disintegration of fragile plaques that makes atherosclerosis lethal, as the fragments can then block critical blood vessels to cause a stroke or heart attack.

The molecule microRNA-210 stabilises deposits in the carotid artery and can prevent them from tearing. Thus, it may prevent dangerous blood clots from forming. The most common cause for the narrowing of the carotid artery is atherosclerosis, where so-called plaques build up on the vessel walls. If a plaque ruptures, blood clots can form that either further occlude the site that is already narrowed, or are carried away by the blood flow, which could lead to vascular occlusion at a different site. If this happens in the carotid artery, it could lead to a stroke. How easily a plaque ruptures depends on how thick the tissue layer surrounding its core is. The thicker this fibrous cap, the more stable and therefore more harmless the vessel deposit.

"New imaging procedures enable us to detect dangerous plaques with increasing precision; but the therapies currently available for removing these unstable plaques and thus preventing a stroke entail a certain amount of risk that the plaques will rupture during the procedure. This is why these therapies are not used on individuals with a narrowed carotid artery who have so far not experienced any symptoms. Traditionally, physicians try to reduce the size of the deposits in the vessels in order to widen the narrowed sites. For narrowed carotid arteries, though, the notion of stabilising the plaques is becoming ever more prevalent. Unlike in the coronary vessels, in the carotid artery plaques rupturing is more dangerous than the narrowing."

Researchers compared material from patients with stable and unstable deposits in the carotid artery. They particularly focused on microRNAs. These molecules are involved in the gene regulation in about 60 percent of mammals' genes. They can prevent gene information that has already been read from being translated into proteins, and have become a focus of biomedical research as active ingredients and starting points for new therapies in recent years. The scientists discovered that microRNA-210 was reduced the most in the blood samples of patients with unstable plaques. These were blood samples that were obtained locally near the vessel deposits. Further examinations showed that microRNA-210 is primarily present in the fibrous caps of plaques and that it inhibits the expression of the APC gene. As a consequence, fewer smooth muscle cells die in the fibrous cap and it becomes more stable. Moreover, the animal model could show that fewer plaques rupture when microRNA-210 is administered.

The scientists are currently researching how microRNA-210 can be applied locally. The risk of adverse events in other organs is much too high if microRNA modulators are administered systemically. The main concern with microRNA-210 is that tumour cells that are possibly already in existence will multiply, because the expression of APC is inhibited. This is because APC is a tumour suppressor gene which inhibits the growth of tumours in the healthy body. In order to avoid such off-target effects, the researchers are currently testing coated stents or balloons that are inserted directly into the carotid artery.

Link: https://www.tum.de/en/about-tum/news/press-releases/detail/article/33846/

As ever more researchers turn their attention to cellular senescence as a cause of aging and age-related disease, more potential approaches to selectively targeting these unwanted cells are emerging. In the paper I'll point out here, the cell surface receptor CD9 is used to target nanoparticles carrying a therapeutic payload into senescent cells. The researchers chose to use rapamycin as the drug payload, as for one it doesn't matter too greatly if it gets into other cells, and secondly there is a fairly active line of research involving mTOR and its influence over the behavior of senescent cells. Rapamycin, as you'll recall, inhibits mTOR, but has some unpleasant side-effects that make it a poor option for a therapeutic. Targeting via nanoparticles in this way greatly lowers the provided dose; it is a way to deliver potentially harmful drugs in order to obtain a narrow set of benefits while minimizing the unwanted side-effects.

For my money, the best use of targeting mechanisms in the case of senescent cells is to deliver cell-killing mechanisms rather than the sort of cell-adjusting mechanisms used here, but when killing cells the targeting method has to have a very high degree of discrimination. To my knowledge, no-one has made it all that far down that road yet. The present approaches to destroying senescent cells, those under active development and heading towards the clinic, don't even try to deliver their therapeutic agents selectively to senescent cells. They are applied to all cells and target senescence in the sense of preferentially activating inside senescent cells. Some are more effective in that discrimination than others, but the basic concept certainly works. So it is interesting to see a group working on the more traditional method of steering delivery via cell surface markers, in order to place the therapeutic into the target cell population only, or at least to the greatest degree possible. A few years back, I had predicted that this would be the sort of technology first used to destroy senescent cells, and was completely incorrect on that front.

Progressive slowdown/prevention of cellular senescence by CD9-targeted delivery of rapamycin using lactose-wrapped calcium carbonate nanoparticles

Cellular senescence refers to a state of irreversible growth arrest and altered function of normal somatic cells after a finite number of divisions. Senescent cells are characterized by a flattened shape, senescence-associated β-galactosidase (SA-β-gal) activity, and hypersecretion of cytokines, chemokines, and proteases, the senescence-associated secretory phenotype (SASP). Senescence partly depends on mechanistic target of rapamycin (mTOR) signaling that mainly regulates tumor suppressor pathways p53/p21 and Rb/p16, and leads to disease development/progression through tissue function impairment. In addition, progressive inability of the immune system to destroy senescent cells during aging results in the accumulation of "death-resistant" cells that accelerate aging and disease development by altering neighboring cell behavior, lowering the pool of mitotic-competent cells, degrading the cellular matrix, and stimulating cancer. Diverse age-related diseases result from cellular senescence progression. Therefore, strategies for the prevention, treatment, or removal of senescent cells are of prime interest for clinical applications.

A recently reported proof-of-concept demonstrated the use of capped mesoporous silica nanoparticles for targeted cargo delivery inside senescent cells mediated by β-galactosidase activity. However, it fails to justify cell-specific uptake of these nanosystems to senescent cells following intravenous or subcutaneous delivery. A mechanism driven approach for specific interaction and uptake of nanoparticles by senescent cells has thus become a challenging necessity. Hence, we proposed a proof-of-concept regarding delivery of rapamycin (Rapa) loaded calcium carbonate (CaCO3) nanoparticles with CD9 receptor mediated targeting, in addition to utilization of β-galactosidase activity, in senescent cells.

Rapamycin (Rapa), an mTOR inhibitor, was found to prevent replicative senescence in rat embryonic fibroblasts by affecting the p53/p21 pathway. In addition, several studies have indicated the beneficial effects of Rapa for life span extension in aging models. More importantly, CD9 - a glycoprotein receptor of the tetraspanin family that regulates cellular activity, development, growth, and motility - is overexpressed in senescent cells and thus, can potentially be used in targeted drug delivery. Although contradictory reports on CD9 receptors in different cancer cells suggest either enhancement or inhibition of growth and motility functions, implying cell type-specific activity, senescent cells are closely related to cancer development. Our study is the first report for the utilization of CD9 receptors in targeting drug-loaded nanoparticles to senescent cells and can be a stepping stone for further research in the field of targeted therapy to senescent cells.

In our study, CD9 monoclonal antibody-conjugated lactose-wrapped calcium carbonate nanoparticles loaded with rapamycin (CD9-Lac/CaCO3/Rapa) were prepared for targeted rapamycin delivery to senescent cells. The nanoparticles exhibited an appropriate particle size (~130 nm) with high drug-loading capacity (~20%). In vitro drug release was enhanced in the presence of β-galactosidase suggesting potential cargo drug delivery to the senescent cells. Furthermore, CD9-Lac/CaCO3/Rapa exhibited high uptake and anti-senescence effects (reduced β-galactosidase and p53/p21/CD9/cyclin D1 expression, reduced population doubling time, enhanced cell proliferation and migration, and prevention of cell cycle arrest) in old human dermal fibroblasts. Importantly, CD9-Lac/CaCO3/Rapa significantly improved the proliferation capability of old cells along with significant reductions in senescence-associated secretory phenotypes (IL-6 and IL-1β). Altogether, our findings suggest the potential applicability of CD9-Lac/CaCO3/Rapa in targeted treatment of senescence.

It is well understood in the research community that enhancement of the cellular maintenance process of autophagy, and in particular the recycling of damaged mitochondria known as mitophagy, is a desirable goal. Many of the methods of modestly slowing aging in laboratory species feature enhanced autophagy, and decline of mitochondrial function is a prominent aspect of the aging process. That part of the aging research community interested in slowing human aging, as opposed to aiming for rejuvenation, includes a number of groups that work on autophagy. Still, little progress has been made towards clinical therapies based on safely increased levels of autophagy. There are many examples of research papers like this one from the past decade, as the life span of short-lived species is very plastic in response to circumstances and metabolic adjustments, but nothing of practical use for humans has yet emerged.

Aging is a major international concern that brings formidable socioeconomic and healthcare challenges. Small molecules capable of improving the health of older individuals are being explored. Small molecules that enhance cellular stress resistance are a promising avenue to alleviate declines seen in human aging. Tomatidine, a natural compound abundant in unripe tomatoes, inhibits age-related skeletal muscle atrophy in mice. Here we show that tomatidine extends lifespan and healthspan in C. elegans, an animal model of aging which shares many major longevity pathways with mammals. Tomatidine improves many C. elegans behaviors related to healthspan and muscle health, including increased pharyngeal pumping, swimming movement, and reduced percentage of severely damaged muscle cells.

Microarray, imaging, and behavioral analyses reveal that tomatidine maintains mitochondrial homeostasis by modulating mitochondrial biogenesis and PINK-1/DCT-1-dependent mitophagy. Mechanistically, tomatidine induces mitochondrial hormesis by mildly inducing ROS production, which in turn activates the SKN-1/Nrf2 pathway and possibly other cellular antioxidant response pathways, followed by increased mitophagy. This mechanism occurs in C. elegans, primary rat neurons, and human cells. Our data suggest that tomatidine may delay some physiological aspects of aging, and points to new approaches for pharmacological interventions for diseases of aging.

Link: https://doi.org/10.1038/srep46208

João Pedro de Magalhães is one of a number of people from the small online transhumanist community of twenty years past who went on to focus on aging research. The present all too short human life span is the most pressing and harmful of limits upon the human condition, and the more people who seek to do something about that, the better. Like many of the more established researchers in the field, de Magalhães has come to think that radical life extension of decades or more in our lifetimes is unlikely, however. To my eyes that is only true if the SENS approach based on repair of root cause molecular damage fails to gather significantly greater support over the next two decades. There is a lot of room yet to achieve great things, especially now that the first SENS approaches are close to the clinic, such as senescent cell clearance.

What are you currently working on?

Although my work integrates different strategies, its focal point is developing and applying experimental and computational methods to help decipher the genome and how it regulates complex processes like ageing. In practice, that means developing and employing modern methods for genome sequencing and also bioinformatics to analyze large amounts of data, for example networks with hundreds of genes. We now know that aging and longevity, like many other biological processes, derive from many genes interacting with each other and with the environment. My lab develops methods to survey and analyze data from thousands of genes simultaneously to identify the most important ones. More specifically, we are now studying new genes associated with aging and longevity as well as new cancer and Alzheimer's disease genes. If we can identify which are the key genes modulating aging or age-related diseases than this will open new opportunities for developing therapeutics. We are also studying new life extending compounds using animal models.

What do you think is the most important contribution you've made to the field?

I am probably best known for the online collection of databases I created, the Human Ageing Genomic Resources (HAGR). I designed HAGR to help researchers study the genetics of human ageing using modern approaches such as functional genomics, network analyses, systems biology and evolutionary analyses. They have been cited hundreds of times and are used widely by the biogerontology research community, facilitating a lot of studies. I am also known for the work I did on sequencing genomes of long-lived species, in particular the naked mole rat and bowhead whale. Lastly, my lab developed various computational approaches to analyze large amounts of data as well as predict new genes, processes and drugs associated with aging and longevity.

What is the approach to fighting ageing you find most promising, besides the one you're pursuing?

There is certainly a lot of promise in stem cells and regenerative medicine. So I am optimistic that there will be new advances and therapies, although things normally take a long time in clinical translation. I'm not sure that telomeres and telomerase will play much of a role. I think telomerase may be used in regenerative medicine and to treat specific diseases, but it is unlikely to become a source of anti-ageing therapies because it also promotes tumorigenesis. Besides, mice have lots of telomerase and yet they age much faster than us. It's some years old but I wrote a review on this topic where I expressed my skepticism of telomerase as a therapy for aging.

Do you expect to see the day ageing is finally defeated? What you will do after that?

I don't think we will defeat aging within my lifetime. I mean, we can't even defeat aging in simple animal models, or defeat a number of simpler human diseases (I have a nasty cold as I write this, like I have every year). So I don't think we will cure aging in the foreseeable future. Like many others in the life extension community, I think cryopreservation may be a plan B, even though it's not a very attractive one (but it's still better than dying!). That's why in the past few years I have become more involved in cryobiology and cryonics. While I am not convinced that the current techniques used in cryonics allow preservation of the self, I think the field can progress rapidly to the point of us as developing reversible human cryopreservation well before aging is defeated.

Link: http://www.leafscience.org/dr-joao-pedro-de-magalhaes-a-life-dedicated-to-conquering-ageing/

The research I'll point out here is an interesting data point to add to what is known of the impact of a life-long exposure to pathogens on aging and longevity. Researchers raised mice in a germ-free environment, and found that they did not suffer anywhere near the same age-related increase in inflammation, and the average life span increased. You might compare it with another recent study in which germ-free mice developed less metabolic waste in brain tissues over a lifetime. The research here focused on the interaction between gut microbiota and the immune system over the course of aging, a topic that has been explored to an increasing degree in recent years. The influence of the microbial populations of the gut on long-term health appears to be of around the same order of magnitude as that of other prominent environmental factors, such as level of exercise, though no-one has yet demonstrated as large an effect as that of calorie restriction via manipulation of gut microbes.

The high level summary is simple to outline, but the picture is a complicated one under the hood. Even given just the three broad categories of (a) immune cells, (b) gut microbes, and (c) pathogens - a dramatic oversimplification of the real picture - we can still argue about the direction of causation. Does exposure to pathogens cause malfunctions in the immune system, that in turn leads to changes in the gut microbe populations, that in turn feed back to cause further immune issues and other problems in intestinal function? Or are direct effects of pathogens on gut microbes more important? Or are other bodily systems involved in a significant way? There is much work yet to be accomplished in this part of the field. Further, the usual caveats apply here despite promising supporting evidence from other parts of the field: mice are not people, and the interactions with pathogens that are important over a mouse life span are unlikely to be the same as those that are most important over a human life span.

That said, there is a good deal of evidence for the aging of the immune system over a normal human life span to be accelerated by exposure to persistent pathogens like cytomegalovirus. An ever increasing fraction of immune cells are dedicated, uselessly, to this class of invader, while other activities are neglected. The immune system malfunctions in ways that promote ever greater inflammation, but with ever less of the usual benefits in terms of increased beneficial immune activity. Transient inflammation in younger people is useful, a necessary part of the way in which the immune system functions. Chronic inflammation in the old, on the other hand, is essentially a form of damage that contributes to the progression of many age-related diseases. Further, we can look at recent human history to see the effects of reduced exposure to infectious pathogens on long-term health and average lifespans. Older people in a given age group today are considerably less physically aged than was the case for that age group a century ago. Further again, there is a fair amount of research in shorter-lived species to suggest that declining intestinal function is an important component of degenerative aging. In flies, for example, it might be the most important component, though in mammals that is probably not the case. That decline is linked, separately, to immune function and the microbes of the gut.

More than a 'gut feeling' on cause of age-associated inflammation

Gut microbes cause age-associated inflammation and premature death in mice. The research shows that imbalances in the composition of gut microbes in older mice cause the intestines to become leaky, releasing bacterial products that trigger inflammation, impair immune function and reduce lifespan. Humans with high levels of inflammatory molecules are more likely to be frail, hospitalized, and less independent. They are also more susceptible to infections, chronic conditions such as dementia and cardiovascular disease and death. Up until now, the cause of the relationship between the composition of gut microbes and inflammation and poor health in the elderly has not been determined.

"To date, the only things you can do to reduce your age-associated inflammation are to eat a healthy diet, exercise and manage any chronic inflammatory conditions to the best of your ability. We hope that in the future we will be able use drugs or pre- or probiotics to increase the barrier function of the gut to keep the microbes in their place and reduce age-associated inflammation and all the bad things that come with it."

In contrast to conventionally raised mice, germ-free mice did not show age-related increases in inflammation and a higher proportion of them lived to a ripe old age. Age is associated with an increase in levels of pro-inflammatory cytokines, such as tumor necrosis factor (TNF), in the bloodstream and tissues. It was found that germ-free mice did not have increased TNF with age. In addition, TNF-deficient mice that did not develop age-associated inflammation or conventional mice that were treated with an anti-TNF drug approved for humans had reduced age-related changes in the microbiome. "We assume that if we reduce inflammation, we improve immune function. If we improve immune function, we maintain the ability to farm a healthy gut microbiota, but we don't know for sure yet. We also believe that targeting age-associated inflammation will improve immune health and we are investigating repurposing drugs that are already on the market and developing novel strategies or therapeutics to this effect."

Age-Associated Microbial Dysbiosis Promotes Intestinal Permeability, Systemic Inflammation, and Macrophage Dysfunction

Levels of inflammatory mediators in circulation are known to increase with age, but the underlying cause of this age-associated inflammation is debated. We find that, when maintained under germ-free conditions, mice do not display an age-related increase in circulating pro-inflammatory cytokine levels. A higher proportion of germ-free mice live to 600 days than their conventional counterparts, and macrophages derived from aged germ-free mice maintain anti-microbial activity.

Co-housing germ-free mice with old, but not young, conventionally raised mice increases pro-inflammatory cytokines in the blood. In tumor necrosis factor (TNF)-deficient mice, which are protected from age-associated inflammation, age-related microbiota changes are not observed. Furthermore, age-associated microbiota changes can be reversed by reducing TNF using anti-TNF therapy. These data suggest that aging-associated microbiota promote inflammation and that reversing these age-related microbiota changes represents a potential strategy for reducing age-associated inflammation and the accompanying morbidity.

Although manipulation of the microbiota may improve health in the elderly, until now it has not been clear whether microbial dysbiosis is a driver of immune dysfunction. For example, it has been demonstrated that gut microbial composition correlates with levels of circulating cytokines and markers of health in the elderly and that intestinal permeability and systemic inflammation increase in old mice, but not whether the microbiota drive these changes. Our data demonstrate that microbial dysbiosis occurs with age, even in minimal microbiota, and these changes are sufficient to promote age-associated inflammation, although we have not determined whether this is due to enrichment of specific species, changes in microbe-microbe interactions, alterations in the functional capacity of the aging microbiota (e.g., changes in short-chain fatty acid production), or loss of compartmentalization of the microbiota as is found in Drosophila.

Although there were significant changes in the composition of the microbiota with anti-TNF treatment, we have not yet identified which members of the microbial community alter barrier function with age. Further experiments will need to be performed to determine if it is the loss of beneficial members of the microbial community, overgrowth of harmful members, or a shift in metabolism that contributes to this phenomenon.

Microglia are a form of specialized immune cell resident in the central nervous system, responsible for mounting a defense against pathogens and clearing out harmful waste materials from brain tissue. They also assist more directly in the function of neurons and neural connections, however. Like all other parts of the immune system, microglia become damaged and dysfunctional with advancing age, and the research community is attempting to better understand this failure in order to address it in some way. There have been initial attempts to try to reverse the signaling environment for microglia in older animals, for example, though it may be that delivering young microglia will turn out to be a more effective stopgap approach. Ultimately, the underlying damage that causes aging and all its dysfunction will have to be repaired in order to put a stop to this and all other forms of degeneration.

The effects of aging on the central nervous system (CNS) are widespread, as are systemic changes in peripheral tissues. The importance of communication between the CNS and the periphery is increasingly recognized, and may be mediated by systemic factors, the autonomic nervous system, commensal bacteria (i.e., the microbiome) and/or the neuro-immune axis. Age-related changes in CNS homeostasis are not solely intrinsic in nature, but are mediated through bidirectional communication between the CNS and the systemic environment. Differences in neuronal function have been observed in the CNS with age, but it is becoming increasingly apparent that it is possible to slow, or even reverse, aging by restoring "youthful" peripheral tissue compartments. This includes the bone marrow niche that gives rise to the body's immune system, which can have a beneficial positive feedback effect on distant areas including the CNS.

No cell is protected from the detrimental effects of aging, and this includes the primary immune cell of the CNS, the resident tissue macrophages known as microglia. These cells represent 5%-15% of all brain cells, and are considered to be the housemaids of the CNS, providing nourishment and support to neighboring neurons, clearing debris, and being the first responders to foreign stimuli. Like their neuronal counterparts, microglia are believed to be post-mitotic and long-lived, with minimal, if any, turnover. Although recent depletion studies imply the existence of latent microglia progenitors, it is not clear what role this proposed population of cells may have in replenishing microglia populations under normal homeostatic conditions across the lifespan. Thus, these cells may still be viewed as especially vulnerable to the cumulative effects of aging, and thus poised to negatively impact the neurovascular niche as a result of a compromised ability to perform essential 'house-keeping' functions. While the role of aging on circulating macrophages and other lymphoid-associated myeloid cells has received significant attention in recent years, our understanding of the age-related changes in the function of CNS-resident microglia is less clear.

Young microglia gradually transition from a ramified morphological state to a deramified, spheroid formation with abnormal processes with chronological age. Several cytoplasmic features are hallmarks of microglial senescence including increased granule formation, autofluorescent pigments such as lipofuscin, and process fragmentation. Age-related neuronal loss reduces the overall level of immunoinhibitory molecules required to maintain microglia in a quiescent state. Basal increases in inflammatory signaling are associated with enhanced reactive oxygen species (ROS) production which results in the generation of free radicals, lipid peroxidation, and DNA damage. This positive feedback loop is further compounded by defects in lysosomal digestion and autophagy, resulting in the potentially toxic buildup of indigestible material. Concurrent reductions in process motility and phagocytic activity lead to decreased immune surveillance and debris clearance, resulting in plaque formation. In turn, microglia activation triggers astrocyte activation and promotes the recruitment of T cells into the aging brain.

These pathological features of microglial aging are highly influenced by the systemic environment. Diminished levels of circulating anti-aging factors in conjunction with increased concentrations of pro-aging factors are critical drivers of microglial senescence. For example, diminished estrogen levels in older females are associated with elevated expression of macrophage-associated genes in the brain. Therapeutic interventions intended to increase anti-aging factors and decrease pro-aging factors appear to be able to halt or delay microglia aging, enhance neurogenesis, and improve cognitive function.

Link: http://www.mdpi.com/1422-0067/18/4/769/htm

The brain generates new cells to replace those lost to injury and age, but only to a very modest degree - nowhere near enough to compensate for the damage that accumulates over a life span. Further, the processes of neurogenesis, the birth and integration of new neurons, decline with age. There is some interest in finding ways to spur greater neurogenesis, as the basis for therapies or enhancement technologies, and here researchers investigate a possible proximate cause of the age-related reduction in the pace at which new neurons are created in brain tissue.

The hippocampus is one neurogenic niche where new neurons arising from neural stem cells (NSCs) are constantly generated throughout life in a process called adult hippocampal neurogenesis. Deficits in this process are observed with aging and are believed to underlie age-related cognitive deficits. However, the molecular identity governing such deficits is not fully understood. A mitotic checkpoint kinase, BubR1, has emerged as a key factor in age-related pathology and lifespan. Whether BubR1 also regulates age-related changes in hippocampal neurogenesis is unknown. Notably, BubR1 is expressed in the postnatal mouse dentate gyrus and is relatively higher in the subgranular zone (SGZ) than the dentate granule layer. In addition, BubR1 is expressed in radial glia-like NSCs (RGCs) and is reduced in an age-dependent manner. We hypothesized that age-dependent regulation of BubR1 plays a possible role in hippocampal neurogenesis.

Using adult BubR1 H/H mice with reduced hippocampal BubR1 levels, we first showed significantly reduced cell proliferation in the SGZ and subventricular zone. Progenitor cell types vulnerable to BubR1 insufficiency included significant reductions in activated RGCs, intermediate progenitor cells (IPCs), and neuroblasts. Subsequently, BubR1 H/H mice exhibited a significant decrease in the density of mature new neurons, while survival of new cells was not affected. Thus, these results indicate that the reduction in hippocampal neurogenesis may result primarily from a decrease in neural progenitor proliferation, rather than affecting survival.

In this study, we have identified several novel functions of BubR1 in the adult brain. First, we show BubR1 level is significantly reduced with age. Given that BubR1 insufficiency contributes to age-related pathology including short lifespan, our findings extend the established function of BubR1 to aging and cognitive decline. Second, BubR1 is primarily known as a key regulator for mitosis. We identify an adult-specific mitotic function of BubR1 in ensuring a precise number of neural progenitors are proliferated and an effective rate of neurogenesis is maintained. Third, we show a critical postmitotic function of BubR1. Rather than affecting cell survival, BubR1 insufficiency impairs neuronal maturation and impairs dendrite morphogenesis. Collectively, our identification of BubR1 as a new and critical factor controlling sequential steps across neurogenesis raises the possibility that BubR1 may be a key mediator regulating aging-related hippocampal pathology. Targeting BubR1 may represent a novel therapeutic strategy for age-related cognitive deficits.

Link: http://onlinelibrary.wiley.com/doi/10.1111/acel.12594/full

Imagine for a moment that the inhabitants of a town beside a river are hampered by their inability to get across the river. They have been talking about getting across the river for so long, and without any meaningful progress towards that goal, that it has become a polarized topic by now. Most people won't mention crossing the river these days because it has become the subject of tall tales and ridicule. The town is growing, however, and now it has a concrete works and enough revenue to order all the rest of the materials needed for a bridge. Accordingly, a bridge faction arises, but is almost immediately set upon by another, larger faction who think that a better use for the concrete and the funding would be a nice viewing platform overlooking the river, and a road leading up to it. Wouldn't that be a benefit to the town, and safely certain in comparison to actually having to set up pilings and cranes and all the rest of what might be needed to build a bridge? Both of these factions amount to only a handful of people in total, however, and are largely ignored by the rest of the town, whose support they need in order to move ahead.

This sketch is somewhat akin to the situation we find ourselves in when it comes to biotechnology and aging. The people who want to take credible paths to human rejuvenation, bringing aging under medical control, now that such a goal is possible given the technology to hand, are a minority in comparison to the people who want to do no more than slightly slow down aging. The difference in the potential benefits produced by these two courses of action is night and day: one does very little, the other is a road to agelessness and an end to all age-related disease. The difference in cost is likely minimal in the grand scheme of things. Yet the majority of that part of the aging research community interested treating aging as a medical condition are following the objectively far worse path, rather than the objectively far better path. Meanwhile, the majority of the public pays no attention and has little to no interest in the topic - despite the fact that this is, quite literally, a matter of life and death.

Thus, there are two battles of importance when it comes to advocacy for the treatment of aging. The first is to create widespread public support for longer, healthier lives and the research needed to achieve that goal. We currently live in a world in which most people are all for cancer research and heart disease therapies, but opposed to or disinterested in research that targets aging, the root cause of those conditions. Progress at the large scale requires greater public support for this cause than presently exists. The second battle is to ensure that the right projects are funded: comprehensive rejuvenation, not a slight slowing of aging. Bringing an end to aging, not just tweaking it a little. Both goals are equally possible, but at present the better of the two has far less support and funding. That this second battle is still being fought, and needs to be fought if we are going to see significant progress in our lifetimes, is why articles like the one quoted below appear every so often - though not as often as they should.

Fear of Life Extension

In about the year 2000, a commandment came down from the very heights of the Geriatric Olympus: "Thou Shalt Not Study Life Extension. Nay, nor shall thou speak wistfully of such a prospect. For it is written that life extension scares the bejesus out of the gods of policy." The fear haunting policy makers is that medical progress will result in longer lives without better health - the specter of millions of empty shells in wheelchairs populating ever-expanding nursing homes. Ever since this commandment, the ruling concept has been "quality, not quantity." We don't want to live longer - just better.

This concept ignores two realities: firstly, that we do want to live longer; secondly, that at a population level, it is impossible to live longer without living better. Conversely, living better means living longer. At one level, these realities are too obvious to require explanation. However, policy gods work at the level of abstract concepts, and strange things can happen when abstractions are substituted for actual experience.

We do want to live longer. As any clinician knows, those with serious chronic illnesses not only cling to life but for the most part enjoy it and are grateful for the opportunity. Even in places with easy access to un-messy and legally sanctioned suicide, there are not that many takers. And it is virtually impossible to separate quality from quantity in human life. Measures that reduce disease also increase longevity, and vice versa. There are rare examples where quality and quantity might diverge - perhaps chemotherapy and radiation for glioblastoma multiforme is one - but I challenge clinicians to come up with common examples. Aggressive end of life care does not increase quantity. Palliative care does not shorten life and in some trials even extends it.

Thirty years ago, there were serious articles by various experts about how the (then) continued increase in life expectancy would lead to an epidemic of Alzheimer's and thence to a need for more nursing homes, more wheelchairs, more of everything unpleasant and costly. But that was silly. People live longer because they are healthier, not because some magic pill or machine keeps decrepit, barely functioning organisms alive. Yet the commandment outlawing enthusiasm for life extension requires researchers to start their publications with statements about wanting only to improve quality, not quantity of life.

The heart is one of the least regenerative organs in the body. Given that, it is interesting to see that in some heart failure patients, the use of mechanical devices to assist heart function gives the heart a chance to somewhat restore itself. The underlying mechanisms have yet to be explored, but it is always possible that the effect might be recreated without the use of devices if better understood.

A study has shown that nearly 40% of severe heart failure patients initially fitted with a mechanical heart which was later removed go on to fully recover. As we face a shortage of donated hearts for transplant, the study authors are calling for the devices to be considered as a tool which can allow patients to restore their health. The research examined the effect of mechanical heart pumps, known as left ventricular assist devices (LVAD). The devices are used to support patients with severe heart failure while they wait for a heart transplant. Surgeons implant the battery operated, mechanical pump which helps the main pumping chamber of the heart - the left ventricle - to push blood around the body. LVADs are used for patients who have reached the end stage of heart failure.

Researchers report that LVAD combined with medication can fully restore heart function in patients. "We talk about these devices as a bridge-to-transplant, something which can keep a patient alive until a heart is available for transplantation. However, we knew that sometimes patients recover to such an extent that they no longer need a heart transplant. For the first time, what we have shown is that heart function is restored in some patients - to the extent that they are just like someone healthy who has never had heart disease. In effect, these devices can be a bridge to full recovery in some patients."

In the clinical trial, 58 men with heart failure were tested for their heart fitness levels. Of the men, 16 were fitted with an LVAD and then had it removed due to the extent of their recovery. Furthermore 18 still had an LVAD and 24 patients were waiting for a heart transplant. On average, a patient had a device fitted for 396 days before it was removed, though it varied from 22 days to 638 days. The participants were compared with 97 healthy men who had no known heart disease. All were tested on a treadmill with a face mask to monitor their oxygen utilisation and heart pumping capability. The authors report that 38% of people who recover enough to allow the device to be removed demonstrated a heart function which was equivalent to that of a healthy individual of the same age. "Our ongoing and future research is aiming to identify the markers of early heart recovery while patients are fitted with a device. These markers will inform clinical care teams to make right decisions about which patient respond well to device and when to consider potential removal or disconnection of the device while ensuring heart failure will not occur again in the future."

Link: http://www.ncl.ac.uk/press/news/2017/04/heartpumprestoreshealth/

Reactive oxygen species (ROS) are largely generated in the mitochondria of the cell, a side-effect of the energetic processes taking place there to power cellular operations. ROS cause damage that must be repaired by reacting with molecular machinery in the cell, and that stress on the cell increases with age, and features prominently in most discussions of aging. ROS also play an important role as signals, however, triggering important processes related as cellular maintenance. That exercise is beneficial, for example, depends upon an increase in ROS production, and a number of ways of increasing life span in laboratory species incorporate some degree of increased ROS generation.

Historically, mitochondrial ROS (mtROS) production and oxidative damage have been associated with aging and age-related diseases. In fact, the age-related increase in ROS has been viewed as a cause of the aging process while mitochondrial dysfunction is considered a hallmark of aging, as a consequence of ROS accumulation. However, pioneering work in Caenorhabiditis elegans has shown that mutations in genes encoding subunits of the electron transport chain (ETC) or genes required for biosynthesis of ubiquinone extend lifespan despite reducing mitochondrial function. The lifespan extension conferred by many of these alterations is ROS dependent, as reduction of ROS abolishes this effect. Moreover, chemical inhibition of glycolysis or exposure to metabolic poisons that block respiratory complex I (CI) or complex III (CIII) also prolong lifespan in C. elegans in a ROS-dependent manner. Various studies have shown that ROS act as secondary messengers in many cellular pathways, including those which protect against or repair damage. ROS-dependent activation of these protective pathways may explain their positive effect on lifespan. The confusion over the apparent dual nature of ROS may, in part, be due to a lack of resolution as without focused genetic or biochemical models it is impossible to determine the site from which ROS originate.

A promising path to resolving ROS production in vivo is the use of alternative respiratory enzymes, absent from mammals and flies, to modulate ROS generation at specific sites of the ETC. The alternative oxidase (AOX) of Ciona intestinalis is a cyanide-resistant terminal oxidase able to reduce oxygen to water with electrons from reduced ubiquinone (CoQ), thus bypassing CIII and complex IV (CIV). NDI1 is an alternative NADH dehydrogenase found in plants and fungi, which is present on the matrix-face of the mitochondrial inner membrane where it is able to oxidize NADH and reduce ubiquinone, effectively bypassing CI. Our group and others have demonstrated that allotopic expression of NDI1 in Drosophila melanogaster can extend lifespan under a variety of conditions and rescue developmental lethality in flies with an RNAi-mediated decrease in CI levels.

To determine the role of increased ROS production in regulating longevity, we utilized allotopic expression of NDI1 and AOX, along with Drosophila genetic tools to regulate ROS production from specific sites in the ETC. We show that NDI1 over-reduces the CoQ pool and increases ROS via reverse electron transport (RET) through CI. Importantly, restoration of CoQ redox state via NDI1 expression rescued mitochondrial function and longevity in two distinct models of mitochondrial dysfunction. We show that mitochondrial ROS production increases with age and that un-detoxified ROS can be detrimental to Drosophila lifespan, while increasing ROS production specifically from reduced CoQ, possibly via RET, acts as a signal to maintain mitochondrial function (notably CI) and extend lifespan. It is possible that an intact CI is required for lifespan extension in fruit flies, as metformin, which increases lifespan by blocking CI and increasing ROS in worms, fails to do so in fruit flies. If the mechanism we describe here is conserved in mammals, manipulation of the redox state of CoQ may be a strategy for the extension of both mean and maximum lifespan and the road to new therapeutic interventions for aging and age-related diseases.

Link: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4835580/

The prospect of replacing lost neurons is one of the major themes of research into Parkinson's disease. The most evident symptoms of this neurodegenerative condition, the tremors and loss of control, are caused by the progressive loss of a small but critical population of dopamine-generating neurons in the brain. This is actually a problem that occurs to all of us to some degree as we age, but Parkinson's patients have either a genetic or environmental vulnerability that makes them less resistant to the underlying processes that drive damage and cell death. As is the case for most neurodegenerative conditions, once you move past the proximate cause of dying cells, the list of mechanisms involved at lower levels in the chain of cause and effect starts to include all of the usual suspects: mitochondrial function; cellular maintenance processes; accumulations of misfolded proteins and other forms of metabolic waste; and so forth.

With the blossoming of the stem cell research community over the past twenty years, replacing lost neurons and their contribution to the functioning of the brain has seemed like a possible short-cut past the difficult question of why exactly it is that these particular neurons are dying. That it is in fact a short cut may or may not be the case, however. Certainly, the root causes of Parkinson's disease are still operating even following a hypothetical safe and reliable replacement of neurons, and it is an open question as to how long they will take to chew through those replacement neurons. Further, actually replacing dopamine-generating neurons safely and reliably has turned out to be a more challenging process than hoped. This is often the case in any field of medical research - even the goals that are easy to explain and visualize, and enjoy widespread support, are long roads. Still, the materials below note one of a number of promising results in neuron replacement that have arrived in recent years. The researchers used cellular reprogramming methods to generate patient-matched neurons from existing support cells in the brain, and went on to show positive results in mice engineered to exhibit Parkinson's symptoms.

Mighty morphed brain cells cure Parkinson's in mice, but human trials still far off

Mice that walk straight and fluidly don't usually make scientists exult, but these did: The lab rodents all had a mouse version of Parkinson's disease and only weeks before had barely been able to lurch and shuffle around their cages. Using a trick from stem cell science, researchers managed to restore the kind of brain cells whose death causes Parkinson's. And the mice walked almost normally. The same technique turned human brain cells, growing in a lab dish, into the dopamine-producing neurons that are AWOL in Parkinson's. Success in lab mice and human cells is many difficult steps away from success in patients. The study nevertheless injected new life into a promising approach to Parkinson's that has suffered setback after setback - replacing the dopamine neurons that are lost in the disease, crippling movement and eventually impairing mental function.

There is no cure for Parkinson's. Drugs that enable the brain to make dopamine help only somewhat, often causing movement abnormalities called dyskinesia as well as other side effects. Rather than replacing the missing dopamine, scientists tried to replace dopamine neurons - but not in the way that researchers have been trying since the late 1980s. In that approach, scientists obtained tissue containing dopamine neurons from first-trimester aborted fetuses and implanted it into patients' brains. Instead, several labs have used stem cells to produce dopamine neurons in dishes. Transplanted into the brains of lab rats with Parkinson's, the neurons reduced rigidity, tremor, and other symptoms. Human studies are expected to begin in the US and Japan this year or next.

Induction of functional dopamine neurons from human astrocytes in vitro and mouse astrocytes in a Parkinson's disease model

Cell replacement therapies for neurodegenerative disease have focused on transplantation of the cell types affected by the pathological process. Here we describe an alternative strategy for Parkinson's disease in which dopamine neurons are generated by direct conversion of astrocytes. Using three transcription factors, NEUROD1, ASCL1 and LMX1A, and the microRNA miR218, collectively designated NeAL218, we reprogram human astrocytes in vitro, and mouse astrocytes in vivo, into induced dopamine neurons (iDANs). Reprogramming efficiency in vitro is improved by small molecules that promote chromatin remodeling and activate the TGFβ, Shh and Wnt signaling pathways. The reprogramming efficiency of human astrocytes reaches up to 16%, resulting in iDANs with appropriate midbrain markers and excitability.

In a mouse model of Parkinson's disease, NeAL218 alone reprograms adult striatal astrocytes into iDANs that are excitable and correct some aspects of motor behavior in vivo, including gait impairments. With further optimization, this approach may enable clinical therapies for Parkinson's disease by delivery of genes rather than cells.

Heart patches are one manifestation of the tissue engineering approach to regenerative medicine. Cells delivered to the patient are usually combined with a biodegradable scaffold material that provides support to help the cells survive and undertake beneficial signaling actions. A heart patch is some amount of this combined material applied to the exterior of the heart, in some cases simply by injection since the scaffold can be made to be a viscous fluid. The researchers here claim better results by abandoning the scaffolds, however, and implanting thin sheets of engineered cells. This paper reports on the results of an early human trial:

Heart failure, caused primarily by ischemic cardiomyopathy (ICM) or dilated cardiomyopathy (DCM), is life-threatening even with excellent treatment. We developed a cell-sheet implantation method that can heal severely damaged myocardium through cytokine paracrine effects, as evidenced by several experiments using infarction or DCM models in both large and small animals. Cell-sheet implants are reported to offer better functional recovery than needle-injection methods, mainly by cytokine paracrine effects despite poor cell survival. Based on these findings from preclinical work, we previously conducted a First-in-Man Clinical Trial using cell-sheet implants. In the present study, we introduced cell-sheet implants to treat cardiomyopathy patients in a Phase I clinical trial to determine the safety, feasibility, and potential effectiveness of cell-sheet implants as a sole therapy.

Fifteen ischemic cardiomyopathy patients and 12 patients with dilated cardiomyopathy, who were in New York Heart Association functional class II or III and had been treated with the maximum medical and/or interventional therapies available, were enrolled. Scaffold-free cell sheets derived from autologous muscle were transplanted over the left ventricle free wall via left thoracotomy, without additional interventional treatments. There were no procedure-related major complications during follow-up. The majority of the ischemic cardiomyopathy patients showed marked symptomatic improvement in New York Heart Association classification and the Six-Minute Walk Test with significant reduction of serum brain natriuretic peptide level, pulmonary artery pressure, pulmonary capillary wedge pressure, pulmonary vein resistance, and left ventricular wall stress after transplantation instead of limited efficacy in dilated cardiomyopathy patients.

This Phase I study found cell-sheet transplantation as a sole therapy to be a feasible treatment for cardiomyopathy. The promising results in the safety and functional recovery seen in this study warrant further clinical follow-up and larger studies to confirm the therapeutic efficacy of autologous skeletal stem-cell sheets for severe congestive heart failure.

Link: https://doi.org/10.1161/JAHA.116.003918

Since aging is a global phenomenon in the body, an accumulation of a small number of forms of root cause molecular damage that produce many more secondary and later consequences, it should be expected to find strong correlations between observed measures of aging. Chance and lifestyle gives some people a larger amount of root cause damage, and that means they have greater degrees of all of the related secondary and later consequences. Better assessments of the correlations between those consequences do not necessarily tell us anything new.

Grey hair has been linked with an increased risk of heart disease in men. "Ageing is an unavoidable coronary risk factor and is associated with dermatological signs that could signal increased risk. More research is needed on cutaneous signs of risk that would enable us to intervene earlier in the cardiovascular disease process." Atherosclerosis and hair greying share similar mechanisms such as impaired DNA repair, oxidative stress, inflammation, hormonal changes and senescence of functional cells. This study assessed the prevalence of grey hair in patients with coronary artery disease and whether it was an independent risk marker of disease.

This was a prospective, observational study which included 545 adult men who underwent multi-slice computed tomography (CT) coronary angiography for suspected coronary artery disease. Patients were divided into subgroups according to the presence or absence of coronary artery disease, and the amount of grey/white hair. The amount of grey hair was graded using the hair whitening score: 1 = pure black hair, 2 = black more than white, 3 = black equals white, 4 = white more than black, and 5 = pure white. Each patients' grade was determined by two independent observers. Data was collected on traditional cardiovascular risk factors including hypertension, diabetes, smoking, dyslipidaemia, and family history of coronary artery disease.

The researchers found that a high hair whitening score (grade 3 or more) was associated with increased risk of coronary artery disease independent of chronological age and established cardiovascular risk factors. Patients with coronary artery disease had a statistically significant higher hair whitening score and higher coronary artery calcification than those without coronary artery disease. In multivariate regression analysis, age, hair whitening score, hypertension and dyslipidaemia were independent predictors of the presence of atherosclerotic coronary artery disease. Only age was an independent predictor of hair whitening. "Our findings suggest that, irrespective of chronological age, hair greying indicates biological age and could be a warning sign of increased cardiovascular risk."

Link: https://www.escardio.org/The-ESC/Press-Office/Press-releases/grey-hair-linked-with-increased-heart-disease-risk-in-men

A growing number of research groups are working on biomarkers of aging based on patterns of DNA methylation, an epigenetic decoration to nuclear DNA that determines the pace at which specific proteins are produced from their genetic blueprints. Quite a few new papers on this topic have caught my attention in the past few weeks, and today I'll point out another one, this time focused on canine species. One of the challenges inherent in this work is that these aging-associated epigenetic patterns are not entirely the same when comparing different mammalian species, yet cost effective life science efforts have to be - at least initially - undertaken in something other than human subjects. The point of building biomarkers of aging is to greatly speed up the development of rejuvenation therapies. Reading the results of a biomarker assay immediately before and after treatment is a very different proposition from having to wait for the entire remaining life span of the study animals in order to determine whether or not a potential therapy actually does in fact extend healthy longevity. Unfortunately, the potential biomarkers of aging must themselves be validated before they can be used, and so we come back to working with shorter-lived animal species for the sake of cost-effectiveness.

In aging research, dogs are a useful intermediary step between mice and humans, when considering the cost to run studies, meaningful differences in cellular biochemistry, and species life span. On that last point, that dogs exhibit such varied life spans between breeds is especially useful. It gives a great deal of flexibility in designing and executing studies that might not otherwise have existed. Studies of approaches to treating aging that are fairly far along, with a good deal of safety data already, and that would be enormously expensive in humans, can even be carried out in companion animals rather than laboratory animals. One research group in the US has set up the Dog Aging Project in order to make some progress on this front, for example. Given this, it isn't surprising to find researchers putting together DNA methylation biomarkers for canine species. As is the case for work on biomarkers of aging in mice, this initiative is a necessary part of making the field of aging research more efficient.

An epigenetic aging clock for dogs and wolves

Technological breakthroughs surrounding genomic platforms have led to major insights about age related DNA methylation changes in humans. In mammals, DNA methylation represents a form of genome modification that regulates gene expression by serving as a maintainable mark whose absence marks promoters and enhancers. During development, germline DNA methylation is erased but is established anew at the time of implantation. Abnormal methylation changes that occur because of aging contribute to the functional decline of adult stem cells. Even small changes of the epigenetic landscape can lead to robustly altered expression patterns, either directly by loss of regulatory control or indirectly, via additive effects, ultimately leading to transcriptional changes of the stem cells.

Several studies describe highly accurate age estimation methods based on combining the DNA methylation levels of multiple CpG dinucleotide markers. We recently developed a multi-tissue epigenetic age estimation method (known as the epigenetic clock) that combines the DNA methylation levels of 353 epigenetic markers known as CpGs. The weighted average of these 353 epigenetic markers gives rise to an estimate of tissue age (in units of years), which is referred to as "DNA methylation age" or as "epigenetic age". DNA methylation age is highly correlated with chronological age across the entire lifespan. We and others have shown that the human epigenetic clock relates to biological age (as opposed to simply being a correlate of chronological age), e.g. the DNA methylation age of blood is predictive of all-cause mortality even after adjusting for a variety of known risk factors.

Many research questions and preclinical studies of anti-aging interventions will benefit from analogous epigenetic clocks in animals. To this end we sought to develop an accurate epigenetic clock for dogs and wolves. Dogs are increasingly recognized as a valuable model for aging studies. Dogs are an attractive model in aging research because their lifespan (around 12 years) is intermediate between that of mice (2 years) and humans (80 years), thus serving as a more realistic model for human aging than most rodents. The maximum lifespan of dogs is known to correlate with the size of their breed. Based on previous studies in human, we expect that the age acceleration (difference between epigenetic age and chronological age) correlates with longevity. We hypothesize that dogs whose epigenetic age is larger than their chronological age are aging more quickly, while those with negative value are aging more slowly. Thus, we would expect to see a correlation between age acceleration and dog breed size. We also sought to build an epigenetic clock for gray wolves because alternative age estimation methods have limitations.

Our study demonstrates that DNA-methylation correlates with age in dogs and wolves as it does in human and related species. This age-dependence of DNA-methylation is conserved at syntenic sites in the respective genomes of these canid species as well for more distantly related mammalian genomes such as human. Overall, our study demonstrates that dogs age in a similar fashion to humans when it comes to DNA methylation changes. Based on our preliminary blood samples of 108 canid specimens, including both dogs and wolves, we accurately measured the methylation status of several hundred thousand CpGs. We demonstrate that these data can produce highly accurate age estimation methods (epigenetic clocks) for dogs and wolves separately. By first removing sites that were variable between dogs and wolves, we could also establish a highly accurate epigenetic clock for all canids (i.e. dogs and wolves combined). This clock allows us to estimate the age of half the canids to within a year.

Researchers here report on yet another genetic method to modestly slow aging in mice, to add to the numerous approaches already demonstrated. Like a range of other interventions that affect the pace of aging in mice, this appears to work at last partially through the well-studied insulin signaling pathway. That is usually a sign that the intervention in question is working through similar mechanisms to those triggered by the practice of calorie restriction, but may or may not be the case here given the specific details.

The vascular system is one of the major target organs affected by aging. In order to maintain vascular integrity, vascular endothelial cells (ECs) should have self-defense systems. We previously reported that vasohibin-1 (Vash1) could be one of such systems. Vash1 was originally isolated as an angiogenesis inhibitor was preferentially expressed in ECs for negative-feedback regulation. However, our subsequent analysis revealed that Vash1 has an additional function that causes an upsurge in stress resistance of ECs by increasing the expression of superoxide dismutase 2 (SOD2) and SIRT1 in ECs. Along with this finding, we observed that the decreased expression of Vash1 promotes vascular diseases such as diabetic nephropathy and atherosclerosis. We then noticed that the expression of Vash1 in ECs is downregulated with aging due to an increase in the expression of a certain microRNA, namely, miR-22. This observation raised the question as to why nature would allow a decrease in the expression of such a valuable protein with aging.

Because of the protective role of Vash1 in the vasculature, in this present study we assumed that vash1-/- mice would have a short lifespan. However, to our surprise, vash1-/- mice lived significantly longer and looked healthier than wild-type (WT) mice. We sought the cause of this healthy longevity and found that vash1-/- mice exhibited mild insulin resistance along with reduced expression of the insulin receptor (insr), insulin receptor substrate 1 (irs-1), and insulin receptor substrate 2 (irs-2) in their white adipose tissue (WAT) but not in their liver or skeletal muscle. The expression of vash1 dominated in the WAT among those 3 organs. Importantly, vash1-/- mice did not develop diabetes even when fed a high-fat diet. These results indicate that the expression of vash1 was required for the normal insulin sensitivity of the WAT and that the target molecules for this activity were insr, irs1, and irs2. The lack of vash1 caused mild insulin resistance without the outbreak of overt diabetes and might contribute to healthy longevity.

Link: https://doi.org/10.1155/2017/9851380

Researchers have constructed a mouse version of the DNA methylation biomarkers of aging currently under development for humans. This will hopefully enable rapid assessment of potential rejuvenation therapies in mice, speeding up progress in the field and lowering costs. There is a fair amount of work to be in order to prove out such a biomarker, however, and that starts with running it against mice subject to the numerous interventions known to modestly slow aging in mammals, including senescent cell clearance. Expanding their initial selection of methods is the next step for this research team.

Lots of factors can contribute to how fast an organism ages: diet, genetics and environmental interventions can all influence lifespan. But in order to understand how each factor influences aging - and which ones may help slow its progression - researchers need an accurate biomarker, a clock that distinguishes between chronological and biological age. A traditional clock can measure the passage of chronological time and chronological age, but a so-called epigenetic clock can measure biological age. Epigenetic clocks already exist to reflect the pace of aging in humans, but in order to measure and test the effects of interventions in the lab, investigators have developed an age-predicting clock designed for studies in mice. The new clock accurately predicts mouse biological age and the effects of genetic and dietary factors, giving the scientific community a new tool to better understand aging and test new interventions.

To develop their "clock," researchers took blood samples from 141 mice and, from among two million sites, pinpointed 90 sites from across the methylome that can predict biological age. (The methylome refers to all of the sites in the genome where chemical changes known as methylation take place, changing how and when DNA information is read). The team then tested the effects of interventions that are known to increase lifespan and delay aging, including calorie restriction and gene knockouts. They also used the clock to measure the biological ages of induced pluripotent stem cells (iPSCs), which resemble younger blood.

The research team hopes that their technique will be useful for researchers who are studying new aging interventions in the lab. Currently, it can take years and hundreds of thousands of dollars to study mice over their lifespans and determine the effectiveness of a single intervention. Although it is no small feat to sequence the entire methylome, the new clock could allow for studies to be carried out much faster and on a larger scale. "Our hope is that researchers will be able to use this biomarker for aging to find new interventions that can extend lifespan, examine conditions that support rejuvenation and study the biology of aging and lifespan control."

Link: https://www.eurekalert.org/pub_releases/2017-04/bawh-ba040517.php

The research I'll point out today is interesting, but should probably be filed away for later consideration once the mechanisms involved are better understood. Researchers have found that delivering the gut microbes of young killifish to older killifish extends the life span of those older fish. This has echoes of parabiosis experiments in mice, linking younger and older animals together, in the sense that it might shine some light on the impact of specific changes that occur over the course of aging. The study takes place in the broader context of recent data that suggests the microbial population of the gut changes significantly with aging, and that gut microbes have a fair-sized influence on health. This might be via modulation of nutrient update, already an important factor in the life span of short-lived species, via interaction with the immune system, or via any number of other still poorly explored or yet to be cataloged mechanisms. It is a young area of research, with a great deal left to explore.

Is the research community likely to generate methods of manipulating the mammalian gut microbiome that produce better results for human long-term health than, say, calorie restriction or exercise? Outside of fixing a range of uncommon medical conditions that turn out to be due entirely or in large part to errant microbes in the gut, I'd say large gains in human healthspan are not all that plausible. There are already a great many ways to influence the gut microbiome, including the aforementioned practice of calorie restriction, and the observed impact of these strategies puts some limits on what it is plausible to expect from a more rigorous, informed, and technologically assisted adjustment of this microbial population. As always, when looking at these results bear in mind that short-lived species have a far greater plasticity of longevity - when compared against humans - when it comes to this sort of intervention. Methods such as calorie restriction, that extend life in mice by 40% or more, are certainly nowhere near as beneficial in humans.

'Young poo' makes aged fish live longer

It may not be the most appetizing way to extend life, but researchers have shown for the first time that older fish live longer after they consumed microbes from the poo of younger fish. So-called 'young blood' experiments that join the circulatory systems of two rats - one young and the other old - have found that factors coursing through the veins of young rodents can improve the health and longevity of older animals. But the new first-of-its-kind study examined the effects of 'transplanting' gut microbiomes on longevity. It is anticipated that scientists will test whether such microbiome transplants can extend lifespan in other animals.

Life is fleeting for killifish, one of the shortest-lived vertebrates on Earth: the fish hits sexual maturity at three weeks old and dies within a few months. Previous studies have hinted at a link between the microbiome and ageing in a range of animals. As they age, humans and mice tend to lose some of the diversity in their microbiomes, developing a more uniform community of gut microbes, with once-rare and pathogenic species rising to dominance in older individuals. The same pattern holds true in killifish, whose gut microbiomes at a young age are nearly as diverse as those of mice and humans.

To test whether the changes in the microbiome had a role in ageing, researchers 'transplanted' the gut microbes from 6-week-old killifish into middle-aged 9.5-week-old fish. They first treated the middle-aged fish with antibiotics to clear out their gut flora, then placed them in a sterile aquarium containing the gut contents of young fish for 12 hours. Killifish don't usually eat faeces, but they would probe and bite at the gut contents to see whether it was food, ingesting microbes in the process. The transplanted microbes successfully recolonized the guts of the fish that received them, the team found. At 16 weeks of age, the gut microbiomes of middle-aged fish that received 'young microbes' still resembled those of 6-week-old fish.

The young microbiome 'transplant' also had dramatic effects on the longevity of fish that got them: their median lifespans were 41% longer than fish exposed to microbes from middle-aged animals, and 37% longer than fish that received no treatment (antibiotics alone also lengthened lifespan, but to a lesser extent). And at 16 weeks - old age, by killifish standards - the individuals that received young gut microbes darted around their tanks more frequently than other elderly fish, with activity levels more like 6-week-old fish. By contrast, gut microbes from older fish had no effect on the lifespans of younger fish. Exactly how microbes influence lifespan is hazy. "The challenge with all of these experiments is going to be to dissect the mechanism. I expect it will be very complex."

Regulation of Life Span by the Gut Microbiota in The Short-Lived African Turquoise Killifish

Gut bacteria occupy the interface between the organism and the external environment, contributing to homeostasis and disease. Yet, the causal role of the gut microbiota during host aging is largely unexplored. Here, using the African turquoise killifish (Nothobranchius furzeri), a naturally short-lived vertebrate, we show that the gut microbiota plays a key role in modulating vertebrate life span. Recolonizing the gut of middle-age individuals with bacteria from young donors resulted in life span extension and delayed behavioral decline. This intervention prevented the decrease in microbial diversity associated with host aging and maintained a young-like gut bacterial community, characterized by overrepresentation of the key genera Exiguobacterium, Planococcus, Propionigenium and Psychrobacter. Our findings demonstrate that the natural microbial gut community of young individuals can causally induce long-lasting beneficial systemic effects that lead to life span extension in a vertebrate model.

It should not be at all surprising to find that the more reliable methods of modestly slowing aging in mammals have an impact on cellular senescence, one of the root causes of aging. Based on the evidence to date, most of these methods are thought to slow aging across the board, influencing all measures of degeneration, though there is some debate over the degree to which rapamycin works by suppressing cancer risk rather than via other mechanisms. Senescent cells accumulate with age, but not to more than a few percent by number in most tissues even in older individual. They cause harm primarily through signaling mechanisms: a senescent cell generates what is known as the senescence-associated secretory phenotype (SASP), a mix of compounds that create inflammation, damage the structures of the extracellular matrix, and alter the behavior of surrounding cells for the worse. Removing senescent cells will deal with this problem, but some research groups are determinedly following the much harder path towards finding ways to reduce or modulate the SASP in order to reduce its harmful effects.

Researchers have found that a compound called rapamycin has unusual properties that may help address neurologic damage such as Alzheimer's disease. The newly-discovered mechanism is what researchers say might help prevent neurologic damage and some related diseases. "The value of rapamycin is clearly linked to the issue of cellular senescence, a stage cells reach where they get old, stop proliferating and begin to secrete damaging substances that lead to inflammation. Rapamycin appears to help stop that process." This secretion of damaging compounds creates a toxic environment called senescence-associated secretory phenotype, or SASP. It's believed this disrupts the cellular microenvironment and alters the ability of adjacent cells to function properly, compromising their tissue structure and function. This broad process is ultimately linked to aging.

"The increase in cellular senescence associated with aging, and the inflammation associated with that, can help set the stage for a wide variety of degenerative disease, including cancer, heart disease, diabetes, and neurologic disease such as dementia or Alzheimer's. In laboratory animals when we clear out senescent cells, they live longer and have fewer diseases. And rapamycin can have similar effects."

Prior to this research, it had only been observed that there was one mechanism of action for rapamycin in this process. Scientists believed it helped to increase the action of Nrf2, a master regulator that can "turn on" up to 200 genes responsible for cell repair, detoxification of carcinogens, protein and lipid metabolism, antioxidant protection and other factors. In the process, it helped reduce levels of SASP. The new study concluded that rapamycin could also affect levels of SASP directly, separately from the Nrf2 pathway and in a way that would have impacts on neurons as well as other types of cells. "Any new approach to help protect neurons from damage could be valuable. Other studies, for instance, have shown that astrocyte cells that help protect neuron function and health can be damaged by SASP. This may be one of the causes of some neurologic diseases, including Alzheimer's disease."

Link: http://oregonstate.edu/ua/ncs/archives/2017/apr/new-function-discovered-compound-may-help-slow-aging

The thymus atrophies considerably following childhood, and then declines further in old age. This organ is where the immune cells called T cells mature, and its decline limits the pace at which new T cells are generated. The slow and faltering rate of immune cell creation is one of the contributing factors to immune system aging; it effectively caps the number of cells present in the body, and that population becomes ever more misconfigured due to exposure to persistent pathogens such as cytomegalovirus. Expanding the supply of immune cells should help to restore some of the lost immune function in older people, and engineering additional thymus tissue for transplantation is one possible approach to this goal. Researchers are making good progress in generating small amounts of functional thymus tissue. As this research demonstrates, the scientific community is now able to adjust the resulting tissue in order to generate T cells with specific desired characteristics.

Researchers have created a new system to produce human T cells, the white blood cells that fight against disease-causing intruders in the body. The system could be utilized to engineer T cells to find and attack cancer cells, which means it could be an important step toward generating a readily available supply of T cells for treating many different types of cancer. The thymus sits in the front of the heart and plays a central role in the immune system. It uses blood stem cells to make T cells, which help the body fight infections and have the ability to eliminate cancer cells. However, as people age or become ill, the thymus isn't as efficient at making T cells.

T cells generated in the thymus acquire specialized molecules, called receptors, on their surface, and those receptors help T cells seek out and destroy virus-infected cells or cancer cells. Leveraging that process has emerged as a promising area of cancer research: Scientists have found that arming large numbers of T cells with specific cancer-finding receptors - a method known as adoptive T cell immunotherapy - has shown remarkable results in clinical trials. Adoptive T cell immunotherapy typically involves collecting T cells from people who have cancer, engineering them in the lab with a cancer-finding receptor and transfusing the cells back into the patient.

Since adoptive T cell immunotherapy was first used clinically in 2006, scientists have recognized that it would be more efficient to create a readily available supply of T cells from donated blood cells or from pluripotent stem cells, which can create any cell type in the body. The challenge with that strategy would be that T cells created using this approach would carry receptors that are not matched to each individual patient, which could ultimately cause the patient's body to reject the transplanted cells or could cause the T cells to target healthy tissue in addition to cancer cells.

Researchers used a new combination of ingredients to create structures called artificial thymic organoids that, like the thymus, have the ability to produce T cells from blood stem cells. The scientists found that mature T cells created in the artificial thymic organoids carried a diverse range of T cell receptors and worked similarly to the T cells that a normal thymus produces. The researchers now are looking into using the system with pluripotent stem cells, which could produce a consistent supply of cancer-fighting T cells for patients in need of immediate life-saving treatment.

Link: http://newsroom.ucla.edu/releases/artificial-thymus-developed-at-ucla-can-produce-cancer-fighting-t-cells-from-blood-stem-cells

The Genome Biology journal recently published a set of open access papers on the epigenetic changes observed in mice subject to a few of the methods known to slow aging in mammals, and you'll find them linked below. In particular the focus is on DNA methylation, an molecular decoration to nuclear DNA that determines the pace at which proteins are produced from the blueprints encoded by specific genes. Changes in the amounts of proteins in circulation inside the cell are the switches and dials of cellular behavior, which in turn feeds back to determine ongoing changes in DNA methylation. It is a complex, dynamic situation.

Some of the thousands of DNA methylation markers that come and go in mammalian cells are reactions to the damage of aging; accumulations of metabolic waste and altered macromolecules. That low-level damage is the same for everyone, and so some part of the changing pattern of DNA methylation that accompanies aging is also the same for everyone. That part of the pattern can thus be used to determine how aged an individual is, how much damage their tissues have sustained, and how likely it is that the accumulated damage will kill them sometime soon. This is, in any case, the hope of researchers working on DNA methylation biomarkers of aging. The data generated to date is quite compelling.

What is the point of all this? The goal is to generate an effective, cheap, accurate biomarker of aging that can be used to quickly assess the performance of proposed rejuvenation therapies. At the present time if researchers selectively eliminate senescent cells from a patient, for example, they can only look at short-term changes, such as how many cells they successfully removed, or whether the patient exhibits immediate benefits in known assays for disease pathology. They cannot currently accomplish a rapid assessment the treatment's outcome on remaining life expectancy and future health. The only way to find out is to wait and see. This makes work on rejuvenation treatments very slow and expensive, as even in mice this requires waiting for years. A robust DNA methylation biomarker of aging, on the other hand, could run immediately before and immediately after a treatment: much faster, and much cheaper. Some teams have already started testing this approach on the presently known methods to slow aging in mice - you might look at a recent Harvard paper that builds upon the observations in the papers linked below, but which is unfortunately not open access.

One interesting point to take away from this is that there remains considerable debate over what is the cart and what is the horse in the matter of aging and alterations in the epigenome. A purist approach to the view of aging as accumulated damage is to see these epigenomic changes such as DNA methylation to be cellular reactions to rising levels of damage, or at least somewhere a fair way downstream of that damage. In these papers you'll see some of the opposite view, that these changes are an important cause of aging - that they are closer to a primary problem than a later downstream change that in and of itself causes further issues. I can't say as I think that is as defensible a viewpoint, but there are many researchers who hold it.

Epigenetic aging signatures in mice livers are slowed by dwarfism, calorie restriction and rapamycin treatment

Global but predictable changes impact the DNA methylome as we age, acting as a type of molecular clock. This clock can be hastened by conditions that decrease lifespan, raising the question of whether it can also be slowed, for example, by conditions that increase lifespan. Mice are particularly appealing organisms for studies of mammalian aging; however, epigenetic clocks have thus far been formulated only in humans. We first examined whether mice and humans experience similar patterns of change in the methylome with age. We found moderate conservation of CpG sites for which methylation is altered with age, with both species showing an increase in methylome disorder during aging.

Based on this analysis, we formulated an epigenetic-aging model in mice using the liver methylomes of 107 mice from 0.2 to 26.0 months old. To examine whether epigenetic aging signatures are slowed by longevity-promoting interventions, we analyzed 28 additional methylomes from mice subjected to lifespan-extending conditions, including Prop1 df/df dwarfism, calorie restriction, or dietary rapamycin. We found that mice treated with these lifespan-extending interventions were significantly younger in epigenetic age than their untreated, wild-type age-matched controls. This study shows that lifespan-extending conditions can slow molecular changes associated with an epigenetic clock in mice livers.

Diverse interventions that extend mouse lifespan suppress shared age-associated epigenetic changes at critical gene regulatory regions

Age-associated epigenetic changes are implicated in aging. Notably, age-associated DNA methylation changes comprise a so-called aging "clock", a robust biomarker of aging. However, while genetic, dietary and drug interventions can extend lifespan, their impact on the epigenome is uncharacterised. To fill this knowledge gap, we defined age-associated DNA methylation changes at the whole-genome, single-nucleotide level in mouse liver and tested the impact of longevity-promoting interventions, specifically the Ames dwarf Prop1 df/df mutation, calorie restriction, and rapamycin.

In wild-type mice fed an unsupplemented ad libitum diet, age-associated hypomethylation was enriched at super-enhancers in highly expressed genes critical for liver function. Genes harbouring hypomethylated enhancers were enriched for genes that change expression with age. Hypermethylation was enriched at CpG islands marked with bivalent activating and repressing histone modifications and resembled hypermethylation in liver cancer. Age-associated methylation changes are suppressed in Ames dwarf and calorie restricted mice and more selectively and less specifically in rapamycin treated mice.

Dietary restriction protects from age-associated DNA methylation and induces epigenetic reprogramming of lipid metabolism

Dietary restriction (DR), a reduction in food intake without malnutrition, increases most aspects of health during aging and extends lifespan in diverse species, including rodents. However, the mechanisms by which DR interacts with the aging process to improve health in old age are poorly understood. DNA methylation could play an important role in mediating the effects of DR because it is sensitive to the effects of nutrition and can affect gene expression memory over time.

Here, we profile genome-wide changes in DNA methylation, gene expression and lipidomics in response to DR and aging in female mouse liver. DR is generally strongly protective against age-related changes in DNA methylation. During aging with DR, DNA methylation becomes targeted to gene bodies and is associated with reduced gene expression, particularly of genes involved in lipid metabolism. The lipid profile of the livers of DR mice is correspondingly shifted towards lowered triglyceride content and shorter chain length of triglyceride-associated fatty acids, and these effects become more pronounced with age. Our results indicate that DR remodels genome-wide patterns of DNA methylation so that age-related changes are profoundly delayed, while changes at loci involved in lipid metabolism affect gene expression and the resulting lipid profile.

Here, researchers identify a form of cellular damage that appears to be a proximate cause of the loss of female fertility with advancing age. But what causes this damage? Tying their observations to other, earlier forms of damage and dysfunction in aged tissues will no doubt be a great deal of work if pursued through purely investigative methods. The fastest approach to such a situation tends to be to fix the damage and see what happens as a result, but the lack of readily available repair therapies has hampered this approach in the past. Now that the first of these treatments are emerging, such as senescent cell clearance, we will start to see something of a renaissance in determining cause and effect throughout the processes of aging.

Researchers have discovered a possible new explanation for female infertility. Thanks to cutting-edge microscopy techniques, they observed for the first time a specific defect in the eggs of older mice. This defect may also be found in the eggs of older women. The choreography of cell division goes awry, and causes errors in the sharing of chromosomes. "We found that the microtubules that orchestrate chromosome segregation during cell division behave abnormally in older eggs. Instead of assembling a spindle in a controlled symmetrical fashion, the microtubules go in all directions. The altered movement of the microtubules apparently contributes to errors in chromosome segregation, and so represents a new explanation for age-related infertility."

Women - and other female mammals - are born with a fixed number of eggs, which remain dormant in the ovaries until the release of a single egg per menstrual cycle. But for women, fertility declines significantly at around the age of 35. "One of the main causes of female infertility is a defect in the eggs that causes them to have an abnormal number of chromosomes. These so-called aneuploid eggs become increasingly prevalent as a woman ages. This is a key reason that older women have trouble getting pregnant and having full-term pregnancies. It is also known that these defective eggs increase the risk of miscarriage and can cause Down's syndrome in full-term babies." Scientists previously believed that eggs are more likely to be aneuploid with age because the "glue" that keeps the chromosomes together works poorly in older eggs. This is known as the "cohesion-loss" hypothesis. "Our work doesn't contradict that idea, but shows the existence of another problem: defects in the microtubules, which cause defective spindles and in doing so seem to contribute to a specific type of chromosome segregation error."

Microtubules are tiny cylindrical structures that organize themselves to form a spindle. This complex biological machine gathers the chromosomes together and sorts them at the time of cell division, then sends them to the opposite poles of the daughter cells in a process called chromosome segregation. "In mice, approximately 50% of the eggs of older females have a spindle with chaotic microtubule dynamics." The researchers conducted a series of micromanipulations on the eggs of mice between the ages of 6 and 12 weeks (young) and 60-week-old mice (old). "We swapped the nuclei of the young eggs with those of the old eggs and we observed problems in the old eggs containing a young nucleus. This shows that maternal age influences the alignment of microtubules independently of the age of the chromosomes contained in the nuclei of each egg." The researchers note that spindle defects are also a problem in humans. In short, the cellular machinery works less efficiently in aged eggs, but this is not caused by the age of the chromosomes.

Link: http://crchum.chumontreal.qc.ca/en/news-briefs/ladies-why-fertility-declines-age

As the publicity materials here note, at least one research group is working on ways to enhance the gene expression of FOXO3, seeing this as a way to favorably adjust the operation of metabolism so as to modestly slow the effects of aging. The researchers have demonstrated enhanced gene expression in mice, but have yet to follow up to show that improved health and longevity result from the application of this method. That might be reasonably expected to occur to some degree, based on other investigations of this gene, and of the particular approach used here.

Researchers have announced the results of an animal study evaluating the effectiveness of a naturally-occurring chemical that holds promise in anti-aging therapy. The Astaxanthin compound CDX-085 (developed by Cardax) showed the ability to significantly activate the FOXO3 gene, which plays a proven role in longevity. "All of us have the FOXO3 gene, which protects against aging in humans. But about one in three persons carry a version of the FOXO3 gene that is associated with longevity. By activating the FOXO3 gene common in all humans, we can make it act like the "longevity" version. Through this research, we have shown that Astaxanthin "activates" the FOXO3 gene." Astaxanthin is a naturally occurring compound found in seafood such as shrimp, lobster, and salmon, and is typically sourced from algae, krill, or synthesis. Multiple animal studies have demonstrated that Astaxanthin reduces inflammation, heart and liver damage, cholesterol levels, and risk of stroke. In humans, Astaxanthin also has been shown to lower inflammation and triglycerides.

For those who have a certain gene (the FOXO3 "G" genotype) there is "extra protection" against the risk of death as you get older, compared to average persons. Using data from the Kuakini Hawaiʻi Lifespan Study, a substudy of the 50-year Kuakini Honolulu Heart Program (Kuakini HHP), and the National Institute on Aging's Health, Aging and Body Composition (Health ABC) study as a replication cohort, researchers found that people with this FOXO3 gene have an impressive 10% reduced risk of dying overall and a 26% reduced risk of death from coronary heart disease over a 17 year period. Data are based on a 17-year prospective cohort study of 3,584 older American men of Japanese ancestry from the Kuakini HHP cohort study and a 17-year prospective replication study of 1,595 white and 1,056 African-American elderly individuals from the Health ABC cohort.

Link: http://jabsom.hawaii.edu/research-university-of-hawaii-reports-ability-of-astaxanthin-to-significantly-activate-fox03-longevity-gene-in-mammals/

Investment in the development of rejuvenation therapies represents an enormous opportunity for profit; these are products for which every adult human being much over the age of 30 is a potential customer at some price point. That is larger than near every existing industry, either within or outside the field of medicine, even given that customers will only purchase such a therapy once every few years, for clearance of metabolic waste, or even just once, for treatments like the SENS approach of allotopic expression of mitochondrial genes. Among the first successful companies in this space, some will grow to become among the largest in the world: I'd wager that the Ford or Microsoft of rejuvenation will be a lot larger than the actual Ford of automobiles or Microsoft of personal computing.

The field of human rejuvenation is also possibly the greatest opportunity for arbitrage ever seen, if we take the most general meaning of that term. The vast majority of people, whether investment professionals or not, greatly undervalue present efforts aimed at the production of rejuvenation biotechnology. They do not have the interest and insight to distinguish between the nonsense of the "anti-aging" marketplace of past years, marginal calorie restriction mimetic drugs, and approaches that target and repair the causes of aging. Only the last of those is capable in principle of producing large and reliable gains in human healthy lifespan, turning back the consequences of aging. The handful of people who do appreciate the possibilities still have a few years to establish positions and invest at a comparatively cheap price before this marketplace becomes a free for all.

It is definitely in our favor for that free for all to happen sooner rather than later, since it will bring a great deal more money to bear on the problem of human aging - a field that is still the poor relation in the medical sciences, looked down upon and given little funding. I suspect it will require senescent cell clearance to reach clinics and be used in hundreds of humans with reliable and public results for that to happen, however. Nonetheless, all fforts to speed matters along are a good thing, and so it is a pleasing to see a strategist like Jim Mellon earnestly advising his peers to enter this space for all the reasons I have given above. The second half of the video here is more concerned with aging, longevity, and rejuvenation therapies than the first half; if you skip ahead to a slide on opinion makers and another on longevity companies, you'll see some names you recognize - including Oisin Biotechnologies, SENS, and the Methuselah Foundation. It is good to hear the voice of an influential group that has performed enough due diligence to appreciate the useful end of the longevity science community, and understand its potential.

Jim Mellon | Main Stage | Master Investor Show 2017

Renowned UK investor and entrepreneur Jim Mellon gives his keynote talk at Master Investor Show 2017. Presenting to a packed-out audience, Jim focuses on longevity as the next 'money fountain' and subject of his forthcoming book, Juvenescence. His engaging, impassionate speech also covers the latest macroeconomic developments and prospects in the U.S. and Europe, and the future trends that could provide returns for investors.

Mann Bioinvest

We believe that over the coming decade the life science sector will be leading one of the most meaningful periods of scientific discovery and advancement. This period of development has been underpinned by two seminal moments - the discovery of the structure of DNA and the sequencing of the human genome; the latter occurring nearly 50 years after the former. Subsequent breakthroughs stemming from the discovery of DNA will give new hope to those with certain diseases who relatively recently would have had none. These breakthroughs are coinciding with a period in which the world's population is undergoing the most ubiquitous and rapid aging in its history. This, we believe, will lead to the life science sector gaining new prominence and that the biggest successes in the sector will ultimately dwarf the likes of Apple, Exxon and BHP that are the current colossi of the stock market.

Lysosomes are the recycling units in the cell, responsible for breaking down damaged structures and proteins into their component parts. Unfortunately, their function declines with age, and most of the evidence associated with this decline indicates that it is important in determining the pace of aging. Less recycling of damaged molecular machinery means greater dysfunction and greater accumulation of further damage. One reason for this progressive failure of lysosomal function, prevalent in long-lived cell populations, is that certain byproducts of metabolism are hard to break down. They accumulate in lysosomes, making them bloated and inefficient. There are numerous other less direct issues as well, associated with the functioning of the cellular maintenance system of autophagy as a whole, not just the lysosome at the end of the recycling path.

As an illustration of that second point, researchers have in the past managed to boost faltering lysosomal function in the aged liver via a gene therapy to increase the number of lysosomal receptors used in the delivery of waste to the lysosome. The research noted here has high-level similarities to that effort, in that researchers are adjusting an aspect of cellular biochemistry that boosts lysosomal activity or efficiency, but without addressing the underlying reasons as to why it fails with age. Nonetheless, some degree of slowed aging and restored tissue function results.

Aging is a phenomenon in which a cell's ability to divide and grow deteriorates as it gets older, and this causes degradation of the body and senile diseases. The inhibition and recovery of aging is an instinctive desire of humans; thus, it is a task and challenge of biologists to identify substances that control aging and analyze aging mechanisms. Researchers have been conducting research to reverse the aging process by shifting the existing academia's 'irreversibility of aging' paradigm. To reverse the aging process, the research team searched for factors that could control aging and tried to discover substances that could restore cell division capacity. As a result, it was confirmed that KU-60019, an inhibitor of ATM protein, which is a phosphorylation enzyme, recovers the functions of aging cells through activation of lysosomal functions and induction of cell proliferation.

The degradation of lysosomes, which are intracellular organelles responsible for autophagy and decomposition of biopolymers such as proteins and lipids in the cell, leads to cell senescence by accumulating biomolecules that must be removed in cells and causes instability of the metabolism such as removal of dysfunctional mitochondria that do not function. The research team was the world's first to confirm that as cell aging progresses, the vacuolar ATPase (v-ATPase) protein involved in the lysosomal activity regulation is phosphorylated by the ATM protein, and the binding force between the units constituting the v-ATPase is weakened, so consequently the function of lysosomes deteriorates.

In addition, the team has proven that the reversible recovery of aging is possible through its experiment that shows the regulation of ATM protein activation by KU-60019 substances induces the reduction of phosphorylation of v-ATPase, thereby inducing recovery of mitochondrial function and functional recovery of the lysosome and autophagy system as well as promoting wound healing in aging animal models.

Link: http://en.dgist.ac.kr/site/dgist_eng/menu/508.do?configNo=96&cmd=read&contentNo=34232

Scientists here report on progress in developing a regenerative therapy for a rotator cuff injuries, a fairly common and troubling problem that is prone to reoccur even following successful surgical treatment. The approach taken is cell therapy combined with a nanoscale scaffold to guide and support the transplanted cells. The researchers claim an unusually robust outcome, which we can hope to be a positive sign for this portion of the field of regenerative medicine. Cell and scaffold approaches are quite varied and widespread, so improvements achieved in the treatment of one type of injury may be applicable to a range of others.

Every time you throw a ball, swing a golf club, reach for a jar on a shelf, or cradle a baby, you can thank your rotator cuff. This nest of tendons connecting your arm bone to your shoulder socket is a functional marvel, but it's also prone to tearing and difficult to surgically repair. Rotator cuff problems are common, with about 2 million people afflicted and about 300,000 rotator cuff repair surgeries every year in the U.S. Surgeons have many techniques to reconnect the tendon to the bone. The problem is that often they don't stay reconnected. In a new study, researchers using a nano-textured fabric seeded with stem cells were able to get torn rotator cuff tendons to regenerate in animals. Not only did the tendons wrapped in the fabric make a better attachment to the bone, they were stronger overall, with a cell structure that looked more like natural, undamaged tissue. Tendons repaired with a purely surgical technique healed with a more disorganized cell structure, which made the tendon itself weaker and more prone to failure.

The combination of the "nano-mesh" with stem cells seems to be critical. Surgeons will sometimes inject stem cells into rotator cuff repairs, but results from this technique are mixed. Stem cells alone don't necessarily stick around at the surgery site. Adding the mesh changes that. The mesh, made of a nanostructured polymer combining polycaprolactone and polyphosphazene provides an attractive habitat for the stem cells to hunker down. Once they settle into the rotator cuff location, the stem cells begin sending out signals directing other cells to align and grow into tendon tissue. Images taken at six and 12 weeks in animals show that torn rotator cuff tissue reorganizes under the influence of the matrix and stem cells. Once the tendon is fully regenerated, the polymer matrix can dissolve. If the combo polymer mesh plus stem cell technique proves durable in human rotator cuff tendons, the researchers won't stop there. "Being able to regenerate complex soft tissues like the rotator cuff is an important step, but we have even bigger goals."

Link: http://today.uconn.edu/2017/04/stem-cell-fabric-innovation-regrows-rotator-cuffs/

The recent announcement of a new approach to selective forcing self-destruction via apoptosis in senescent cells, and the prospects of using it as a therapy to reverse the accumulation of such cells and their contribution to aging, produced a wave of attention from the mainstream media. As is usually the case, little of that attention was well-informed or particularly discriminating when it came to the large differences in expectation value for potential ways to intervene in the aging process. When it comes to impact on age and age-related disease, clearing senescent cells is in a completely different category from, say, calorie restriction and calorie restriction mimetic drugs, but you wouldn't know that if your only source of information is the press.

Aging is caused by accumulated molecular damage of various sorts, damage that occurs as a side-effect of the normal operation of cellular biochemistry. That damage then causes secondary and later forms of damage and dysfunction, a growing chain of cause and consequence that ends with age-related diseases and death. Broadly speaking, there are two approaches to aging as a medical condition. The first, and by far the most common approach is to tinker with the operation of metabolism in order to modestly slow down the accumulation of damage - such as via replicating the calorie restriction response shown to lengthen life in short-lived species. This typically involves drug discovery and mapping cellular biochemistry in search of points at which to intervene, the latter of which is an enormously expensive and slow process. The research community doesn't have anywhere near the level of understanding needed to proceed rapidly in this effort, and this is well illustrated by the past two decades spent in search of ways to safely mimic the calorie restriction response. There is very little of practical use to show for that yet, despite the enormous outlay in time and funding.

The second approach is to repair the molecular damage that is the root cause of aging. Unlike the full extent of cellular biochemistry in metabolism and aging, that damage is well cataloged and well understood - what isn't known are the full details of how it interacts to cause specific manifestations of aging. That knowledge isn't needed in order to produce meaningful outcomes, however. To the extent that funding can be found, the work of repairing this damage could move ahead rapidly. Unfortunately, outside a few areas such as amyloid clearance in Alzheimer's disease and some portions of the stem cell field, this isn't a majority concern in the research community. Even senescent cell clearance, now a very exciting area with a great deal of venture funding for commercial development, was a poorly funded backwater as recently as six years ago. Unfortunately, that is presently the position for other equally important areas of repair, such as clearance of cross-links that damage elasticity in blood vessels and other tissues. There remains a great deal of work to do in order to give repair of the causes of aging the prominence it merits.

The search to extend lifespan is gaining ground, but can we truly reverse the biology of ageing?

It was once a fringe topic for scientists and a pseudo-religious dream for others. But research into the biology of ageing, and consequently extending the lifespan of humans and animals, has become a serious endeavour. The true promise of ageing research is that rather than tackling individual diseases one at a time, a single drug would treat all the diseases that arise in old age, at once. The idea of extending human life makes some uneasy, as preventing death seems unnatural. But this is already happening. Drugs and interventions developed over the past century that have almost doubled human life expectancy could be considered as anti-ageing. But when we talk about an anti-ageing pill, we mean one that targets the process of ageing itself. There is already a list of such drugs shown to extend the lives of lab animals. Many of these work through mimicking the effects of a near starvation diet.

Calorie restriction has for over 80 years been the most well-studied intervention known to delay ageing. The willpower required to maintain a near starvation diet for an entire lifetime is beyond most. But regular, short term calorie restriction has strong benefits for metabolic health. Animal studies show a reliable extension in lifespan during intermittent fasting. Early on, the effectiveness of restricting calories led scientists to hunt for genes that mediated these effects, but the long-term effects of restricting calories on ageing in humans have yet to be fully characterised, and such a study in humans would be difficult to perform.

Another anti-ageing strategy is one called "senolysis": that is, killing off old and damaged or "senescent" cells. These cells take up space, grow larger, and release substances that cause inflammation. When mice are genetically engineered so that it is possible to kill off senescent cells, health is drastically improved and animals live 20 to 30% longer. The hunt is now on for "senolytic" drugs, which can selectively kill off senescent cells. One company, UNITY Biotechnology, recently raised US$116 million to achieve this.

Are You Rich Enough To Live Forever?

The California Health and Longevity Institute (CHLI) is a combination spa, medical clinic, fitness center, and research institution founded in 2006 by David Murdock, a 93-year-old billionaire who made a fortune in real estate and later bought the Dole Foods company, and who has something of an obsession with increasing his time on this earth through the combination of science and lifestyle choices. His successors are numerous. Oracle co-founder Larry Ellison, who has said that "death never made any sense to me," has spent $430 million on anti-aging research; Google founders Sergey Brin and Larry Page launched Calico, a secretive company that's seeking to extend lifespan through genetic research and drug development. Ex-financier and philanthropist Michael Milken is funneling money toward speeding up the development of drugs and other medical treatments for the chronic diseases associated with aging, and Jeff Bezos has just invested in a company called UNITY Biotechnology that is "targeting cellular mechanisms at the root of age-related diseases."

Meanwhile, PayPal co-founder and early Facebook investor Peter Thiel's Breakout Labs funds companies trying to extend the useful life of various body parts; Thiel himself has reportedly given millions to a foundation aiming to increase the human life-span. I wondered aloud why anti-aging research is happening in such concentration around the city and why so much of it is funded with tech money. "I think there's a fundamental optimism here that doesn't exist in other places. Silicon Valley is full of the kind of people who think that being rejected 43 times is not a reflection of their likelihood of success." That's precisely the attitude required to believe that death can be forestalled, or even foiled.

At the Buck Institute 180 scientists work to develop therapies to slow aging. One of them is Judith Campisi, a cancer researcher who, years back, began studying senescent cells-cells that have stopped dividing. Initially senescence wasn't thought of as bad but rather as the alternative to cells becoming cancerous. But she started to think the people in her field had it all wrong-that senescent cells were dangerous because they were oozing yucky stuff that caused inflammation in the body. (One of the hallmarks of aging is that the body carries around more inflammation, which is a major factor in, if not the cause of, age-related diseases, including cancer and heart and liver disease.) Senescent cells, Campisi and colleagues found, were essentially polluting their neighbors, causing time's ravages. Last year Campisi helped found UNITY Biotechnology, a lifespan-enhancing biotech firm in San Francisco that had received $20 million in financing even before Jeff Bezos jumped in. "We're trying to devise ways now to tame that secretory characteristic of the cell. The other next step is to make them go away."

The immune cells known as macrophages roam our tissues in search of debris and malfunctioning cells to engulf and break down. When they encounter something that they cannot handle, however, they start to become a part of the problem that they are attempting to solve. This is perhaps most apparent in the development of atherosclerosis, when macrophages attempt to sweep up damaged lipids and in the process become foam cells, packed so full of fats and cholesterols that they cannot function properly. The plaques that form in blood vessels walls as a part of the progression of atherosclerosis are in large part comprised of foam cells, the remains of previous foam cells, and the lipids that they tried and failed to clean up.

How is it that a macrophage can get itself into this state, taking in so much waste and debris that it simply falls apart? The paper here examines that question, albeit with a focus on how macrophages engulf fat cells elsewhere in the body. The end result is much the same, in the sense that the macrophage becomes bloated by lipids and in consequence becomes a harmful foam cell. This transformation only adds to any ongoing problems in the tissue that required the presence of a macrophage in the first place.

Macrophage interactions with adipocytes are important both in states of metabolic dysfunction and in healthy adipose tissue expansion and remodeling. Despite this importance, our understanding of macrophage-adipocyte interactions is incomplete. It is known that adipose tissue macrophages transform into foam cells and drive the inflammatory changes that occur in adipose tissue, and it appears that macrophages play a protective role in adipose homeostasis, but mount a maladaptive immune response in the setting of obesity. In the setting of obesity, it has been proposed that hypertrophic adipocytes release triglycerides and nonesterified fatty acids that the macrophage can then passively internalize using standard endocytic mechanisms. However, in this study, we show that, rather than endocytosis of released lipids, the macrophages themselves actively participate in lipid liberation from the adipocyte.

Our laboratory and others have described a process in which large moieties or species tightly bound to the extracellular matrix are initially digested by macrophages in an extracellular acidic lytic compartment. We describe this process as exophagy. We have studied exophagy in the context of macrophage degradation of aggregated low-density lipoprotein (LDL), as occurs during atherogenesis. Exophagic catabolism of aggregated LDL results in uptake of cholesterol by the macrophage, leading to foam cell formation. While foam cell formation has been an area of extensive study in the atherosclerosis field, macrophage foam cell formation in adipose tissue has only been reported recently. Given the similarities between these two systems, we examined whether exophagy could be responsible for macrophage degradation of dead adipocytes. This would allow extracellular catabolism and subsequent uptake of pieces of the adipocyte, facilitating macrophage foam cell formation as a consequence of clearing dead adipocytes. Exophagy-mediated foam cell formation is a highly efficient means by which macrophages internalize large amounts of lipid, which may overwhelm the metabolic capacity of the macrophage, as has been demonstrated in the setting of atherosclerosis, leading to a maladaptive inflammatory response. This biology may have particular relevance during clearance of dramatically enlarged adipocytes, as occurs in the setting of obesity.

Here, we demonstrate that adipose tissue macrophages form an extracellular acidic hydrolytic compartment containing lysosomal enzymes delivered via exocytosis. Initial catabolism of the dead adipocyte occurs in these extracellular compartments, allowing the macrophage to internalize pieces of the adipocyte and transform it into a foam cell. We show that macrophage foam cell formation is specific to interaction with dead or dying adipocytes and is blocked when exophagy is inhibited.

Link: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4878183/

As examinations of aging go, this open access overview of kidney decline and kidney disease is more focused on the mechanics of the problem than most, which makes it an interesting read. As a bonus, it opens by touching on the thorny topic of whether aging is a disease, and where the arbitrary boundary lies between aging and disease. Kidney disease is not as large a problem in our species as heart disease and cancer, but that is only because most people are killed by something else first. Age-related fibrosis eats away at kidney tissue until there is no longer enough left fully functional to do its job. It is an unpleasant decline, and modern medicine has little in the way of effective interventions. It is to be hoped that near future therapies capable of clearing senescence cells will have a significant positive impact on fibrosis in all organs, and thus prove to be useful treatments for kidney aging, but the proof of that remains to be accomplished.

Aging is a universal biological phenomenon, except perhaps in the genus Hydra, which appears to be immortal. As such, it is difficult to label aging as a disease, at least when a departure from "normality" is a criterion for a disease. The fundamental processes responsible for aging are still incompletely understood, but environment, genes and chance all play important roles. These processes can be accelerated by diseases which tend to aggregate in older persons, such as diabetes, cancer, hypertension and atherosclerosis, largely because the aged have had more time to acquire these degenerative diseases. When one attempts to define these diseases in the older person, it is frequently necessary to adjust criteria for what might be expected from chronological aging per se; for example in the detection of osteoporosis by DEXA scanning or for detection of chronic obstructive pulmonary disease by spirometry. The disentangling of the intertwined phenomena of age-related disease and physiologic aging can be difficult and challenging. As succinctly captured by Tom Kirkwood in 1999, "grasping the correct distinction between normal aging and disease smacks of a semantic quibble, but words are powerful and the consequences of how we use them can be far-reaching".

The kidneys age in a stereotypical fashion, affecting many aspects of their function, such as glomerular filtration rate (GFR). The aggregate GFR of both kidneys (wkGFR) is equal to the product of the number of functioning nephrons (NN) and the average GFR of single nephron (snGFR). Although difficult to study in humans, the investigation of values for the elements of this equation, according to healthy (physiologic) aging, has yielded some interesting findings. We are all born with a complement of nephrons determined in large part by the process of nephrogenesis in utero. Thus, one can only lose, not gain nephrons as one ages and the NN at any age is determined by NN at birth (nephron endowment) and the rate of post-natal loss of nephrons. Among 1638 living donors in a past study, an average adult 18-29 years old has about 1,008,000 glomeruli per kidney, 991,000 of which are presumably functioning and 17,000 of which have undergone a scarring process known as focal and global glomerulosclerosis (FGGS).

Thus, according to the equation above, if the wkGFR for two kidneys is 110ml/min, the average snGFR of the functioning nephrons in a healthy young adult is about 55 nl/min. By age 70-75 years the average number of glomeruli per kidney has declined to about 660,000, of which 520,400 are presumably functioning and 142,000 have undergone FGGS. If the normal wkGFR for a healthy 70-75 year old is about 75 ml/min (a loss of 35 ml/min over 5 decades), then the average snGFR is about 57 nl/min, not much different than an adult 50 years younger. Note that the absolute total number of non-sclerotic and sclerotic nephrons decrease by 35% with aging, so some nephrons must have been completely resorbed, as a consequence of atrophy and sclerosis. If these derived values represent the true state of renal physiology in the aging kidney, then healthy aging is associated with a substantial decline (35%) in total glomeruli, and an even greater number of functioning (non-sclerotic) glomeruli with aging about 48% (from 991,000 per kidney to 520,400 per kidney) over 50 years.

The mechanisms underlying this loss of nephrons with healthy aging remain uncertain, but unlike nephron loss accompanying surgical reduction of nephron mass or certain disease states associated with loss of function nephron number, the reduction of functioning nephrons in aging is not apparently accompanied by a compensatory increase in snGFR of surviving nephrons, at least not until the extremes of age have been attained. In addition, it seems that factors in addition to aging per se are responsible for the observed nephron loss other than age per se. The loss of nephrons is accompanied by interstitial fibrosis proportional to the severity of FGGS, and by tubular hypertrophy that somewhat attenuate the loss of cortical volume seen in aging kidneys.

Link: http://www.scielo.br/scielo.php?script=sci_arttext&pid=S0101-28002017000100059