Fight Aging!

Telomerase provides the primary mechanism by which cells lengthen their telomeres. In our species only stem cells and cancer cells do this, while in mice more types of cell use more telomerase. Telomere length determines the limit to cell divisions, a little of the length being lost each time a cell divides. Cells that can lengthen their telomeres can continue dividing indefinitely, and that is how stem cells can continually deliver a useful supply of daughter cells to support surrounding tissues. It is also how cancer grows. Cancer and regeneration are the two sides of the same coin of growth and regeneration, one controlled, the other uncontrolled. Thus, broadly speaking, there are two things that can be done with telomerase in medicine, and both projects, while in the comparatively early stages, have a fair number of research groups involved.

Firstly, blocking the ability of telomerase to lengthen telomeres is the larger part of the basis for a universal cancer therapy. Some 90% of cancers abuse telomerase in order to grow and spread. If that can be shut down, then the cancer will be halted in its tracks - any cancer. The challenge of cancer research is not that it is hard and expensive, but rather that most approaches to treating cancer are highly specific to just a few types out of the hundreds of forms of cancerous tissue. This is a poor strategy. Meaningful progress towards defeating cancer will require the development of therapies that can instead be applied to many, or for preference all cancers. Thus blocking telomere lengthening has the potential to completely change the economics of the field, making it feasible to bring an end to cancer within our lifetimes and within the present budget allocated to that goal.

Secondly, taking the opposite approach to increase the activity of telomerase may prove to be a way to enhance regeneration and tissue maintenance, and therefore compensate for the onset of aging and age-related degeneration. In animal studies the outcome of additional telomerase is somewhat analogous to the effects of stem cell therapies, in that cellular activity increases to produce greater healing than normally take place. This is of particular interest in the old, who suffer in part because stem cell activity declines with age, and frailty and organ failure encroaches as a result. Telomerase gene therapies have been used to extend life in mice, and have the secondary effect in that species of reducing cancer rates. This second item is a very interesting outcome, given the role of telomerase in cancer, and we might speculate that it occurs because of improved immune function - enough of a benefit there to counteract any increased cancer risk as old and damaged cells are given the opportunity to do more and divide more often. There is uncertainty as to whether the outcomes in mice reflect the balance of effects that would occur in humans, since mice have a very different balance of telomerase activity. Investigations are ongoing, and great deal remains to be explained.

Therapeutic Targeting of Telomerase

Telomere length and cell function can be preserved by the human reverse transcriptase telomerase (hTERT), which synthesizes the new telomeric DNA from a RNA template, but is normally restricted to cells needing a high proliferative capacity, such as stem cells. Consequently, telomerase-based therapies to elongate short telomeres are developed, some of which have successfully reached the stage I in clinical trials. Telomerase is also permissive for tumorigenesis and 90% of all malignant tumors use telomerase to obtain immortality. Thus, reversal of telomerase upregulation in tumor cells is a potential strategy to treat cancer.

Natural and small-molecule telomerase inhibitors, immunotherapeutic approaches, oligonucleotide inhibitors, and telomerase-directed gene therapy are useful treatment strategies. Telomerase is more widely expressed than any other tumor marker. The low expression in normal tissues, together with the longer telomeres in normal stem cells versus cancer cells, provides some degree of specificity with low risk of toxicity. However, long term telomerase inhibition may elicit negative effects in highly-proliferative cells which need telomerase for survival, and it may interfere with telomere-independent physiological functions. Moreover, only a few hTERT molecules are required to overcome senescence in cancer cells, and telomerase inhibition requires proliferating cells over a sufficient number of population doublings to induce tumor suppressive senescence. These limitations may explain the moderate success rates in many clinical studies.

Despite extensive studies, only one vaccine and one telomerase antagonist are routinely used in clinical work. For complete eradication of all subpopulations of cancer cells a simultaneous targeting of several mechanisms will likely be needed. Possible technical improvements have been proposed including the development of more specific inhibitors, methods to increase the efficacy of vaccination methods, and personalized approaches.

Telomerase activation and cell rejuvenation is successfully used in regenerative medicine for tissue engineering and reconstructive surgery. However, there are also a number of pitfalls in the treatment with telomerase activating procedures for the whole organism and for longer periods of time. Extended cell lifespan may accumulate rare genetic and epigenetic aberrations that can contribute to malignant transformation. Therefore, novel vector systems have been developed for a 'mild' integration of telomerase into the host genome and loss of the vector in rapidly-proliferating cells. It is currently unclear if this technique can also be used in human beings to treat chronic diseases, such as atherosclerosis.

It is important to note that therapies like telomerase enhancement or stem cell transplants do little to nothing to address a range of other issues that cause age-related disease. Age-related changes such as mitochondrial DNA damage, persistent cross-links, and the accumulation of other metabolic waste such as lipofuscin are not going to be meaningfully affected. Each of those individually probably causes enough harm to kill people. So while adjusting stem cells and regeneration can be beneficial, it does not repair these forms of underlying damage, and thus is limited in the degree to which it can turn back the clock. A good way to look at this is in terms of the stem cell therapies now becoming more widely available that address joint paint and dysfunction. They help many patients to a greater degree than any other form of therapy presently available. They do not and cannot remove liver spots or undo macular degeneration, or turn back stiffening of arteries and loss of elasticity of skin, all items driven by the forms of damage noted above. Rejuvenation will in the end require a complete toolkit.

Alzheimer's disease is associated with the aggregation of misfolded amyloid-β and tau proteins. The consensus position is that these aggregates are the primary cause of pathology, though the biochemistry involved is exceedingly complex and still being mapped. A sizable faction in the research community is working on immunotherapies to clear out misfolded amyoid, tau, or both, though so far this has proven to be more challenging than hoped. One of the potential issues is the risk of such a therapy generating greater inflammation in a patient whose condition is already inflammatory. This article gives an overview of one line of research into tau immunotherapies, and notes a recent step forward towards solving the inflammation problem:

The tangled buildup of tau protein in brain cells is a hallmark of the cognitive decline linked with Alzheimer's disease. Antibodies have been shown to block tau's spread, but some scientists worry it could also fuel inflammation. Now, researchers have found that an antibody's ability to recruit immune cells - known as its effector function - is not necessary for stopping tau's spread. Alzheimer's disease causes a characteristic constellation of pathologies: accumulation of amyloid-β plaques outside neurons, neurofibrillary tangles of tau inside brain cells, and chronic inflammation. Clinical research has mostly focused on targeting amyloid-β with antibody therapies, and several treatments based on this approach are currently in clinical trials. But recent efforts have zeroed in on tau as a new potential target.

Antibodies are known to spur the brain's defense system, microglia, to absorb and degrade tau, but their recruitment of immune cells may also worsen inflammation. Researchers wondered whether effector function was necessary for stopping tau's spread. To find out, the researchers raised transgenic mice that develop a tau pathology similar to that seen in Alzheimer's disease. The team treated the animals with antibodies that had either strong effector function or none at all. The animals that received antibodies with no effector function were able to clear tau as effectively as those that received full-effector function antibodies. "Low and behold, we don't need effector function in order to achieve a halting of accumulation of tau pathology." The findings suggest the antibodies could have an indirect effect on microglial activation, and may be unnecessary for therapeutic effect. The findings are likely to reignite an ongoing debate in the field over whether antibodies target tau inside or outside brain cells.

Link: http://www.the-scientist.com/?articles.view/articleNo/46677/title/Toward-an-Immunotherapy-for-Alzheimer-s-Disease/

One approach to regenerative medicine is to use donor extracellular matrix as a scaffolding material. The extracellular matrix is the support structure created by cells that determines the structural properties of a tissue. Its presence in a regenerative therapy can guide cells to rebuild lost tissue to some degree, but a better understanding of how this actually works under the hood could be used to improve the quality of the outcome, as well as to hopefully allow the development of a viable artificial replacement for natural donor matrix materials.

Researchers have identified a mechanism by which bioscaffolds used in regenerative medicine influence cellular behavior, a question that has remained unanswered since the technology was first developed several decades ago. Bioscaffolds composed of extracellular matrix (ECM) derived from pig tissue promote tissue repair and reconstruction. Currently, these bioscaffolds are used to treat a wide variety of illnesses such hernias and esophageal cancer, as well as to regrow muscle tissue lost in battlefield wounds and other serious injuries.

Researchers know that ECM is able to instruct the human body to replace injured or missing tissue, but exactly how the ECM material influences cells to cause functional tissue regrowth has remained a fundamental unanswered question in the field of regenerative medicine. In the new study, the team showed that cellular communication occurs using nanovesicles, extremely tiny fluid-filled sacs that bud off from a cell's outer surface and allow cells to communicate by transferring proteins, DNA and other "cargo" from one cell to another. Exosomes are present in biological fluids such as blood, saliva and urine, where they influence a variety of cellular behaviors, but researchers had yet to identify them in solid body tissues. "We always thought exosomes are free floating, but recently wondered if they are also present in the solid ECM and might facilitate the cellular communication that is critical to regenerative processes."

To explore this possibility, researchers used specialized proteins to break up the ECM, similar to the process that occurs when a bioscaffold becomes incorporated into the recipient's tissue. The research team then exposed two different cell types - immune cells and neuronal stem cells - to isolated matrix bound vesicles, finding that they caused both cell types to mimic their normal regrowth behaviors. "Sure enough, we found that vesicles are embedded within the ECM. In fact, these bioscaffolds are loaded with these vesicles. This study showed us that the matrix bound vesicles are clearly active, can influence cellular behavior and are possibly the primary mechanism by which bioscaffolds cause tissue regrowth in the body."

Link: http://www.eurekalert.org/pub_releases/2016-07/uops-prs072816.php

Whenever looking at correlations between behavior and lifespan, or behavior and health, one should always ask whether calorie intake or physical activity level could be involved. Both animal and human studies tell us that the effects of both of these items are large in comparison to almost all other commonly varying factors, with smoking being one of the few exceptions to that rule. In recent years, the growing use of accelerometers rather than self-reporting in studies of exercise have revealed that even quite modest physical activity correlates with a sizable difference in outcomes in later life. Animal studies tell us that exercise does in fact cause improvements in health and at least healthy life span if not maximum life span. It is very hard to pull out causation from human statistics, but it is reasonable to arrange one's life on the basis that causation in other mammals matches up with causation in humans in this matter.

Retirement as an institution has interesting correlations with life span, especially in those countries where it is voluntary, and people are not forced into it, pushed out of their own lives by uncaring bureaucrats. More than one set of research results indicates that retirement is bad for health, and there is the suggestion that this might be because of declining physical activity. Certainly it is easy enough to point to correlations between ill health and retirement - people who age more rapidly or become ill and frail will certainly retire at much higher rates. Much of this research goes beyond the event of retirement itself to look at what happens later, however, and that is where suggested causation emerges from the data.

The open access paper I'll point out today might be taken to indicate that most earlier studies of this nature are perhaps overly simplistic. There are many life paths to consider: an obese individual who retires due to ill health is in a very different bracket of influences and outcomes from a thin individual who transitions from a desk job to actively gardening during the day. Some groups of people do actually undertake more physical activity following retirement. The paper itself splits out retirees into a fair number of categories, and it is worth looking through to find the tables and charts. What we might take away from this is a reminder that rejuvenation therapies are on the horizon, some already in early clinical development, and for many of us a few years here or a few years there may wind up being the difference between living to benefit or dying just at the verge of the new era of treatments for the causes of aging.

Does retirement mean more physical activity? A longitudinal study

Participation in physical activity declines with age concurrent to an increasing risk of preventable health conditions like type 2 diabetes. Yet physical activity is widely recognized as crucial for strengthening and maintaining physical and mental health during aging. Some transitions out of the labor market, such as retirement and semi-retirement, may free up time that could be used to (re) engage in physical activity. Retirement can be seen, therefore, as a potentially sensitive period in the lifecourse to target interventions for promoting healthy ageing. Evidence on physical activity during retirement from cross-sectional studies is mixed and limited by the spectre of reverse causality. Some longitudinal studies have the potential to approximate the transition to retirement, so should be regarded as higher quality evidence. Of the longitudinal studies, some have attempted to isolate the impact of retirement on leisure-time physical activity specifically. Others have investigated whether trajectories in physical activity across retirement vary by indicators of socioeconomic circumstances. Findings remain equivocal, however, providing no firm answer on how retirement affects participation in physical activity.

Accordingly, the purpose of this longitudinal study was to examine participation in different intensities of physical activity among people transitioning out of full-time employment to different forms of retirement, while also accounting for transitions to unemployment, part-time work, or disability status. Data was obtained for 5,754 people in full-time employment aged 50-75 from the US Health and Retirement Survey. Logistic regression was used to examine trajectories in twice-weekly participation in light, moderate and vigorous physical activity among those transitioning to part-time work, semi-retirement, full retirement, or economic inactivity due to disability, in comparison to those remaining in full-time employment.

Twice weekly participation in vigorous and light physical activity changed little for those who remained in full-time employment, while moderate physical activity decreased between baseline and follow-up. Differences in physical activity according to transitional categories at follow-up were evident. Baseline differences in physical activity across all intensities were greatest among participants transitioning from full-time to part-time employment compared to those who remained in full-time employment throughout the study period. Those transitioning to unemployment were already among the least physically active at baseline, irrespective of intensity. Those transitioning to full-time retirement were also among the least active. Declines in physical activity were reported for those transitioning to economic inactivity due to a disability. Physical activity increased regardless of intensity among participants transitioning to semi-retirement and full retirement. Light physical activity increased for those transitioning to unemployment, though less change was evident in moderate or vigorous physical activity.

Insufficient physical activity is suggested to cause 6% of coronary heart disease, 7% of type 2 diabetes, 10% of breast cancer, 10% of colon cancer, and 9% of premature mortality. Although finding opportunities to promote the initiation and maintenance of physically active lifestyles is needed across the lifecourse, this study supports previous evidence that indicates the process of retirement as one such time period. Inevitably, the findings raise questions and hypotheses requiring analyses that are beyond the remit of the paper and, in some cases, also the data available. For example, is the rise in physical activity regardless of intensity among people moving into semi-retirement due to less time spent in employment? Why are people who move into part-time work already more physically active than their counterparts who remained in full-time work? Is the rise in light physical activity among people who become unemployed sustained among those who re-enter some level of employment? What factors buffer the potential impact of disability on the substantial decreases in physical activity? What types of activities do people become more or less engaged in and are there differences between transitional groups? To what extent do changes in physical activity coinciding with the transition out of full-time employment reflect personal choices versus any number of possible competing demands upon time, including informal caring and volunteering? This is not an exhaustive list and it is clear that much remains unknown. Yet, the need to promote physical activity in ageing populations remains a pressing concern and these hypotheses warrant investigation in order to target future interventions accordingly.

There are always many ways to influence any specific process in cells and tissues. When it comes to enhanced muscle growth, the most popular approaches so far are myostatin inhibition, such as via gene knockout or the use of antibodies, or increased levels of the myostatin inhibitor follistatin. Both of these have been shown to greatly increase muscle mass in a number of species, and are thus potential treatments to compensate for the loss of muscle mass and strength that occurs over the course of aging. Physical weakness is a large component of age-related frailty, and even partially removing that part of the aging process is a worthy goal. The research group noted here has taken a different approach to this area of biochemistry, targeting smad7 to inhibit processes that break down muscle tissue:

"Chronic disease affects more than half of the world's population. It occurs with chronic infection, muscular dystrophy, malnutrition and old age. About half the people who die from cancer are actually dying from muscle wasting. What kills a lot of people isn't the loss of skeletal muscle but heart muscle. The heart literally shrinks, causing heart failure." In cachexia, tumors secrete hormones that cause muscle deterioration; in effect, the body eats its own muscles, causing weakness, frailty and fatigue. Researchers have long sought to stop this process, but failed to find a safe way. That's because the hormones that cause wasting - in particular, a naturally occurring hormone called myostatin - play important roles elsewhere in the body.

So researchers needed a way to stop myostatin, but only in muscles. Their solution: an adeno-associated virus - a benign virus that specifically targets heart and skeletal muscle. The virus delivers a small piece of DNA - a signaling protein called Smad7 - into muscle cells. Smad7 then blocks two signaling proteins called Smad2 and Smad3, which are activated by myostatin and other muscle-wasting hormones. By blocking those signals, Smad7 stops the breakdown of muscles. "Smad7 is the body's natural break and, by inhibiting the inhibitor, you build muscle." In 2015, the researchers launched AAVogen, a company that will develop this discovery into a commercial drug, AVGN7.

Link: https://news.wsu.edu/2016/07/26/scientist-develops-gene-therapy-muscle-wasting/

Researchers here note that leukotriene receptor antagonists appear to reduce inflammation and increase plasticity in the brains of rats. They pin down the receptor GPR17 as a protein of interest in this effect. While not directly addressing underlying damage and change that causes inflammation and loss of neural plasticity, it is possible that this type of approach may produce sufficient benefits in humans to merit development. The same arguments apply here as for other classes of therapy that improve tissue maintenance without doing much to reduce the molecular damage that drives aging, such as stem cell transplants. There are clearly meaningful benefits in that case, and so long as this sort of research and development doesn't result in the abandonment of attempts to repair damage and thus halt and reverse aging, it is worth pursuing.

Counteracting some, or ideally all, of such age-related changes might rejuvenate the brain and lead to preservation or even improvement of cognitive function in the elderly. The feasibility of such an approach was recently demonstrated by experiments exposing the aged brain to a young systemic environment, that is, young blood, through heterochronic parabiosis. The aged brain responded to young blood by reduced microglia activation, enhanced neurogenesis, and importantly, by improved cognition. Vice versa, old blood caused premature ageing of the young brain and led to impaired cognition. A proteomic approach identified eotaxin, a chemokine involved in asthma pathology, as one of the molecules that is elevated in ageing and that contributes to neuroinflammation, reduced neurogenesis and to impaired cognition. This triggered us to hypothesize that, aside from eotaxin, additional mechanisms that are originally related to peripheral inflammatory conditions such as asthma might act or even be present in the central nervous system (CNS), where they potentially modulate degenerative and regenerative events.

Leukotriene signalling is well studied in the field of asthma. Leukotrienes mediate inflammatory reactions associated with increased vascular permeability, and leukotriene receptor antagonists such as the drug montelukast have been successfully developed to treat asthmatic patients. The role of leukotrienes in the brain, in particular their contribution to degeneration and regeneration, is less clear and sometimes even controversial. Nevertheless, elevated levels of leukotrienes were reported in acute as well as chronic CNS lesions, and also in the aged brain, where they might mediate neuroinflammatory responses including microglia activation. Here, we demonstrate that montelukast reduces neuroinflammation, restores blood-brain barrier integrity and increases neurogenesis specifically in the brain of old rats, the latter being mediated through inhibition of the GPR17 receptor. Most importantly, montelukast treatment restores cognitive function in the old animals, paving the way for future clinical translation for the treatment of dementias.

The effect on neurogenesis was, like the anti-inflammatory activity, specific to old rats. Thus, montelukast might stimulate neural progenitor proliferation only in situations in which neurogenesis is compromised. Montelukast might liberate progenitors from age-associated inhibitory mechanisms, which most likely include elevated levels of leukotrienes. Obviously, the extrapolation of these results from normal ageing to neurodegenerative diseases is intriguing, and some of the beneficial effects of montelukast in animal models of neurodegeneration might well be attributed to enhanced neurogenesis. In general, a clear dissection between neurogenesis- and neuroinflammation-mediated effects on cognition is not straightforward as neurogenesis and neuroinflammation strongly influence each other. For example neural progenitors induce microglia proliferation and activation, and vice versa, microglia regulate adult hippocampal neurogenesis.

Link: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4639806/

Occasionally I'll post research that is only tenuously relevant to aging, but nonetheless fascinating. That is the case for this article and open access paper on a fairly new and still poorly understood area of telomere biology. The researchers link exercise to the generation of TERRA, or telomeric repeat-containing RNA, which might lead to all sorts of speculation among long-time readers here. Exercise, telomere length, and aging are all in the same general bucket of items with many established links. Speculation is all that can be done by onlookers at the present time, however, given that the research community has yet to establish firm connections leading from TERRA to any of the behaviors of telomeres and, separately, exercise that are known to be relevant in aging. Still, reading through gives a good sense of just how complex the situation is under the hood. There are no simple relationships in biochemistry.

Telomeres are repeating DNA sequences that cap the ends of chromosomes. Every time a cell divides a little of the telomere is lost as the cell's DNA is replicated. When the remaining telomeres become too short the cell self-destructs or becomes senescent. This is a part of the Hayflick limit, which has evolved to ensure that most cells can only replicate so many times. Every tissue consisting of such limited cells is supported by a much smaller population of stem cells, which use telomerase to lengthen their telomeres and thus consistently produce an ongoing supply of new cells with long telomeres to replace those that reach their limits. The situation in which only some cells are privileged to divide indefinitely exists because it keeps cancer rates low enough for complex long-lived species to exist and evolve. These days telomere length and telomerase are hot topics in aging research, though not all of it is entirely justified to my eyes. Telomerase gene therapies have been shown to extend life in mice, which may be a result that works along the same lines as stem cell therapies, by increasing the activity of cells and maintenance of tissues. Average telomere length declines with age, but this is a statistical relationship across populations, of limited use for individual diagnosis. Telomere length seems very much like a marker and not a cause of aging.

Telomeres are DNA, and DNA encodes blueprints for proteins. A part of the process of gene expression by which proteins are created is transcription, wherein DNA is used as the pattern to produce RNA molecules. Are telomeres transcribed just like the rest of the nuclear DNA? Yes, as it turns out. Telomeric DNA is transcribed to produce TERRA molecules. What does TERRA do? That is an interesting question with few firm answers at the present time, but a lot of leads and maybes. Telomeres are not just passively sitting there: they encode for RNA, and that RNA does things. By linking TERRA to exercise, known to improve health via a variety of mechanisms, there is the thought that perhaps there are more direct connections than previously thought between changing telomere length and the various options like exercise and calorie restriction known to slow the progression of aging. It is particular interesting, for example, that TERRA may regulate the activity of telomerase, though as for much of the other results relating to TERRA this is fairly tentative and subject to revision. Is this all really relevant to the future of our lives, however? Probably not, as exercise, calorie restriction, and similar ways to modestly slow aging are not the gateways to human rejuvenation. They do too little to address the forms of damage that cause aging, and only repair of that damage, rather than merely slowing it down, can greatly extend life. But that said, this is a most interesting space in the study of cellular biology.

Exercise Boosts Telomere Transcription

When healthy individuals perform a cardiovascular workout, their muscles increase transcription of telomeres. A novel transcription factor appears to promote telomere transcription and provides the first direct evidence that telomere transcription is linked to exercise and metabolism in people. Telomeres were thought to be transcriptionally silent until several years ago when researchers found that mammalian telomeres, including human ones, are readily transcribed into telomeric repeat-containing RNA (TERRA). These RNA molecules have been shown to associate with telomeres but whether and how TERRA can protect telomeres - the repetitive sequences at the ends of linear chromosomes that form a sort of aglet to protect the structures - or promote the lengthening of the ends of chromosomes is not yet fully understood.

Researchers first analyzed human telomeric sequences for potential transcription factor binding sites. The researchers identified a potential binding site for the transcription factor nuclear respiratory factor 1 (NRF1), then confirmed its ability to bind the ends of chromosomes in human cancer cell lines. Because NRF1 is activated when stores of ATP are depleted, as during exercise, the team next enlisted 10 young and healthy volunteers to a low- or high-intensity workout on a stationary bicycle for 45 minutes. The researchers took muscle biopsies and blood samples prior to, right after, and 2.5 hours after the exercise. TERRA levels were increased 2.5 hours after both the low and high intensity workouts and were highest after the high intensity exercise. This is the first evidence that telomeres are transcribed in non-dividing human tissue. Exercise produces reactive oxidative species (ROS) that may damage telomeres. The researchers are now addressing the hypothesis that the TERRA molecules produced from NRF1-dependent telomere transcription may act as scavenger molecules that react with the ROS, protecting the telomere itself from oxidation. "As it is not yet established what role TERRA plays at mammalian telomeres, it is premature to speculate on the effect of NRF1 and TERRA upregulation in exercise on telomere biology or aging."

Nuclear respiratory factor 1 and endurance exercise promote human telomere transcription

DNA breaks activate the DNA damage response and, if left unrepaired, trigger cellular senescence. Telomeres are specialized nucleoprotein structures that protect chromosome ends from persistent DNA damage response activation. Whether protection can be enhanced to counteract the age-dependent decline in telomere integrity is a challenging question. Telomeric repeat-containing RNA (TERRA), which is transcribed from telomeres, emerged as important player in telomere integrity. However, how human telomere transcription is regulated is still largely unknown.

We identify nuclear respiratory factor 1 and peroxisome proliferator-activated receptor γ coactivator 1α as regulators of human telomere transcription. In agreement with an upstream regulation of these factors by adenosine 5′-monophosphate (AMP)-activated protein kinase (AMPK), pharmacological activation of AMPK in cancer cell lines or in normal nonproliferating myotubes up-regulated TERRA, thereby linking metabolism to telomere fitness. Cycling endurance exercise, which is associated with AMPK activation, increased TERRA levels in skeletal muscle biopsies obtained from 10 healthy young volunteers. The data support the idea that exercise may protect against aging.

The SENS Research Foundation is currently raising funds for the next step in its cancer research program: building one of the necessary foundations for a universal cancer therapy, one form of treatment that can in principle halt all types of cancer. This requires putting a stop to the lengthening of telomeres in cancer cells, as without that ability cancer tissue cannot grow and spread. This is the one actionable common mechanism shared by all cancers. Cancer cells can use telomerase or alternative lengthening of telomeres (ALT) to extend telomere length, and while some research groups are working on telomerase inhibition, it is unfortunately the case that very few people are working on ALT. Since it has been demonstrated in mice that telomerase cancers can become ALT cancers, both approaches are needed to build a truly universal cancer treatment. Thus the SENS team has stepped in to fill the gap, and needs our help to raise the funds to make this happen.

The Major Mouse Testing Program staff writers took the opportunity to catch up with SENS Research Foundation's Dr. Haroldo Silva who is leading the OncoSENS campaign seeking cures for ALT Cancer.

I saw the article "Control ALT, Delete Cancer" about this project that you co-wrote in April, 2015. Why are you only now starting the crowdfunding effort?

Because we are now at the point where our hard work paid off and we were able to overcome most of the technical hurdles associated with making our novel ALT-specific assay compatible with robotic/automation methods. This is essential to performing high-throughput and large-scale screening studies. We will be measuring a particular biomarker that has only been observed in ALT cancers, namely C-circles, which are circular pieces of DNA containing a repetitive sequence only found at the ends of chromosomes (i.e., telomeres). The more ALT activity is present in a given cancer, the higher the levels of C-circles present in them. Therefore, once we exposed the ALT cancer cells to different compounds we will measure C-circle content quickly to assess if any of the compounds was able to inhibit the ALT pathway.

If your screening does find a promising compound, what do you plan to do with it? Will you patent its anti-ALT properties?

After exhaustive validation of the initial positive screening results, the next step will depend on the nature of the particular compound. If it is currently used in patients for cancer or any other indications we could approach the company that commercializes it to start a joint development program focused on ALT cancer therapy. Otherwise we will explore alternative ways of moving the development of these potential therapies into the private sector. We will absolute aim to patent any compounds that we find helpful in the fight against cancer whenever possible. It takes an average of 12 years for a compound to go from discovery to clinical use in the US. Now, it is possible to reduce that time significantly in case the promising compound we find in our screening is either already approved for clinical use or has been through extensive clinical trials. We will be testing such compounds as part of our screening as explained above. Alternatively, we could target initially ALT cancers that affect less than 200,000 patients in the US in order to obtain orphan drug designation, which can significantly expedite the approval process. This would pave the way for bringing therapies to more common ALT cancers.

How many other groups have also looked at ways to inhibit ALT?

There are very few research groups performing ALT-related cancer research worldwide, especially when you compare it to the amount of scientific output from telomerase-based cancer research efforts. Even within the research groups dedicating a lot of resources to ALT research, none of them to the best of our knowledge have the technical capability to perform such a large small molecule screening in the way we are planning to do it. Our technological achievement with the C-circle assay puts our group in a unique position to perform the largest screening study ever attempted in the field of ALT cancer research.

Link: http://majormouse.org/?q=node%2F225

Researchers here provide evidence in mice to suggest that stem cell treatments could be used to address some forms of glaucoma, usually caused by an increase in pressure in the eye that can damage the optic nerve and other structures. The types of glaucoma of interest here are those in which the drainage channels for aqueous humour deteriorate, as those channels might be induced to regenerate via the transplantation of stem cells produced from the patient's own tissues:

Researchers injected stem cells into the eyes of mice with glaucoma. The influx of cells regenerated the tiny, delicate patch of tissue known as the trabecular meshwork, which serves as a drain for the eyes to avoid fluid buildup. When fluid accumulates in the eye, the increase in pressure could lead to glaucoma. The disease damages the optic nerve and can result in blindness. "We believe that replacement of damaged or lost trabecular meshwork cells with healthy cells can lead to functional restoration following transplantation into glaucoma eyes."

One potential advantage of the approach is that the type of stem cells used - called induced pluripotent stem cells - could be created from cells harvested from a patient's own skin. That gets around the ethical quandary of using fetal stem cells, and it also lessens the chance of the patient's body rejecting the transplanted cells. The researchers were able to get the stem cells to grow into cells like those of the trabecular meshwork by culturing them in a solution that had previously been "conditioned" by actual human trabecular meshwork cells. The researchers were encouraged to see that the stem cell injection led to a proliferation of new endogenous cells within the trabecular meshwork. In other words, it appears the stem cells not only survived on their own, but coaxed the body into making more of its own cells within the eye, thus multiplying the therapeutic effect. The team measured the effects in the mice nine weeks after the transplant. Lab mice generally live only two or three years, and nine weeks is roughly equal to about five or six years for humans.

The researchers say they are confident that their findings hold promise for the most common form of glaucoma, known as primary open angle glaucoma. They aren't sure yet if their mouse model is as relevant for other forms of the disease. Another possible limitation of the research: It could be that new trabecular meshwork cells generated from the stem cell infusion eventually succumb to the same disease process that caused the breakdown in the first place. This would require retreatment. It's unclear, though, whether an approach requiring multiple treatments over time would be viable. The researchers plan to continue studying the approach.

Link: http://www.research.va.gov/currents/0716-5.cfm

A large fraction of the public funding devoted to aging research goes towards Alzheimer's disease, a very broad set of initiatives that dovetail with other large investments in mapping and understanding the biochemistry of the brain. This is a diverse area of study, since it involves figuring out how a fair-sized slice of the brain actually works at the detail level in order to understand how it becomes broken in this particular case. This means that a great many papers and research results flow past on a weekly basis. Not all of them are useful; institutions of public funding always turn into jobs programs over time, and that inevitably means a lot of people working on things that are neither useful nor interesting. Further, these sorts of institutions are so risk averse that they essential stop funding true fundamental research, the high-risk search for new knowledge. To have a good shot at winning a grant from the National Institute on Aging you really have to be working on something that is already fairly well known and characterized - grant awarding bodies want to see little risk, and want to pay for an expected outcome. Which is the antithesis of actual research. This is why most of the important work at any given time, the real cutting edge in medical research, is funded by some combination of philanthropy and creative accounting by lab managers.

The nature of government programs is a big problem for any group that seeks to use the public funding mainstream as a guide to what they should be doing to help things move faster in the field. If you simply follow that lead, you wind up like the Ellison Medical Foundation, spending a lot of money on fundamental research to no good end, with very little in the way of practical outcomes to show for it at the end of the day. The National Institute on Aging playbook includes a large amount of waste and make-work, and all too little in the way of earnestly pushing the bounds of the possible. In this day and age, an era of rapid progress in biotechnology and medicine, both pushing the bounds of the possible and practical outcomes should be high on the priority list for aging research, meaning radically better and more effective ways to treat aging and age-related disease. Still, there is a lot of Alzheimer's research underway, and some of it is interesting, potentially useful, or at the very least not make-work. A few recent examples can be found below.

Scientists discover how proteins in the brain build-up rapidly in Alzheimer's

Fibrils, known as amyloids, become intertwined and entangled with each other, causing the so-called 'plaques' that are found in the brains of Alzheimer's patients. Spontaneous formation of the first amyloid fibrils is very slow, and typically takes several decades, which could explain why Alzheimer's is usually a disease that affects people in their old age. However, once the first fibrils are formed, they begin to replicate and spread much more rapidly by themselves, making the disease extremely challenging to control.

Despite its importance, the fundamental mechanism of how protein fibrils can self-replicate without any additional machinery is not well understood. Researchers found that the seemingly complicated process of fibril self-replication is actually governed by a simple physical mechanism: the build-up of healthy proteins on the surface of existing fibrils. The researchers used a molecule known as amyloid-beta, which forms the main component of the amyloid plaques found in the brains of Alzheimer's patients. They found a relationship between the amount of healthy proteins that are deposited onto the existing fibrils, and the rate of the fibril self-replication. In other words, the greater the build-up of proteins on the fibril, the faster it self-replicates. They also showed, as a proof of principle, that by changing how the healthy proteins interact with the surface of fibrils, it is possible to control the fibril self-replication. "This discovery suggests that if we're able to control the build-up of healthy proteins on the fibrils, we might be able to limit the aggregation and spread of plaques."

Antibiotic treatment weakens progression of Alzheimer's disease through changes in the gut microbiome

Two of the key features of Alzheimer's disease are the development of amyloidosis, accumulation of amyloid-ß (Aß) peptides in the brain, and inflammation of the microglia, brain cells that perform immune system functions in the central nervous system. Buildup of Aß into plaques plays a central role in the onset of Alzheimer's, while the severity of neuro-inflammation is believed to influence the rate of cognitive decline from the disease. For this study, researchers administered high doses of broad-spectrum antibiotics to mice over five to six months. At the end of this period, genetic analysis of gut bacteria from the antibiotic-treated mice showed that while the total mass of microbes present was roughly the same as in controls, the diversity of the community changed dramatically. The antibiotic-treated mice also showed more than a two-fold decrease in Aß plaques compared to controls, and a significant elevation in the inflammatory state of microglia in the brain. Levels of important signaling chemicals circulating in the blood were also elevated in the treated mice.

While the mechanisms linking these changes is unclear, the study points to the potential in further research on the gut microbiome's influence on the brain and nervous system. "We don't propose that a long-term course of antibiotics is going to be a treatment - that's just absurd for a whole number of reasons. But what this study does is allow us to explore further, now that we're clearly changing the gut microbial population and have new bugs that are more prevalent in mice with altered amyloid deposition after antibiotics."

Pim1 inhibition as a novel therapeutic strategy for Alzheimer's disease

Clinically, Alzheimer's disease (AD) is characterized by impairments of memory and cognitive functions. Accumulation of amyloid-β (Aβ) and neurofibrillary tangles are the prominent neuropathologies in patients with AD. Strong evidence indicates that an imbalance between production and degradation of key proteins contributes to the pathogenesis of AD. The mammalian target of rapamycin (mTOR) plays a key role in maintaining protein homeostasis as it regulates both protein synthesis and degradation. A key regulator of mTOR activity is the proline-rich AKT substrate 40 kDa (PRAS40), which directly binds to mTOR and reduces its activity. Notably, AD patients have elevated levels of phosphorylated PRAS40, which correlate with Aβ and tau pathologies as well as cognitive deficits. Physiologically, PRAS40 phosphorylation is regulated by Pim1, a protein kinase of the proto-oncogene family. Here, we tested the effects of a selective Pim1 inhibitor (Pim1i), on spatial reference and working memory and AD-like pathology in 3xTg-AD mice.

We have identified a Pim1i that crosses the blood brain barrier and reduces PRAS40 phosphorylation. Pim1i-treated 3xTg-AD mice performed significantly better than controls. Additionally, 3xTg-AD Pim1i-treated mice showed a reduction in soluble and insoluble Aβ40 and Aβ42 levels, as well as a 45.2% reduction in Aβ42 plaques within the hippocampus. Furthermore, phosphorylated tau immunoreactivity was reduced in the hippocampus of Pim1i-treated 3xTg-AD mice by 38%. Mechanistically, these changes were linked to a significant increase in proteasome activity. These results suggest that reductions in phosphorylated PRAS40 levels via Pim1 inhibition reduce Aβ and Tau pathology and rescue cognitive deficits by increasing proteasome function. Given that Pim1 inhibitors are already being tested in ongoing human clinical trials for cancer, the results presented here may open a new venue of drug discovery for AD by developing more Pim1 inhibitors.

Brain cell death in Alzheimer's linked to structural flaw

Studying cells from postmortem brains of people who had Alzheimer's disease, researchers previously found that areas of DNA that are typically tightly wound in the cell's nucleus are instead relaxed and unwound in brain cells from Alzheimer's patients. When DNA is unwound it can switch on genes that should be turned off. In the new study, the researchers took a closer look at the nuclei of Alzheimer's patients' brain cells to find out how the DNA becomes unwound. When the researchers used a very high-resolution microscopy technique that let them observe the entire nucleus, they were surprised to see tunnels running through the nucleus of brain cells from people with Alzheimer's disease that were not seen in normal brain cells. "We wanted to find out if these tunnels were actually causing neurons to die or whether they were a side effect of the disease. Using the fly model of Alzheimer's disease we genetically blocked the process of tunnel formation and found that indeed less brain cells died and the flies lived longer. We are now performing lab experiments to see if we can also block the process using drugs."

After identifying this first potential new drug target, the researchers continued their experiments to further elucidate this biological pathway. The cell nucleus is surrounded by what is known as the lamin nucleoskeleton, a structural scaffold made of the protein lamin. They found that when the lamin nucleoskeleton is disrupted and tunnels form, the DNA inside can no longer anchor to the nucleoskeleton and becomes unraveled. In other words, the interaction between tightly wound DNA and the nucleoskeleton is required to maintain the overall 3D architecture of the DNA. They also discovered that the tau that aggregates in the brains of people with Alzheimer's disease disrupts the lamin nucleoskeleton by overstabilizing the actin cytoskeleton found outside of the nucleus, in the cell's cytoplasm. This interrupts the normal coupling between the actin cytoskeleton and the lamin nucleoskeleton, which, in turn, causes the tightly wound DNA to relax. This causes genes to turn on that are not supposed to and, consequently, brain cells die.

Researchers have demonstrated some restoration of strength in patients with severe muscle injuries, using scaffold materials derived from the extracellular matrix (ECM) of pig tissues. This is an incremental step forward towards the end goal of complete regeneration, but shows the potential utility of suitable guide materials to spur reconstruction of missing tissues. This has some relevance to the issue of age-related loss of muscle mass and strength; many of the approaches used to regenerate severe muscle injuries may see adaptation to restoration of muscle in the elderly, though for preference not those involving surgical procedures.

For the Muscle Tendon Tissue Unit Repair and Reinforcement Reconstructive Surgery Research Study, 11 men and two women who had lost at least 25 percent of leg or arm muscle volume and function first underwent a customized regimen of physical therapy for four to 16 weeks. Researchers then surgically implanted a "quilt" of compressed ECM sheets designed to fill in their injury sites. Within 48 hours of the operation, the participants resumed physical therapy for up to 24 additional weeks. By six months after implantation, patients showed an average improvement of 37.3 percent in strength and 27.1 percent in range of motion tasks compared with pre-operative performance numbers. CT or MRI imaging also showed an increase in post-operative soft tissue formation in all 13 patients.

The new data builds upon a 2014 study that showed damaged leg muscles grew stronger and showed signs of regeneration in three out of five men whose old injuries were surgically implanted with ECM derived from pig bladder. Those patients also underwent similar pre- and post-operative physical therapy. The recent results included more patients with varying limb injuries; used three different types of pig tissues for ECM bioscaffolds; investigated neurogenic cells as a component of the functional remodeling process; and included CT and MRI imaging to evaluate the remodeled muscle tissue. "The three different types of matrix materials used all worked the same, which is significant because it means this is a generic property of these materials and gives the surgeons a choice for using whichever tissue they like."

Link: http://www.upmc.com/media/NewsReleases/2016/Pages/regenerative-medicine-muscle-injuries.aspx

In this research, the scientists involved investigate a potential role for the gene nanog in the aging of stem cells, a prospect that has been studied for a few years now. Nanog is involved in pluripotency, the ability of embryonic stem cells to generate any cell type, but, as is the case for most cellular biology, not in a straightforward way. In recent years, with the development of induced pluripotent stem cells, a great deal of attention has been directed towards the molecular biology of genes such as nanog.

To battle aging, the human body holds a reservoir of nonspecialized cells that can regenerate organs. These cells are called adult stem cells, and they are located in every tissue of the body and respond rapidly when there is a need. But as people age, fewer adult stem cells perform their job well, a scenario which leads to age-related disorders. Reversing the effects of aging on adult stem cells, essentially rebooting them, can help overcome this problem.

In the new study, researchers introduced Nanog into aged smooth muscle stem cells and found that Nanog opens two key cellular pathways: Rho-associated protein kinase (ROCK) and Transforming growth factor beta (TGF-β). In turn, this jumpstarts dormant proteins (actin) into building cytoskeletons that adult stem cells need to form muscle cells that contract. Force generated by these cells ultimately helps restore the regenerative properties that adult stem cells lose due to aging.

Additionally, the researchers showed that Nanog activated the central regulator of muscle formation, serum response factor (SRF), suggesting that the same results may be applicable for skeletal, cardiac and other muscle types. The researchers are now focusing on identifying drugs that can replace or mimic the effects of NANOG. This will allow them to study whether aspects of aging inside the body can also be reversed. This could have implications in an array of illnesses, everything from atherosclerosis and osteoporosis to Alzheimer's disease.

Link: http://www.buffalo.edu/news/releases/2016/07/023.html

Today I'll point out a very readable scientific commentary on mutations in mitochondrial DNA (mtDNA) and the importance of understanding how these mutations spread within cells. This is a topic of some interest within the field of aging research, as mitochondrial damage and loss of function is very clearly important in the aging process. Mitochondria are, among many other things, the power plants of the cell. They are the evolved descendants of symbiotic bacteria, now fully integrated into our biology, and their primary function is to produce chemical energy store molecules, adenosine triphosphate (ATP), that are used to power cellular operations. Hundreds of mitochondria swarm in every cell, destroyed by quality control processes when damaged, and dividing to make up the numbers. They also tend to promiscuously swap component parts among one another, and sometimes fuse together.

Being the descendants of bacteria, mitochondria have their own DNA, distinct from the nuclear DNA that resides in the cell nucleus. This is a tiny remnant of the original, but a very important remnant, as it encodes a number of proteins that are necessary for the correct operation of the primary method of generating ATP. DNA in cells is constantly damaged by haphazard chemical reactions, and equally it is constantly repaired by a range of very efficient mechanisms. Unfortunately mitochondrial DNA isn't as robustly defended as nuclear DNA. Equally unfortunately, some forms of mutation, such as deletions, seem able to rapidly spread throughout the mitochondrial population of a single cell, even as they make mitochondria malfunction. This means that over time a growing number of cells become overtaken by malfunctioning mitochondria and fall into a state of dysfunction in which they pollute surrounding tissues with reactive molecules. This can, for example, increase the level of oxidized lipids present in the bloodstream, which speeds up the development of atherosclerosis, a leading cause of death at the present time.

The question of how exactly some specific mutations overtake a mitochondrial population so rapidly is still an open one. There is no shortage of sensible theories, for example that it allows mitochondria to replicate more rapidly, or gives them some greater resistance to the processes of quality control that normally cull older, damaged mitochondria. The definitive proof for any one theory has yet to be established, however. In one sense it doesn't actually matter all that much: there are ways to address this problem through medical technology that don't require any understanding of how the damage spreads. The SENS Research Foundation, for example, advocates the path of copying mitochondrial genes into the cell nucleus, a gene therapy known as allotopic expression. For so long as the backup genes are generating proteins, and those proteins make it back to the mitochondria, the state of the DNA inside mitochondria doesn't matter all that much. Everything should still work, and the present contribution of mitochondrial DNA damage to aging and age-related disease would be eliminated. At the present time there are thirteen genes to copy, a couple of which are in commercial development for therapies unrelated to aging, another couple were just this year demonstrated in the lab, and the rest are yet to be done.

Still, the commentary linked below is most interesting if you'd like to know more about the questions surrounding the issue of mitochondrial DNA damage and how it spreads. This is, as noted, a core issue in the aging process. The authors report on recent research on deletion mutations that might sway the debate on how these mutations overtake mitochondrial populations so effectively.

Expanding Our Understanding of mtDNA Deletions

A challenge of mtDNA genetics is the multi-copy nature of the mitochondrial genome in individual cells, such that both normal and mutant mtDNA molecules, including selfish genomes with no advantage for cellular fitness, coexist in a state known as "heteroplasmy." mtDNA deletions are functionally recessive; high levels of heteroplasmy (more than 60%) are required before a biochemical phenotype appears. In human tissues, we also see a mosaic of cells with respiratory chain deficiency related to different levels of mtDNA deletion. Interestingly, cells with high levels of mtDNA deletions in muscle biopsies show evidence of mitochondrial proliferation, a compensatory mechanism likely triggered by mitochondrial dysfunction. In such circumstances, deleted mtDNA molecules in a given cell will have originated clonally from a single mutant genome. This process is therefore termed "clonal expansion."

The accumulation of high levels of mtDNA deletions is challenging to explain, especially given that mitophagy should provide quality control to eliminate dysfunctional mitochondria. Studies in human tissues do not allow experimental manipulation, but large-scale mtDNA deletion models in C. elegans have proved to be helpful, showing some conserved characteristics that match the situation in humans, as well as some divergences. Researchers have used a C. elegans strain with a heteroplasmic mtDNA deletion to demonstrate the importance of the mitochondrial unfolded protein response (UPRmt) in allowing clonal expansion of mutant mtDNAs to high heteroplasmy levels. They demonstrate that wild-type mtDNA copy number is tightly regulated, and that the mutant mtDNA molecules hijack endogenous pathways to drive their own replication.

The data suggests that the expansion of mtDNA deletions involves nuclear signaling to upregulate the UPRmt and increase total mtDNA copy number. The nature of the mito-nuclear signal in this C. elegans model may have been the transcription factor ATFS-1 (activating transcription factor associated with stress-1), which fails to be imported by depolarized mitochondria, mediates UPRmt activation by mtDNA deletions. A long-standing hypothesis proposes that deleted mtDNA molecules clonally expand because they replicate more rapidly due to their smaller size. To address this question, researchers examined the behavior of a second, much smaller mtDNA deletion molecule. They found no evidence for a replicative advantage of the smaller genome, and clonal expansion to similar levels as the larger deletion. In human skeletal muscle, mtDNA deletions of different sizes also undergo clonal expansion to the same degree. Furthermore, point mutations that do not change the size of the total mtDNA molecule also successfully expand to deleterious levels, indicating that clonal expansion is not driven by genome size. Thus, similar mechanisms may be operating across organisms. In the worm, this involves mito-nuclear signaling and activation of the UPRmt.

There is some debate over interpretation of results. One paper indicates that UPRmt allows the mutant mtDNA molecules to accumulate by reducing mitophagy. Another demonstrates that the UPRmt induces mitochondrial biogenesis and promotes organelle dynamics (fission and fusion). Both papers show that by downregulating the UPRmt response, mtDNA deletion levels fall, which may allow a therapeutic approach in humans. Could there be a similar mechanism in humans, especially since some features detected in C. elegans are also present in human tissues, including the increase in mitochondrial biogenesis and the lack of relationship between mitochondrial genome size and expansion? It is likely that there will be a similar mechanism to preserve deletions since, as in the worm, deletions persist and accumulate in human tissues, despite an active autophagic quality-control process. Although the UPRmt has not been characterized in humans as it has in the worm, and no equivalent protein to ATFS-1 has been identified in mammals, proteins such as CHOP, HSP-60, ClpP, and mtHSP70 appear to serve similar functions in mammals as those in C. elegans and suggest that a similar mechanism may be present.

Mice lacking p21 can regenerate small wounds without scarring, something that is not normally possible in adult mammals. Separately, SDF-1 has been identified as a signal to recruit and activate stem cells, and efforts are underway build regenerative therapies on this basis. Here, scientists dig further into the intersection of these two lines of research to find - as in other studies - that immune system involvement seems to be key to the process. They show that an existing class of drug can induce healing of minor injuries without scars in mice by blocking some of the immune cell activities that normally take place in mammalian wound healing. Ultimately, the goal in this and a range of similar research is to establish whether or not our biochemistry is capable of salamander-like regeneration of limbs and organs, and if so which of the numerous differences between highly regenerative and less regenerative species are blocking this ability.

The ability to regenerate lost organs following trauma is one of the great unsolved mysteries in medical research, and understanding the basis of mammalian regenerative biology is relevant to human regenerative medicine. In mammals, traumatic injuries typically heal with a fibroblast- and collagen-rich response, producing a fibrous scar rather than full reconstitution of cellular subtypes and functional tissue architecture. A central focus of regenerative and developmental biology is to restore normal tissue structure and function after injury. Astonishing examples of tissue and organ regeneration following injury include appendage and eye regeneration in amphibians and teleosts. Limited examples of tissue regeneration also exist in mammals, suggesting that mechanisms governing tissue regeneration may be evolutionarily conserved. Here, we investigated mouse ear regeneration to identify cellular, genetic, and signaling mechanisms driving mammalian appendage regeneration.

Mice lacking p21 fully regenerate injured ears without discernable scarring. Here we show that, in wild-type mice following tissue injury, stromal-derived factor-1 (Sdf1) is up-regulated in the wound epidermis and recruits Cxcr4-expressing leukocytes to the injury site. In p21-deficient mice, Sdf1 up-regulation and the subsequent recruitment of Cxcr4-expressing leukocytes are significantly diminished, thereby permitting scarless appendage regeneration.

The hypothesis that wound epidermis initiates or regulates tissue regeneration has been suggested in other species. In salamanders, the absence of the wound epidermis prevents limb regeneration. Deer antlers regenerate annually, but antlerogenesis is lost if the skin overlying the antler bone pedicle is removed and replaced with a full-thickness skin graft. These findings suggest a two-way interaction between the overlying skin and underlying skeletal tissues and cell types to coordinate tissue regeneration. Our identification of p21-dependent Sdf1 production by keratinocytes at the wounded edge is consistent with this possibility. Further localization of this effect may benefit from studies of mice with conditional p21 knockout alleles, when available. How multiple tissue-specific precursor cells expand and collaborate to restore integrated tissue architecture and function also remains to be defined.

While immune cell recruitment is required to initiate early wound-healing responses, previous studies have demonstrated that some forms of immunosuppression can accelerate subsequent regeneration. In humans, fetal skin regenerates after injury without scarring (unlike adult wound healing), a phenomenon accompanied by reduced immune cell infiltration and decreased inflammation. In our studies, we found that decreased Sdf1 expression and diminished recruitment of Cxcr4+ leukocytes promote tissue regeneration. The balance between inflammatory responses and tissue regeneration is likely to be complex and multiphasic. Further studies are needed to investigate the subsets of wound Cxcr4+ leukocytes recruited by Sdf1 and understand how these cells normally promote wound healing, fibrosis, and scar formation.

Using AMD3100, an established antagonist of Cxcr4 signaling, we induced appendage regeneration in wild-type animals. In the past, AMD3100, either by itself or in combination with platelet-derived growth factor or tacrolimus, improved wound healing and scar formation in diabetic mice and mice receiving thermal burns. Here we show that AMD3100 treatment promotes tissue regeneration and restores normal tissue structure and function after injury in a scarless manner. Currently, short courses of AMD3100 are used to mobilize bone marrow stem cells for transplantation in humans, and a common side effect of AMD3100 is peripheral blood leukocytosis. We speculate that the peripheral blood leukocytosis seen in patients may also result from disruption of Sdf1-mediated leukocyte trafficking, and future studies are needed to understand this mechanism more precisely. Collectively, our observations suggest that the clinical uses of AMD3100 may be expanded to include treatment of traumatic appendage wounds or chronic nonhealing wounds in skin. These are common problems that lack effective treatments and represent an important unmet need in current clinical practice.

Link: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4617975/

The press here reports on the positive results of a recent small trial of the introduction of stem cells during bypass surgery for heart attack survivors. Stem cell therapies have over the past decade demonstrated highly variable outcomes in patients, and the methodology of delivery has been shown to be very important. A fair amount of the work accomplished in this field over the past fifteen years has involved trying to determine why seemingly similar approaches to the use of stem cells in regenerative medicine can produce both very successful and marginal outcomes. This therapy, for example, isn't all that different from others that have failed to move the needle in heart regeneration.

People suffering from heart disease have been offered hope by a new study that suggests damaged tissue could be regenerated through a stem cell treatment injected into the heart during surgery. The small-scale study followed 11 patients who during bypass surgery had stem cells injected into their hearts near the site of tissue scars caused by heart attacks. One of the trial's most dramatic results was a 40% reduction in the size of scarred tissue. Such scarring occurs during a cardiac event such as a heart attack, and can increase the chances of further heart failure. The scarring was previously thought to be permanent and irreversible.

At the time of treatment, the patients were suffering heart failure and had a very high (70%) annual mortality rate. But 36 months after receiving the stem cell treatment all are still alive, and none have suffered a further cardiac event such as a heart attack or stroke, or had any readmissions for cardiac-related reasons. Twenty-four months after participants were injected with the stem cell treatment there was a 30% improvement in heart function, 40% reduction in scar size, and 70% improvement in quality of life, as judged by the Minnesota living with heart failure (MLHF) score. "It's an early study and it's difficult to make large-scale predictions based on small studies. But even in a small study you don't expect to see results this dramatic. These are 11 patients who were in advanced heart failure, they had had a heart attack in the past, multiple heart attacks in many cases. The life expectancy for these patients is less than two years, we're excited and honoured that these patients are still alive." The next study will include a control group who undergo bypass but do not receive stem cell treatment, to measure exactly what impact the treatment has.

Link: https://www.theguardian.com/science/2016/jul/24/stem-cell-trial-suggests-damaged-heart-tissue-regenerated

Science News recently lumped together a few popular science articles on aging research into a special issue on the subject. As the blurb notes, aging is very much neglected in comparison to its importance, and accepted despite the damage it does. Defeating aging should be the primary focus of medical research, given that it kills about twice as many people as all of the other causes of death put together, and is the root cause of an even larger proportion of disability, pain, suffering, and medical expense. That it isn't is just another sign that we humans are not good at priorities and common sense.

Everyone ages. Growing old is a fundamental feature of human existence. But, our scientific understanding of aging pales in comparison to its significance in our lives. While new studies reveal exciting prospects for slowing the effects of aging, its causes and extensive effects remain enigmatic. Scientists are still divided on some fundamentals of aging, and that's why aging research raises some interesting questions. For example, how does it change the brain? How did different life histories evolve? How old is the oldest blue whale? This special report addresses those questions and more.

I'll link to the first of the articles below, and leave an exploration of the others as an exercise for the reader. That first article is a fairly standard example of this sort of thing, covering a few recent and more publicly discussed research initiatives in the field. As is usually the case, it largely focuses on ways to modestly slow aging, such as calorie restriction mimetic research, or to spur greater stem cell activity in old individuals, such as some of the leads resulting from parabiosis research. It omits any explicit mention of the SENS approach to rejuvenation research, which is, sadly, still par for the course, even as it examines some of the current progress in senescent cell clearance, a topic that has been on the SENS list for fifteen years at this point. That was a decade in advance of any meaningful attempts to remove senescent cells in the laboratory, and it is worth recalling that, as for other aspects of SENS, this was mocked within the scientific community at the time. Those who said as much back then now largely pretend that they agreed this was a viable approach all along; such is human nature. The SENS vision for medical control of aging hasn't changed, and is well known in the field now, but still working its way to greater material support. So when a journalist calls up half a dozen researchers to chat about their research the odds are still pretty good that none of those worthies will have any aspect of the presently active SENS programs in his or her list of pet topics.

This is unfortunate, as it means that most popular science journalism continues to propagate an unrealistic view of the near future of aging research, especially when it comes to expectations for the odds of greatly extending the healthy human life span. There is an opportunity to be seized here, a way to build rejuvenation therapies that can extend life to a far greater extent than is possible via approaches such as calorie restriction mimetics, trials of drugs like metformin, or other marginal strategies that aim to alter the operation of metabolism so as to slightly slow aging. Putting SENS repair strategies like senescent cell clearance side by side with calorie restriction mimetics is to create a false equivalence - these things are not the same at all. Repair can in principle create rejuvenation and indefinite healthy life spans, only limited by the quality of the repair implementation. All of these other technologies to slightly slow aging can do no such thing: they are very limited in comparison, and even if perfected can at most add a few years to human life spans. There is a huge difference between repairing the damage that causes aging and merely slowing down the accumulation of that damage, and that difference is being ignored by people who should know better. Why does this matter? Because building the rejuvenation therapies envisaged in great detail in the SENS proposals, some of which are coming into being in a few startup companies at the present time, requires large-scale support: money, advocacy, discussion, and most importantly widespread understanding.

A healthy old age may trump immortality

On the inevitability scale, death and taxes are at the top. Aging is close behind. It's unlikely that scientists will ever find a way to avoid death. And taxes are completely out of their hands. But aging, recent research suggests, is a problem that science just might be able to fix. As biological scientists see it, aging isn't just accumulating more candles on your birthday cake. It's the gradual deterioration of proteins and cells over time until they no longer function and can't replenish themselves. In humans, aging manifests itself outwardly as gray hair, wrinkles and frail, stooped bodies. Inside, the breakdown can lead to diabetes, heart disease, cancer, Alzheimer's disease and a host of other problems.

Scientists have long passionately debated why cells don't stay vigorous forever. Research in mice, fruit flies, worms and other lab organisms has turned up many potential causes of aging. Some experts blame aging on the corrosive capability of chemically reactive oxygen molecules or "oxidants" churned out by mitochondria inside cells. DNA damage, including the shortening of chromosome endcaps (called telomeres) is also a prime suspect. Chronic, low-grade inflammation, which tends to get worse the older people get, wreaks so much havoc on tissues that some researchers believe it is aging's prime cause, referring to aging as "inflammaging." All these things and more have been proposed to be at the root of aging.

Some researchers, like UCLA's Steve Horvath, view aging as a biological program written on our DNA. He has seen evidence of a biological clock that marks milestones along life's path. Some people reach those milestones more quickly than others, making them older biologically than the calendar suggests. Others take a more leisurely stroll, becoming biological youngsters compared with their chronological ages. Many others, including Richard Miller, a geroscientist at the University of Michigan, deny that aging is programmed. Granted, a biological clock may measure the days of our lives, but it's not a ticking time bomb set to go off on a particular date. After all, humans aren't like salmon, which spawn, age and die on a schedule. Instead, aging is a "by-product of running the engine of life," says biodemographer Jay Olshansky of the University of Illinois at Chicago. Eventually bodies just wear out. That breakdown may be predictable, but it's not premeditated.

Despite all the disputes about what aging is or isn't, scientists have reached one radical consensus: You can do something about it. Aging can be slowed (maybe even stopped or reversed). But exactly how to accomplish such a counterattack is itself hotly debated. Biotechnology and drug companies are developing several different potential remedies. Academic scientists are investigating many antiaging strategies in animal experiments. (Most of the research is still being done on mice and other organisms because human tests will take decades to complete). Even researchers who think they have finally come up with real antiaging elixirs say they don't have the recipe for immortality, though. Life span and health span, new research suggests, are two entirely separate things. Most researchers who work on aging aren't bothered by that revelation. Their goal is not necessarily extending life span, but prolonging health span - the length of time people live without frailty and major diseases.

The glass half full view, to counter my glass half empty points above, is that one of the SENS approaches to treating the causes of aging has finally taken wing and left the nest in these past few years. Senescent cell clearance now appears in popular science articles, is worked on by a number of unaffiliated research groups, has demonstrated life extension in mice, and is under clinical development in multiple companies. As removal of senescent cells proves its worth, other lines of SENS research, other forms of damage to be repaired to create rejuvenation, and the overall strategic approach of focusing on damage and its repair, will gain greater support.

Most aging research starts in short-lived species far removed from our own in the tree of life. There is a trade-off involved: it is much cheaper to explore and experiment with interventions in aging in a short-lived species, but the more distant the species the less likely that the results will be useful for longer-lived mammals. Fortunately many of the fundamental mechanisms relevant to aging are very similar across most of the animal kingdom, and even between yeast and humans. Low-cost exploration is very necessary in a field with little funding and an enormous, complex problem space. Without the use of flies, worms, and other short-lived species, most aging research would simply never happen. In recent years killifish have been inducted into the list of species used for aging research, which is an involved process in and of itself. This article looks at some of the high points:

Of the many varieties of killifish, the turquoise killifish (Nothobranchius furzeri) has the shortest lifespan - the briefest of any vertebrate bred in captivity, ranging from 3 to 12 months depending on strain and living conditions. Using killifish to study ageing is not a new idea. In the late twentieth century, scientists studied ageing in one species, Nothobranchius guentheri, that lives for about 14 months. But given techniques available at the time, they could come up with only basic descriptions of ageing features. Now, however, advances in molecular analysis have set up excellent conditions in which to develop the model and investigate mechanisms behind its dotage. The killifish's brief lifespan, relative to those of longer-lived models such as mice and zebrafish, enables ageing research to progress apace. And because the fish is a vertebrate, the research is more directly relevant to people than are studies of short-lived organisms such as fruit flies or nematodes.

The ephemeral existence that so appeals to scientists is an evolutionary adaptation to the fish's natural environment: their accelerated development enables them to live and reproduce in transient mud pools during the wet season in equatorial Africa. But that begged another question: would killifish age in a way that parallels the human process? The answer is yes: the fish do get 'old' before they die. Having shown that killifish decline with age, scientists now want to understand how the process occurs. One key resource is the collection of several strains from Africa whose genomes are not identical. By cross-breeding two strains, researchers created fish with a range of lifespans. They then compared the genomes and longevities of parent and second-generation progeny, and identified a few chromosomal regions, each with hundreds of genes that might influence ageing. Although these did not directly reveal genes involved in longevity, they suggested possible candidates. From this study, the scientists estimated that about 32% of variation in lifespan among turquoise killifish results from genetics, a figure comparable to the 20-35% estimated genetic contribution in mice.

Link: http://dx.doi.org/10.1038/535453a

The stem cells responsible for muscle growth and regeneration are perhaps the best studied of such populations. It seems that most of the new and interesting insights into the nuts and bolts of stem cell biology are coming from this part of the field, in any case. The therapies emerging from research along these lines should include ways to restore the diminished activity of stem cells in older people, with effects most likely similar to present stem cell therapies, but with greater control and selectivity in outcomes. In particular, researchers are very interesting in finding ways to boost muscle growth in older people in order to compensate for the characteristic loss of muscle mass and strength that occurs with aging.

Researchers found that levels of a single protein known as AUF1 determine whether pools of stem cells retain the ability to regenerate muscle after injury and as mice age. Changes in the action of AUF1 have also been linked by past studies to human muscle diseases. More than 30 genetic diseases, collectively known as myopathies, feature defects in this regeneration process and cause muscles to weaken or waste away. Clinical presentation and age of diagnosis vary, but "this work places the origin of certain muscle diseases squarely within muscle stem cells, and shows that AUF1 is a vital controller of adult muscle stem cell fate."

The study results revolve around one part of gene expression, in which the instructions encoded in DNA chains for the building of proteins are carried by intermediates known as messenger RNAs (mRNAs). Proteins comprise the body's structures, enzymes and signals. The expression of certain genes that need to be turned on and off quickly is controlled in part by the targeted destruction of their mRNA intermediates, a job assigned to proteins like AUF1. The investigators found that among the functions controlled by mRNA stability is the fate of stem cells. Following skeletal muscle injury, muscle stem cells receive a signal to multiply and repair damaged tissue, a process that the researchers found is controlled by AUF1. Among the mRNA targets of AUF1 in muscle stem cells, they discovered one that encodes a "master regulator" of adult muscle regeneration, a protein known as MMP9. This enzyme breaks down other proteins, ultimately controlling their expression levels.

The investigators showed that they could restore normal muscle stem cell function and related muscle regeneration in mice lacking AUF1 by repurposing a drug developed for cancer treatment that blocks MMP9 activity. "This provides a potential path to clinical treatments that accelerate muscle regeneration following traumatic injury, or in patients with certain types of adult onset muscular dystrophy. We may be able to treat a variety of degenerative diseases by enhancing resident tissue stem cells through targeting MMP9 and its pathways, even those with normal AUF1."

Link: http://www.eurekalert.org/pub_releases/2016-07/nlmc-gcr072016.php

Five years from now, it will be possible to take a trip overseas to have most of the senescent cells that have built up in your tissues cleared away via some form of drug or gene therapy treatment. That will reduce your risk of suffering most age-related diseases, and in fact make you measurably younger - it is a narrow form of rejuvenation, targeting just one of the various forms of cell and tissue damage that cause aging, age-related disease, and ultimately death. I say five years and mean it. If both of the present senescent cell clearance startup companies Oisin Biotechnologies and UNITY Biotechnology fail rather than succeed, and it is worth noting that the Oisin founders have a therapy that actually works in animal studies, while drugs and other approaches have also been shown to both clear senescent cells and extend life in mice, then there will be other attempts soon thereafter. The basic science of senescent cell clearance is completely open, and anyone can join in - in fact the successful crowdfunding of the first Major Mouse Testing Program study earlier this year was exactly that, citizen scientists joining in to advance the state of the art in this field.

Five years from now, however, there will be no definitive proof that senescent cell clearance extends life in humans, nor that it reduces risk of age-related disease in our species over the longer term. There will no doubt be a few more studies in mice showing life extension. There will be initial human evidence that clearance of senescent cells causes short-term improvements in technical biomarkers of aging such as DNA methylation patterns, or more easily assessed items such as skin condition - given how much of the skin in old people is made up of senescent cells - or markers of chronic inflammation. These are all compelling reasons to undertake the treatment, but if you want definite proof of life extension you'll have to wait a decade or more beyond the point of first availability, as that is about as long as it takes to put together and run academic studies that make a decent stab at quantifying effects on mortality in old people.

Uncertainty is the state of affairs when considering the effects of potentially life-extending therapies on human life span. Consider the practice of calorie restriction, for example, where theory suggests the likely outcome is a few extra years, but certainly not a large number of extra years or else it would be very apparent in epidemiological data. I think that an enterprising individual could, given a good relationship with the Calorie Restriction Society, put together a 20-year or 40-year study to that would - in theory - produce a decent set of data on practitioners and outcomes in the wild. It won't happen, most likely, because for one the funding isn't there for such a study, and secondly we'll be well into the era of widely available rejuvenation therapies along the way. Those calorie restriction practitioners will be taking advantage of treatments to repair the causes of aging just like everyone else.

Further, consider the possible effects of bisphosphonate treatment. There is some suggestion that this could add five years to life expectancy, a huge effect to go otherwise unnoticed for a treatment that quite a lot of people undergo in old age - but that may be exactly what has happened, for all we know. There is little work on replication or investigation, sadly. I point this out as an example of the degree to which uncertainty can and does exist for human data, as well as just how hard and expensive it is to dispel. It would take a large study, a lot of work, and waiting for a decade or so to figure out whether this bisphosphonate effect is real.

Now, consider that five years of additional life is not so far off a realistic expectation for the first prototype of any SENS-style rejuvenation therapy, such as senescent cell clearance, that repairs just one of the forms of damage that cause aging. Fixing one thing only gets you so far, as all the other forms of damage will still, on their own, kill you. Aubrey de Grey of the SENS Research Foundation believes that only small gains in overall life span are possible without addressing all of the causes of aging. This is a position well supported by statistical evidence for what would happen if, say, all cardiovascular disease or all cancer was eliminated without affecting other age-related disease. Only a few years of life expectancy would be gained in either of those cases. Arguments against that position run along the lines of suggesting that any repair of damage should produce incremental increases in life span, with reference to reliability theory, or that since all forms of damage and disease interact with one another, removing one will tend to slow the others. But we really won't know for sure until these therapies are out there in use and data is being gathered. You can only go so far in mice, especially given that their life spans are very much more plastic in response to circumstances than ours.

The reason I point out all of this is to note that the next couple of decades are going to be an increasingly confusing time for people who want to purchase elective therapies to extend healthy life. Things that actually work to a significant degree are going to be available alongside increasingly effective stem cell therapies and the same old garbage from the "anti-aging" marketplace that does absolutely nothing but part fools from their money. There will be infinite shades of grey between all of those things. You only have to look at the opportunists selling supposed longevity-enhancing supplements today based on calorie restriction mimetic research, and the articles in which that research is presented as equivalent and equal to SENS rejuvenation research approaches such as clearing senescent cells, to see how this is going to go. To navigate this near future market, for the decade or two it will take for the approaches that actually work to definitively prove their worth in human studies, you must understand more of the underlying science. You must be able to explain to yourself why damage repair approaches like those of the SENS portfolio are more likely to be effective than calorie restriction mimetic supplements - in short, your participation in the market will be guided by your take on the science. This is far from an academic exercise; time matters greatly.

Researchers have demonstrated the ability to build organoids of many different tissue types, starting with just a cell sample. The open access paper linked here is one example of many at the present time. These organoids are tiny sections of functional or partially functional organ tissue, limited in size because the research community has yet to develop a reliable means of incorporating the intricate branching vasculature needed to support thicker and larger masses. Still, this is enough to build useful products, either for research such as drug development or even for transplantation in some cases. For organs that are essentially chemical factories, that function doesn't require the original organ to be exactly replicated in shape and size - transplanting a few dozen organoids grown from the patient's own cells might be good enough to form the basis for a viable therapy.

The idea to construct in vitro 3D tissue-like structures to be used as model system for the respective organ is an appealing experimental approach. The main focus hereby is to exploit the in vivo physiological mechanism that occurs during organ development or healing (regeneration) and to implement similar mechanisms to develop a functional tissue in vitro. Such 3D liver-like structures would for example meet the needs of the pharmacological and toxicological industry for drug screening. The main techniques to generate 3D cellular constructs are either the formation of spheroids or building of tissue-like structures by placing sheets of cells and extracellular matrix components on top of each other. The disadvantage of spheroids is that the cells are distributed randomly without formation of spatial organization i.e., liver spheroids neither possess typical hepatic cord-like alignment of polarized hepatocytes nor sinusoids lined with endothelial cells reflecting the in vivo situation. Similarly, 3D liver models generated using sandwich cultures can never fully recapitulate the true in vivo architecture of the organ. Such ex vivo formation of tissue for most complex organs such as heart, kidney or brain would be very challenging.

However, the liver is exceptional in its ability to regenerate. It is well established that fully differentiated adult liver is capable of regeneration as long as a sufficient amount of intact liver remains after damage. Therefore, in principle any differentiated adult liver cell should harbor the potential to proliferate and regenerate to a complex and functional organ under suitable conditions. Indeed, induced-pluripotent stem cells (iPSC) stimulated to become hepatic endoderm-like cells (iPSC-HE) together with mesenchymal stem cells (MSC) and human umbilical vein endothelial cells (HUVEC), self-organize in vitro into macroscopically visible 3D cell clusters by an intrinsic organizing capacity. When these structures were transplanted into mice, they became vascularized, engrafted into the recipient's tissue and produced hepatic factors like albumin. Possible applications of such an organoid structure include replacement therapy but also the possibility to study hepatotoxic effects of new compounds. They could as well be used as simplified model system to investigate processes like liver regeneration, fibrogenesis or malignant transformation. Due to the fact that these organoids are formed out of different cell types, which are in 3D contact to each other, they can be expected to represent a system which is much closer to the depicted in vivo situation than conventional approaches.

In the present work we analyzed if liver organoids could also be generated from adult, differentiated cells and if these organoids can be cultured for long-term to study liver functions. Instead of stem cells, hepatocytes were used to reflect the parenchymal cells of the liver. In order to depict the native physiological condition of liver, we further used liver sinusoidal endothelial cells (LSECs) instead of conventional endothelial cells like HUVECs. LSECs are a specialized type of scavenger endothelial cells that are able to endocytose an array of physiological and foreign macromolecules and colloids from the blood. The generation of these cells involves stable transduction of primary cells with lentiviral constructs carrying sequences which code for certain proliferation-inducing factors. These cells are cultured in medium containing a defined mixture of growth factors, allowing tighter control over proliferation (up to 40 population doublings). Employing this process, almost unlimited numbers of cells from one donor can be obtained. Our results show that liver organoids can be generated and these organoids after culturing them for a period of 10 days, express several marker proteins, genes and enzymes to a degree that is comparable to adult human liver. Furthermore, the architecture of these liver organoids to some degree resembles typical hepatic structures.

Link: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4619350/

Most people and most organizations consider the present to be a good model for the future, and base long-term plans on present trends. They are always surprised by change, despite living in an era characterized by rapid change driven by technological progress. The present slow upward trend in remaining human life expectancy at age 65 - perhaps a year every decade - is not the result of any deliberate effort to intervene in the aging process. It is a byproduct of general improvements in the medical technology that is used to attempt to patch over the consequences of aging at the late stage: efforts to keep a damaged machine running without fixing the damage, in other words. This is challenging and expensive, but nonetheless as biotechnology advances small gains are achieved. How very much faster and more effective will this be when the research community redirects its attention to the causes of aging? That is the question, and it isn't hard to see that there is a world of difference between repairing the damage that causes dysfunction and ignoring that damage.

Yet most people don't pay attention to what is going on in the lab, to what is under development in startups, or to what the scientific community is saying, but rather only to existing products that are widely available and well advertised. As a consequence they will be surprised, and potentially unprepared to take advantage of new options that can actually achieve rejuvenation to some degree. Retirement will be transformed radically by rejuvenation biotechnology within our lifetimes. New therapies that collectively add decades to life by repairing the damage that causes aging - an option unavailable today - will certainly be a reality in the 2030s, since the first are in clinical development today. You won't hear any of this from the mainstream of financial planning, as illustrated in this article, but as it is reasonably priced rejuvenation therapies and continued participation in the workforce may be the only good option for many people given the absence of savings in most societies today:

First, you were supposed to die at 85. Then 90. Now 95 and even 100 are common defaults when financial planners tell people how much to save for retirement. Except that's nuts. In the U.S., the typical man at age 65 is expected to live another 18 years. The typical woman, about 20. Yet many financial planners contend we should save as if we're all going to be centenarians. That notion so offends adviser Carolyn McClanahan that she confronted a speaker at a financial planning conference who contended that death at 100 should be the default assumption. "Even when you have a 350-pound guy who smokes?" says McClanahan. Advances in medical science "aren't happening that fast."

Some saving is essential. Obviously. But saving for a retirement that ends at age 100 means you'll need a nest egg that's about 40 percent larger than what you'd need for a normal life expectancy. While there's a 70 percent chance that at least one member of a married couple will make it to 85, the odds are only 20 percent either partner will make it to 95, and even lower that anyone will see 100. "Most of our improvements in life expectancy are coming from the decline in child mortality. The actual survival rate of people in their 80s and 90s is not increasing very fast."

If a 35-year-old wanted to replace 60 percent of her current $60,000 salary at age 65, she would need about $1.2 million at retirement age if she expects to live to 85. Stretch that to 100, and she'll need about $1.7 million. (These figures assume 3 percent average annual inflation and a 7 percent return on investments. Your mileage may vary.) Currently most workers (54 percent) have less than $25,000 saved for retirement. Uncertainty about longevity is just one of many unknowns in financial planning, says Bob Veres, a financial planning industry consultant. So-called "safe" withdrawal rates of 4 percent annually may actually be too conservative in most markets. Also, people often spend less as they age, which makes planners' typical assumptions that spending will increase with inflation each year too conservative. Cautious assumptions may stave off lawsuits, Veres says, but they "diminish the spending capacity of people who retire today."

Link: http://www.cbsnews.com/news/should-you-save-enough-to-live-to-100/

In recent news, researchers have identified CD47, mainly of interest in cancer therapies up until this point, as a potential therapeutic target to diminish the vicious circle of mechanisms that causes fatty plaques to grow in blood vessel walls. Everyone suffers from this problem as they age, and it leads to the condition known as atherosclerosis. The plaques start as tiny areas of inflammation, spawned by an overreaction to damaged lipid molecules, but this can spawn a cycle of ever greater inflammation, futile immune system intervention, and cell death that produces a growing graveyard of cell debris and fats. The resulting plaque narrows and remodels its blood vessel, contributing to vascular stiffening and consequent hypertension that in turn results in other forms of cardiovascular disease. Ultimately, one or more plaques grow fragile and fragment, rupturing or blocking blood vessels to cause a stroke, heart attack, or similar likely fatal event.

The SENS rejuvenation research point of view here, as for all age-related disease, is to focus on root causes or other important differences between young and old tissues, and consider how to revert or block these changes in a narrow, targeted manner. For example, the damaged lipids that seed lesions in blood vessel walls arise in part as the end result of a lengthy Rube Goldberg chain of events that starts with forms of mitochondrial DNA damage. Therefore allotopic expression gene therapy to duplicate mitochondrial genes in the cell nucleus, and thus ensure that they can continue to supply necessary proteins even if damaged in the mitochondria, should reduce incidence of atherosclerosis. That experiment lies perhaps five to ten years in the future at the present time, depending on funding. Another SENS approach is to clear out the worst of the waste compounds in plaques that can overwhelm and kill the macrophage immune cells that are drawn in to clean up the mess. Macrophage death is an important component of the vicious cycle that causes plaques to grow once established, making it a beacon of inflammation that draws in immune cells to their death. If the cell death could be cut down, then the immune system could successfully clean up atherosclerotic plaques. Similarly, making macrophages much more resilient would also be helpful, and for exactly the same reasons.

At a high level the progression of atherosclerosis is fairly well understood, with the vicious cycle of inflammation and immune cell death sitting at the heart of it. At the detailed level of cellular mechanisms, however, there is a steady process of new discoveries as researchers find and map the blind spots. For example, the smooth muscle cells in blood vessel walls are now known to play a more active role than was once thought, and, considered overall, the various types and states of cells involved are not at all as clearly demarcated as was the case a decade ago. It is a complex process. That complexity is a good reason to focus in on specific mechanisms likely to disrupt the cycle - that cells arrive to clean up the mess, become overwhelmed, die, and add to the debris. Anything that keeps macrophages alive and working efficiently to remove the compounds making up the plaque should be beneficial.

Anti-tumor antibodies could counter atherosclerosis

Normally, as a cell approaches death, its CD47 surface proteins start disappearing, exposing the cell to macrophages' garbage-disposal service. But atherosclerotic plaques are filled with dead and dying cells that should have been cleared by macrophages, yet weren't. In fact, many of the cells piling up in these lesions are dead macrophages and other vascular cells that should have been cleared long ago. Researchers performed genetic analyses of hundreds of human coronary and carotid artery tissue samples. They found that CD47 is extremely abundant in atherosclerotic tissue compared with normal vascular tissue, and correlated with risk for adverse clinical outcomes such as stroke.

Much of what's now known about CD47's function stems from pioneering work in cancer research. In the late 1990s and early 2000s, researchers first identified CD47 as being overexpressed on tumor cells, which helps them evade destruction by macrophages. They went on to show that blocking CD47 with monoclonal antibodies that bind to and obstruct the protein on tumor cells restores macrophages' ability to devour those cells. Phase-1 clinical safety trials of CD47-blocking antibodies in patients with solid tumors and blood cancers are now underway.

In a laboratory dish, anti-CD47 antibodies induced the clearance of diseased, dying and dead smooth muscle cells and macrophages incubated in conditions designed to simulate the atherosclerotic environment. And in several different mouse models of atherosclerosis, blocking CD47 with anti-CD47 antibodies dramatically countered the buildup of arterial plaque and made it less vulnerable to rupture. Many mice even experienced regression of their plaques - a phenomenon rarely observed in mouse models of cardiovascular disease. Looking at data from other genetic research, the scientists learned that surplus CD47 in atherosclerotic plaques strongly correlates with elevated levels, in these plaques, of a well-known inflammation-promoting substance called TNF-alpha. Further experiments showed that TNF-alpha activity prevents what would otherwise be a progressive decrease of CD47 on dying cells. Hence, those cells are less susceptible to being eaten by macrophages, especially in an atherosclerosis-promoting environment. "The problem could be an endless loop in which TNF-alpha-driven CD47 overexpression prevents macrophages from clearing dying cells in the lesion. Those cells release substances that promote the production of even more TNF-alpha in nearby cells."

Cytomegalovirus (CMV) is one of the most prevalent of the many forms of persistent herpesvirus that our immune system cannot effectively clear from the body. It has few obvious immediate effects in most people, and you probably never noticed when you were first infected. The overwhelming majority of people test positive for infection by the time old age rolls around. There exists a range of fairly compelling evidence to suggest that long-term CMV infection is a primary cause of immune system dysfunction in aging, and the paper linked here adds to that collection. There are only so many immune cells that can be supported at once by our adult biology, and an ever larger fraction of this capacity becomes uselessly specialized to CMV, unable to respond to new threats. The best treatment for this problem isn't to get rid of CMV, as that probably won't greatly help people with very damaged immune systems, but to remove the unwanted immune cells and replace them with fresh new cells that can do their jobs.

Epigenetic mechanisms such as DNA methylation (DNAm) have a central role in the regulation of gene expression and thereby in cellular differentiation and tissue homeostasis. It has recently been shown that aging is associated with profound changes in DNAm. Several of these methylation changes take place in a clock-like fashion, i.e. correlating with the calendar age of an individual. Thus, the epigenetic clock based on these kind of DNAm changes could provide a new biomarker for human aging process, i.e. being able to separate the calendar and biological age.

Information about the correlation of the time indicated by this clock to the various aspects of immunosenescence is still missing, however. As chronic cytomegalovirus (CMV) infection is probably one of the major driving forces of immunosenescence, we now have analyzed the correlation of CMV seropositivity with the epigenetic age in the Vitality 90+ cohort of birth year 1920 (122 nonagenarians and 21 young controls, CMV seropositivity rates 95% and 57%, respectively). The data showed that CMV seropositivity was associated with a higher epigenetic age in both of these age groups (median 26.5 vs. 24.0 in the young controls and 76.0 vs. 70.0 in the nonagenarians). Thus, these data provide a new aspect to the CMV associated pathological processes.

Link: http://dx.doi.org/10.1016/j.exger.2015.10.008

This popular science article examines a few of the current efforts to build the foundation for therapies to treat aging and its consequences, with a particular focus on parabiosis research in which the circulatory systems of old and young individuals are linked. This approach is being used to investigate differences in levels of gene expression that occur with age, most likely in reaction to rising levels of cell and tissue damage, and especially those changes connected to decline in stem cell function. A promising sign for the near future of advocacy for longevity science is that journalists, such as the author of this piece, are starting to understand the importance of treating the root causes of aging and age-related disease, rather than focusing on each disease of aging in its late stages and trying to patch over the consequences.

First, let's go over what will happen to us as we grow old. Sometime after age 50, depending on personal genetics and life history, our gums withdraw, we lose our hair, our saliva glands falter, and our teeth grow brittle and break off or fall out. Our skin gets thinner, less flexible; it sags, wrinkles, and is discolored by "liver spots." Our bones lose density and strength and shrink in size as our joints swell. Our shoulders slump, our spines buckle and hump. Our muscles atrophy and waste away so we lose mobility as we grow progressively weaker. Our balance and hearing deteriorate. Our eyes dry and lose their ability to focus, so we're more likely to fall, and our bones break more easily. We're slower to heal and more vulnerable to infection as we do, if we do. Hormone levels change. Our memory fails, and most of us, almost all of us, will develop dementia if we live long enough.

Living until 120, the life-span traditionally attributed to Moses, seems more like a curse than a blessing. But it doesn't have to be that way. I've spent the last year talking with scientists around the world about why we've been so successful treating the diseases of youth and middle age and yet haven't made similar progress against end-of-life afflictions. What I found is that scientists at Stanford, Harvard, USC, Wake Forest, UC Berkeley, San Francisco, USC, and Cambridge University, at Scripps Institute, the SENS Research Foundation, and Buck Institute for Research on Aging are unanimous in agreement: Science has gained the ability to intervene successfully in the aging process and to delay and to selectively reverse its effects. The speed at which these new technologies and techniques - which now exist - move from the lab to the clinic is directly dependent on public awareness and support.

Scientists have traditionally studied diseases separately because they have separate pathologies. Heart disease mostly comes from accumulated fat deposits clogging arteries, cancers from DNA damage, Alzheimer's and other dementias from damaged brain cells, etc. - and each disease has multiple contributing factors. But they share a common feature: Aging drives them all. If we delay aging and rejuvenate organs, tissues, and cells, we can prevent or remediate them all. Although aging is the major risk factor for developing most adult-onset diseases, systematic investigations into the fundamental physiology, biology, and genetics of aging are only just beginning. Yet there's good reason to be confident that moving away from the "infectious disease" model and shifting research dollars from individual diseases of aging to the basic biology of aging will be productive.

Link: http://www.tabletmag.com/jewish-news-and-politics/201752/beyond-120

Today, July 19th, Aubrey de Grey of the SENS Research Foundation and Haroldo Silva, lead SENS cancer researcher, are hosting an AMA - Ask Me Anything - event at /r/futurology. They will be there for a few hours to answer questions on rejuvenation research, fundraising for work on aging and cancer, and other aspects of the work of the SENS Research Foundation. This is a chance to ask about the SENS approach to a universal cancer therapy, one that targets the common mechanism of telomere lengthening that all cancers must employ to grow. The SENS researchers are focused on alternative lengthening of telomeres, ALT, a collection of processes that are still comparatively unexplored, yet essential to this approach to cancer therapies. The AMA started at 1PM EST and is ongoing at the time of posting, so if you jump in there is still the chance to have questions answered.

Below, I've digested a number of the questions and responses, with some light editing for clarity where necessary. As you can see, quite the range of topics are covered, from the cancer research that is the subject of the present SENS crowdfunding initiative at Lifespan.io to the newly announced large-scale funding initiative Project|21, from present day politics and economics relevant to research to the personal organization of future longevity assurance therapies, and more besides.

Would the anti-ALT small molecules just prevent the cancer cells from dividing eventually, or would they actually kill the cancer cells?

It really depends on how exactly the small molecules we find inhibit the ALT pathway. They could just prevent telomere elongation which will eventually result in complete cessation of tumor growth as you pointed out. On the other hand, these molecules can interfere in the process in such a way as to cause abnormal chromosome fusions which will actually kill cancer cells.

How can you be certain that telomeric C-circles are the only method for cancer cells to achieve ALT? Or that there are a finite number of ways for cells to achieve ALT?

C-circles are currently the best biomarker identified to date that is most closely associated with ALT activity. It represents our best chance to help us develop ALT-specific cancer therapies as well as demystify how this mechanism of telomere maintenance works. However, we do not know which specific role(s) C-circles are playing in the ALT pathway. We also do not know how cancer cells initiate ALT activity.

Given small molecules often have side effects, why not use an intra-cellular method such as DRACO to target telomeric C-circles and induce apotosis? Or alternatively, do telomeric C-circles present material on major histocompatibility complexes (MHCs) that could be targeted with genetically engineered T cells?

C-circles are composed of DNA with the repetitive sequences found at telomeres. Targeting C-circles directly and specifically is not feasible since there is no way to differentiate between C-circles and regular telomeres. Additionally, there is no evidence at present that targeting C-circles would actually inhibit ALT activity. Since C-circles are just DNA strands, they cannot be presented on MHCs for T cell signaling or other stimulation of the immune system.

Given that an anti ALT therapy will probably be given along with an anti-telomerase therapy, won't this affect cell replacement by regular stem cells that can no longer replace tissues for the duration of the treatment? We produce a million new T cells per second, how long can a dual therapy be endured before damaging the subject?

We envision that the side-effects associated with telomerase inhibition will be worked out in the current clinical trials by the time that ALT-specific experimental treatments reach such advanced stages in development. The ALT-specific therapy will of course have no effect on stem cells.

Will the human clinical trials resulting from Project|21 address all 7 categories of aging damage? If not, what is their goal?

No. The goal of Project|21 is to clear the path to the first genuine clinical trials in rejuvenation biotechnology. This will involve building better collaborations, better regulatory frameworks for rejuvenation clinical work, and pushing the first technologies specific to rejuvenation that are available and at a stage where early clinical work is truly feasible. We think this will involve technologies in intracellular damage repair, and technologies in senescent cell work, and other likely candidates for the first clinical work. The comprehensive solution, however, will require a larger selection of technologies and the investment and development power of more industrial partners (and the early successes of Project|21 will be used to precipitate that).

Robust mouse rejuvenation (RMR) will probably require simultaneous, high-quality implementation of all the SENS strands in mice, because the omission of any one strand will probably cause the mice to die on schedule. Project|21, on the other hand, is only about getting part-way to the equivalent stage in humans: first of all we would only be implementing a subset of the SENS therapies, and secondly we'd only be beginning the experiment (the clinical trial), whereas RMR is defined in terms of the outcome.

How satisfied are you with the progression of science in regards to human longevity?

We're about where I thought we'd be in the context of the funding that has been available, but that's only about 1/3 as far forward from 2005 as I'd have expected to be with even 10x more funding, i.e. with on the order of 30 to 100 million per year. We really need to ramp up that funding!

An important question would be what we can actively do to convince our leaders to give the billions of dollars from our national budget not to neverending wars and killing people, but instead to curing aging medical and scientific research?

Political leaders don't lead, they follow, in order to get re-elected. So, the sequence is painfully clear: first convince the mainstream biogerontologists. Once they are on board it's easy: they convince the likes of Oprah, they convince the public, and they in turn convince the politicians. Or we could just convince one billionaire...

How does Liz Parrish's work at BioViva impact what you are accomplishing at SENS?

There are a lot of strong feelings about BioViva swirling around the net at the moment, but it's really not as alarming as is being suggested. To address the various aspects of this issue: Stimulating expression of telomerase and follistatin are plausible ways to derive some aspects of rejuvenation; if I were to choose two genes with which to do what Liz has done, those would be quite high on my list. Yes, the SENS strategy for addressing cancer is the opposite of stimulating telomerase, but that doesn't take away from the fact that such stimulation can have beneficial effects. Gene therapy is certainly highly experimental still, so there is a definite risk to doing what Liz did. However, we must also remember that the public's attitude to medical risk is way over-conservative; for illustration, Mary Ruwart calculated that at least 50x more people die from slow approval of good drugs than from approval of bad drugs. Self-administration has a long and distinguished history in biology research. Even such luminaries as Haldane used to do it. The tests that have been done thus far to determine the effect of the therapy are certainly very inadequate, but I'm guessing that that is mainly because of budget limitations. As far as I know, BioViva has not thus far offered this therapy (or any other) to the public for money.

What you do guys think about all this Nicotinamide Riboside business? Will this have an impact on longevity in humans?

I'm generally pessimistic about the human longevity potential for any intervention that seeks to mimic calorie restriction, i.e. to induce the same changes of gene expression that CR induces, because the best that can be expected from such an approach is what CR itself gives, and that seems to be much less in long-lived species than in short-lived ones. But there may nonetheless be good health benefits, so I'm all for this research.

Are there any well-known people who support human longevity? Couldn't the support of people like Bill Gates or Elon Musk considerably boost funding of any projects?

We have support from a few celebrities, such as Steve Aoki and Edward James Olmos, but we definitely need more. Yes, any billionaire would do!

I'm concerned that there will be a mad rush for volunteers or a price gauge for treatments. How can I become a volunteer? How may the average human being access early treatments?

I'm quite sure that the arrival of these therapies will be preceded by at least a decade by the widespread realisation that they are coming. During that decade, society will do whatever is necessary to ensure universal access.

I am among the minority of people who have said at a every young age that I want to live a very long time, 150+, but all my friends and family all say they would never want to live that long. How do we change people's perception of growing old and make them think long term?

That's the wrong thing to try to convince people of. Instead, convince them that the diseases of old age are inseparable from the aspects of age-related ill-health that we don't label as diseases, so that the only way we'll ever "cure" Alzheimer's, etc, is by defeating the whole lot together. Then they won't be distracted by the unnerving side-effect that they might end up living a long time.

What's your take on why parabiosis seems to rejuvenate mice? Is damage cleared or what's going on? If not, why do the aged mice seem to perform better?

It presumably works by a combination of restoring good things that are less abundant in old blood and removing bad things that are more abundant in old blood. What those things are is still a huge research area. Damage in the SENS sense is probably not cleared except that there may be some stimulation of stem cell division and thus restoration of cell number, though "pre-damage" may well be cleared somewhat via shifts in the kinetics of its creation and repair. There are bound to be epigenetic mediators of the effect.

Recently, there seems to be an uptick in startups focused on reversing aging. Does that seem to be the case to you?

Yes, there certainly are more such startups around, including ones spun out of our own work such as Ichor Therapeutics. It's happening simply because more and more rejuvenation research is getting to a stage of sufficient proof of concept that the more visionary investors are seeing the light at the end of the commercial tunnel.

There are plenty of results from the past decade to illustrate that the methodology by which a therapy is delivered makes a great deal of difference to the outcome in patients. Here, for example, researchers have found a way to improve the performance of viruses engineered to preferentially target cancer cells. We've been hearing less of this approach to cancer in the past few years, given the progress and more widespread support for cancer immunotherapy as a technology platform, but there are still many researchers working on the use of viruses in targeted cancer therapy, and a number of promising studies have resulted.

The researchers found that injecting oncolytic viruses (viruses that target cancer cells) intravenously into the spleen boosts immune response faster and higher than traditional vaccine methods. Typically, physicians need to wait weeks or months to administer a booster vaccine, with the down time potentially deadly. "Normally, you have to wait until the immune response is down to administer the booster vaccine, but this means that, with severe and dangerous diseases, the response would wane. You don't want to give cancer any time to spread. What injecting the viruses into the spleen does is it allows us to bypass the regulatory mechanism that would limit its effectiveness. When we conducted these tests in animals, we saw high success rates in treatment of cancer."

The findings apply to many types of cancer, including breast cancer, leukemia, prostate cancer and osteosarcoma (bone cancer), and tumours in the brain, liver and skin. The researchers conducted the tests in mice, and in cats brought to their veterinary center. Trials on dogs should begin within the next year. Under traditional treatment options, the tumours grew and mice died. When the researchers started injecting the viruses into the spleen, the tumours disappeared. "By getting the vaccine to this unique location in the body, we were able to get an unprecedented immune response in minimal time. This is a fundamentally new way to treat cancer that bypasses many common side effects. These therapies are safer and more targeted." The findings are already leading to clinical trials for people, and the study could help researchers in other fields, including those looking to treat virulent diseases. "This research focuses on cancer, but certainly these findings would be applicable to other diseases. We just need to connect with people in those fields."

Link: http://news.uoguelph.ca/2016/07/ovc-cancer-breakthrough-finding-leads-human-clinical-trials/

With age, harmful waste products accumulate in cells as a normal side-effect of cellular processes. Some of these cannot be easily degraded and build up inside the recycling units called lysosomes, especially in the long-lived cells of the nervous system. This includes retinal cells, and there this process contributes to conditions such as macular degeneration. Lysosomes become bloated and dsyfunctional, unable to perform their normal tasks of braking down waste and damaged cellular structures. Here, researchers identify another essential role for lysosomes in retinal cells, and it is not unreasonable to propose that this, too, suffers because of the build up of waste materials. The SENS approach to this problem is to create new drugs, usually based on mining the bacterial world for suitable enzymes, that can break down some of the worst of the problem waste compounds. This is presently under active development at Ichor Therapeutics.

A research team has pinpointed how immune abnormalities beneath the retina result in macular degeneration, a common condition that often causes blindness. Although macular degeneration eventually damages or kills the light-sensitive rods and cones, it starts with injury to the retinal pigment epithelium (RPE). The RPE, a single layer of cells beneath the rods and cones at the back of the eye, performs many functions essential for healthy vision. The damage starts with a disturbance of immune proteins called complement, which normally kill disease-causing organisms by boring holes in their cell membranes.

"The light-detecting cells in the retina are totally dependent on the RPE for survival. but the RPE cells are not replaced through the lifespan. So we asked, 'What are the innate protective mechanisms that keep the RPE healthy, and how do they go awry in macular degeneration?'" Researchers focused on two protective mechanisms: the protein CD59, which regulates complement activity when attached to the outside of RPE cells; and lysosomes, spherical structures that plug pores created by the complement attack. Together, they offer an in-depth defense. "CD59 prevents the final step of attack that forms the pore. Once a pore forms, the cell can move a lysosome to close it."

If the complement attack is not defeated, the opening in the RPE cell membrane allows the entry of calcium ions, which spark a long-term, low-grade inflammation that inhibits both protective mechanisms, creating a vicious cycle of destruction. The inflammation in the RPE damages mitochondria, structures that process energy inside all cells. This could eventually lead to a decline or death of the photoreceptor cells, once they are deprived of their essential housekeepers. The result is the loss of central, high-resolution vision. Crucially, the study identified the enzyme aSMase that is activated by excess cholesterol in the RPE, which neutralizes both protective mechanisms, and found that drugs such as desipramine used to treat depression neutralized that enzyme and restored the protection - and the health of RPE cells - in a mouse model.

Link: http://news.wisc.edu/macular-degeneration-insight-identifies-promising-drugs-to-prevent-vision-loss/

There is a month left to go in the SENS crowdfunding campaign that aims to accelerate development of an important component of a universal cancer therapy, a way to block the mechanisms of telomere lengthening that every type of cancer depends upon. The SENS Research Foundation and Lifespan.io volunteers are looking for donors to put up matching funds of a few thousand dollars or more, in order to take that news and that inducement to a number of conferences and other events over the next few weeks. More than 150 people have donated to the campaign to date, and we'd like to triple that number in the next 30 days.

To start things off, I'll offer up $2,000 of my own funds: the next $2,000 in donations to this SENS cancer research initiative will be matched dollar for dollar. That is a start, and if you can join in to help out, please contact me to let me know. Can you help to make a difference here?

With last week's $10 million pledge in support of other portions of the SENS rejuvenation research portfolio, we can clearly see that grassroots fundraising works. It lights the way, and as we grow the community and show our determination, that success draws in larger donors. When this is amply demonstrated by the arrival of large amounts of new funding ... well, that is precisely the time to pile on and keep up the good work. All major medical research non-profits have several tiers of fundraising, from grassroots to high net work philanthropy, and all of these tiers are essential: they can't exist without one another. The SENS Research Foundation is transitioning to become a solid organization with a high end tier of fundraising to complement our efforts, and that couldn't exist without the support of the grassroots. It is a sign that we are winning.

We have been very focused on senescent cells, mitochondrial DNA damage, and glucosepane clearance these past few years, but don't forget that there are other parts of the SENS program that are just as important in the bigger picture of human rejuvenation. Building a universal, cost-effective therapy that works for all forms of cancer is one of those parts. The random mutations to nuclear DNA, different in every cell, that accumulate with age will be one of the hardest types of damage to fix, and mutation is the root cause of cancer. There will be a transitional era ahead in which people will live for decades longer in far better health than do today's elderly, thanks to first generation rejuvenation therapies, but they will still have high levels of nuclear DNA damage and thus high cancer risk. The rejuvenation toolkit needs to include a far better approach to cancer. You can see the SENS approach to speeding progress towards this goal in the recent interviews linked below, and at the /r/futurology AMA with Aubrey de Grey and Haroldo Silva that will be held tomorrow:

Haroldo Silva is a research scientist at the SENS Research Foundation (SRF), a non-profit organization focused on transforming the way the world researches and treats age-related disease. Since 2013, Haroldo has led a project at SRF that aims to treat and prevent cancers that rely on a process known as Alternative Lengthening of Telomeres (ALT). The ALT mechanism is present in 10-15% of all cancers, including some of the most clinically challenging cancers to treat, such as pediatric and adult brain cancers, soft tissue sarcoma, osteosarcoma, and lung cancers.

Every time a healthy cell divides, the DNA at the ends of its chromosomes, called telomeres, gets shorter. When the telomeres shorten too much, the cell permanently stops dividing and either remains dormant or dies. Telomere shortening acts as a natural biological mechanism for limiting cellular life span, but virtually all types of cancer cells bypass this process, allowing them to replicate indefinitely until they impair healthy tissue and organ function. A "universal" cancer treatment absolutely needs to address the two ways by which cancer cells lengthen and maintain their telomeres: i.e., they either express an enzyme called telomerase or they switch on ALT. The ALT process enables cancer cells to continue to elongate their telomeres, but without telomerase. The exact mechanism by which this occurs is not well understood by scientists, but a reliable biomarker that clearly indicates when ALT is happening was discovered by Silva's collaborator, Dr. Jeremy Henson, back in 2009.

In the war against cancer, there are several anti-telomerase therapies in advanced stages of clinical development, but nothing currently exists that is capable of specifically targeting ALT. Silva's current research project "Control ALT Delete Cancer" aims to find drugs that specifically shut down the ALT pathway, therefore preventing cancer growth and paving the way toward the first ever ALT-specific anticancer therapeutics.

Methuselah Foundation Podcasts: Episode 007 - Control Alt Delete Cancer

Hello and welcome to Episode 7! On this episode, we'll talk with Dr. Haroldo Silva and David Halvorsen of the SENS Research Foundation. They've launched a new crowdfunding campaign designed to attack and stop cancer using a new approach. You'll hear what that approach is, why they think it has a good chance of success, and you can help in the fight.

Researchers suggest, from an examination of epidemiological data, that stroke is for most patients a preventable occurrence largely driven by hypertension, inactivity, and obesity. In this the implication is that better life choices in the environment of present day medical technologies could push stroke to occur at greater ages, such that most older people would die from other consequences of aging first - more a matter of postponement than prevention per se. Lowering age-related increases in blood pressure is known to lower the risk of all cardiovascular issues, and the effects of inactivity and obesity on life expectancy and risk of age-related disease are well proven. Hypertension is driven by stiffening of blood vessels, which is caused at root by fundamental damage processes such as cross-linking in blood vessel walls, inflammation due to the presence of senescent cells, and so forth. The bad life choices mentioned above will speed up stiffening in blood vessels and consequent hypertension, but this end state will still exist, further down the line, even for those people who live the healthiest lives. This will continue to be the case until new therapies are built to repair the root causes - which should in my opinion be the highest priority, over and above campaigns aimed at adjusting behavior.

Hypertension (high blood pressure) remains the single most important modifiable risk factor for stroke, and the impact of hypertension and nine other risk factors together account for 90% of all strokes, according to an analysis of nearly 27,000 people from every continent in the world. Stroke is a leading cause of death and disability, particularly in low-income and middle-income countries. The two major types of stroke include ischaemic stroke (caused by blood clots), which accounts for 85% of strokes, and haemorrhagic stroke (bleeding in the brain), which accounts for 15% of strokes. Prevention of stroke is a major public health priority, but needs to be based on a clear understanding of the key preventable causes of stroke. This study builds on preliminary findings from the first phase of the INTERSTROKE study, which identified ten modifiable risk factors for stroke in 6,000 participants from 22 countries. The full-scale INTERSTROKE study included an additional 20,000 individuals from 32 countries in Europe, Asia, America, Africa and Australia, and sought to identify the main causes of stroke in diverse populations, young and old, men and women, and within subtypes of stroke.

To estimate the proportion of strokes caused by specific risk factors, the investigators calculated the population attributable risk for each factor (PAR; an estimate of the overall disease burden that could be reduced if an individual risk factor were eliminated). The PAR was 47.9% for hypertension, 35.8% for physical inactivity, 23.2% for poor diet, 18.6% for obesity, 12.4% for smoking, 9.1% for cardiac (heart) causes, 3.9% for diabetes, 5.8% for alcohol intake, 5.8% for stress, and 26.8% for lipids (the study used apolipoproteins, which was found to be a better predictor of stroke than total cholesterol). Many of these risk factors are known to also be associated with each other (e.g. obesity and diabetes), and when combined together, the total PAR for all ten risk factors was 90.7%, which was similar in all regions, age groups and in men and women.

Link: http://www.eurekalert.org/pub_releases/2016-07/tl-tls071416.php

The protein gadd45a and its relatives in the same group are involved in many processes relevant to aging, and can be adjusted to modestly extend life in flies. Gadd45a is in particular implicated in muscle atrophy, a process that significantly contributes to frailty in aging, and here researchers continue to dig into the biochemistry of this relationship:

Skeletal muscle atrophy is a serious and highly prevalent condition that remains poorly understood at the molecular level. Previous work found that skeletal muscle atrophy involves an increase in skeletal muscle Gadd45a expression, which is necessary and sufficient for skeletal muscle fiber atrophy. However, the direct mechanism by which Gadd45a promotes skeletal muscle atrophy was unknown. To address this question, we biochemically isolated skeletal muscle proteins that associate with Gadd45a as it induces atrophy in mouse skeletal muscle fibers in vivo.

We found that Gadd45a interacts with multiple proteins in skeletal muscle fibers, including, most prominently, MEKK4, a MAP kinase kinase kinase that was not previously known to play a role in skeletal muscle atrophy. Furthermore, we found that, by forming a complex with MEKK4 in skeletal muscle fibers, Gadd45a increases MEKK4 protein kinase activity, which is both sufficient to induce skeletal muscle fiber atrophy and required for Gadd45a-mediated skeletal muscle fiber atrophy. Together, these results identify a direct biochemical mechanism by which Gadd45a induces skeletal muscle atrophy and provide new insight into the way that skeletal muscle atrophy occurs at the molecular level.

Link: http://dx.doi.org/10.1074/jbc.M116.740308

As regular readers will know, I've long considered the cryonics industry to be a sensible, necessary undertaking in an uncertain world. For those of us interested in longevity, the primary plan is to accelerate development of rejuvenation therapies to the point at which we can achieve actuarial escape velocity: that we'll benefit somewhat from the first generation of therapies, and thus survive long enough to benefit from the second, much better generation of therapies, and so on, until aging is comprehensively defeated and our remaining healthy, youthful, vigorous lifespans become indefinite in length. It is almost certainly the case that some people alive today will achieve that goal. The open question is whether or not that group includes you and I, and that isn't something that can be predicted at the present early stage of development, in which the first true rejuvenation therapies, capable of repairing the cell and tissue damage that causes aging, are not even in the clinics yet.

Uncertainty is one of the reasons why advocacy and fundraising is so important. It is also the reason why a backup plan is a good thing to have. The only viable backup plan for the foreseeable future is cryopreservation, which is to say the low-temperature storage of the brain following clinical death in the hope of future restoration. The evidence is good for vitrification of brain tissue to preserve the fine structure of tissue that encodes the mind, and while the process in practice can always be improved in quality and organization, the (currently unknown) odds of survival following cryopreservation are infinitely higher than those attending any other end of life choice. After the grave there is only oblivion, but for so long as the data of the mind is preserved, there is hope that sufficiently advanced medical nanotechnology will one day bring you back.

I have put off signing up for cryopreservation for a decade or so. This isn't uncommon; after all, it involves paperwork, adult responsibility, planning ahead, thinking about unpleasant events, and all that. People put off many other things for these and similar reasons. Writing wills, buying houses, getting married, starting companies, and so on. That doleful feeling of some unknown scope of paperwork that will have to be accomplished in the event that you do get your act together and set forth to be a responsible adult is ever a strong deterrent. Still, sooner or later all these tasks have to be carried out, and while no-one enjoys wading through legal documents, it is never as bad as you think it is going to be. If you are unfamiliar with the process of signing up for cryonics organization membership and cryopreservation, let me tell you that it is much less work than buying a house. It is about two and half times the work of getting a life insurance policy, if that helps calibrate things any better. Typically, it runs as follows:

1) Contact one of the established cryonics providers (Alcor or the Cryonics Institute in the continental US) and ask to join. They will send you a raft of paperwork typical of membership organizations, but since it involves the highly regulated area of end of life decisions you will have to have some of the documents witnessed and notarized. You are signing up to pay a monthly fee to help keep the lights on, and to donate your remains to the provider on death, but this is all provisional pending organization of payment.

2) Obtain life insurance to pay for your eventual cryopreservation. This is where you will want advice, as there are only a few life insurance companies that have experience with this sort of thing. I recommend chatting to Rudi Hoffman, who has acted as an insurance agent for for scores of people in the cryonics community. Paying for cryopreservation with life insurance involves establishing a policy that will pay out to the cryonics organization on death rather than to the more usual parties, such as family members. The matter of how large a policy to purchase is an interesting question, and I encourage you to read an earlier post that walks through that topic. The short of it is that more is generally better, as the future is uncertain. Life insurance companies will want to pick through your medical records, will send a nurse to check your vital signs, and will usually find some reason to charge a little more than the early, optimistic quote that was given sight unseen.

3) Then you wait for paperwork to cross the country back and forth, as everyone involved between you, the cryonics provider, the insurance agent, and the insurer has to sign everything. It might take a month or two, depending on how many of the end points are comfortable with electronic document exchange, but there is usually a lot of back and forth required. There is always time to stop and think about any particular choice.

4) With membership and contracts in hand, you should take care of a few other supporting legal documents. This means making a will that determinedly and in no uncertain terms states your wish to be cryopreserved, and just as importantly establishing what is known as a living will or advance healthcare directive, a declaration of who you want to have power of attorney in the case of your incapacity, and what actions they should take. That should obviously be someone you trust to ensure that you are cryopreserved, and who for preference has absolute no financial interest in the outcome one way or another. Because the contents of the will and living will are somewhat non-standard, you will probably have to make use of an actual living, breathing attorney rather than one of the very helpful standardized form legal services that have sprung up of late.

There are cautionary tales in the cryonics community regarding people who trusted their immediate family to ensure that they were cryopreserved, and those family members then sabotaged the arrangements in order to access the life insurance funds. This has happened on numerous occasions. Much as I might sound a misanthrope to say this, the best assumption to keep in mind when setting up the legal aspects of your cryopreservation is this: when on your deathbed, everyone not employed by the cryopreservation organization is a potential adversary, interested in the funds that they might be able to obtain for themselves at the cost of your survival. It doesn't matter how well you know people today, or the nature of your relationships with them. Cryopreservation is (hopefully) decades in your future, half a lifetime or more away: people change, and people who don't even exist today will be involved in your end of life care, having legally meaningful ties to you by kinship. Fortunately, it is possible to arrange matters to make it very hard for even family members to sabotage your arrangements, and most of these approaches are well documented by the cryonics providers.

For example, firstly you should ensure that no-one in your family is even named in the life insurance policy you are buying. It should pay out to the cryonics organization, and you might pick an entirely unrelated charity to benefit should you be unfortunate enough to die in a way that prevents your cryopreservation - thus the incentives align for the cryonics provider to try their best, as they get nothing if they fail, and your family has no interest in the outcome either way. Secondly, persuade as many close family members as possible to sign and have witnessed affidavits of support for your cryopreservation. Third, structure your will and living will to ensure that there are material incentives for your family in the event that you are successfully cryopreserved, and there are no material incentives for any of them to block that outcome. Fourth, record your determination to be cryopreserved, both in your will and in other media, and keep that reasonably up to date. Lastly for this list there is the matter of avoiding the unwanted attention of the state in the form of autopsy or other delays after death. The best methods here vary by jurisdiction, but in some states registering a religious objection can work well.

The best way to keep everyone on your side in the matter of cryonics is to ensure that all of the incentives align with the outcome of a successful cryopreservation, should it come to that. The moment that someone can benefit by making it hard to achieve that goal - that is when the problems start. Relying on the essential goodness of human nature has never been terribly effective when it comes to expecting people to follow through with something that they themselves do not support, or think is frivolous, or which requires them to sacrifice their own gain. If you are in the room and exerting your will, that is one story, but when you are gone, it is quite another.

Aging came into being very early in the history of life, resulting from the evolution of strategies to deal with the inevitable accumulation of metabolic waste and damaged molecules in single-celled organisms: operating any sort of machinery produces wear and byproducts, and this is just as true of biological machinery. This can be seen in bacteria today, where cell division can shift most or all of the damage onto one of the daughter cells, using reproduction as a way to dilute waste and damage to maintain a core population that is pristine. The cost is a secondary population that is aging, becoming more damaged over time. These strategies were inherited by multicellular organisms, and show up in, for example, stem cell populations that must maintain themselves for long periods of time. There is a clear spectrum of collective action in mechanisms relevant to aging that reaches from the bacterial collaboration observed in the research here to the highly organized behavior of tissues and their stem cells in our species. At root, it is all about how to deal with damage, and aging is absolutely a matter of damage accumulation.

Microorganisms like bacteria reproduce by growing and dividing into two new bacteria. The older the bacteria, the more defects they have accumulated. When bacteria divide, the two new bacteria look the same, but the question is whether the defects are divided equally between the two new individuals. The researchers performed experiments in the laboratory and made model calculations. They wanted to investigate what was best for the bacterial community. Would it be best to have a colony that was aged to the same degree? Or would it be better for the colony to have the aging defects accumulate in some individuals, while others were free of aging defects and were thus younger?

In the laboratory they studied the bacterial colonies under different conditions and influences. The measurements showed that when a colony was left in peace, the bacteria shared almost symmetrically, so the new individuals were fairly similar with the same number of defects. However, if they exposed the colony to 'stress' in the form of heat or bacteriostatic compounds, cell division was asymmetrical. Now the defects gathered in one bacterium, which then aged and also grew at a slower rate. "What we have found is that the asymmetry of cell division is not controlled genetically. It is a process that is controlled by the physical environment. Through collective behaviour, the bacterial colony that is exposed to stress can stay young, produce more offspring and keep the colony healthier." This is a process that is probably universal and applies to cells in many organisms, including for stem cells. A single individual cell cannot overcome the damage, but the group of cells can do so together. The strength lies in the collective behaviour.

Link: http://www.nbi.ku.dk/english/news/news16/bacteria-avoid-age-defects-through-collective-behaviour/

It is known that the practice of calorie restriction, reducing calorie intake while still obtaining sufficient micronutrients, reduces inflammation in animals. This is one of many beneficial changes in the operation of metabolism observed to result from calorie restriction, and this intervention is well documented to extend life spans in short-lived species. Here researchers show that the same effects on inflammation occur in our species. Chronic inflammation rises with aging as the immune system becomes ever more dysfunctional, and contributes to the progression of all of the common age-related diseases. Inflammation is also produced by visceral fat tissue, however, which is one of the reasons why being overweight lowers life expectancy and increases risk of suffering age-related disease. Reduced amounts of visceral fat are probably an important cause of lower inflammation due to reduced calorie intake.

Restricting calories by 25 percent in healthy non-obese individuals over two years, while maintaining adequate protein, vitamin, and mineral intake, can significantly lower markers of chronic inflammation without negatively affecting other parts of the immune system. "Previous studies in animals and simple model organisms over the past 85 years have supported the notion that calorie restriction can increase the lifespan by reducing inflammation and other chronic disease risk factors, but with mixed results about whether it has a negative or null effect on cell-mediated immune responses. This is the first study to examine these effects over two years on healthy, normal- or slightly over- weight individuals and observe that caloric restriction reduces inflammation without compromising other key functions of the immune system such as antibody production in response to vaccines."

After six weeks of baseline testing, which included metabolic measurements to determine their total daily energy expenditure, and blood collection to evaluate inflammation and cell-mediated immunity markers, 220 eligible individuals were randomized into two groups and further stratified by site, sex, and body mass index. The control group maintained their normal diet for the duration of the study, while the test group was provided with support to maintain a high-satiety diet that restricted their calories by 25 percent including customized behavioral guidance. The test group was also given multivitamin and mineral supplements to prevent micronutrient malnutrition. To maintain a 25 percent reduction in calories the test group's calorie prescriptions were reduced three times through the two-year study to coincide with their weight loss based on body fat, and muscle mass calculations.

The research team found that the test group had a significant and persistent reduction in inflammatory markers with no discernible difference in immune responses from the control group at the end of 24 months. However, while reduction in weight, fat mass, and leptin levels were most pronounced at 12 months they were not accompanied by the significant reduction in C-reactive protein and TNF alpha, both indicators of inflammation, until 24 months. This delay suggests that long-term calorie restriction, at least 24 months, induces other mechanisms that may play a role in the reduction of inflammation.

Link: http://now.tufts.edu/news-releases/moderately-reducing-calories-non-obese-people-reduces-inflammation

Today I'll point out a brace of recent research materials, all of which focus on the aging brain. A great deal of aging research is focused on the effects of aging in the brain, in part driven by the large level of investment in Alzheimer's disease research, and this overlaps with ongoing efforts to understand how the brain works: how it gives rise to the mind and how specific functional aspects of the mind work, all the way down to the level of proteins and intricate cellular structures such as synapses. While some researchers restrict themselves to investigation and observation, trying to fill in the large blank spaces on the map of the brain, others are working to find ways to repair some of the damage and reverse some of the declines. Forms of cell therapy are perhaps the closest to being broadly useful at the present time, but all sorts of ways to clear out cellular garbage and unwanted metabolic waste - such as the amyloid associated with Alzheimer's disease - are headed in the general direction of viability for clinical development.

Not this year, but certainly within the next decade, new classes of treatment will arrive, therapies that can at least partially address some of the fundamental causes of functional decline in the aging brain, rather than trying to patch over the consequences as so much of present day medicine does. Initially these therapies will be highly restricted, available only in trials, or for patients in the late stages of neurodegenerative conditions. That is the outcome that the current regulatory system forces upon us. There will be a mild but sweeping revolution then, I hope, as treatments for the causes of aging become a reality, that will tear down the ridiculous systems of regulation that stifle development, with the result that effective therapies will become far less costly and far more widely available. A treatment that can address the causes of age-related disease is a treatment that should be undertaken by everyone on a regular basis, not just those who are heavily damaged by the processes of aging, and not just those groups that unaccountable bureaucrats decide should gain access. Today, the foundations for that future are still being built, one incremental step at a time, but is never too early to plan ahead.

The brain needs to 'clean itself up' so that it can 'sort itself out'

When neurons die, their remains need to be eliminated quickly so that the surrounding brain tissue can continue functioning. A type of highly specialised cell known as microglia is responsible for this process which is called phagocytosis. Neurons are known to die during the convulsions associated with epilepsy. But contrary to expectations, in this condition the microglia are "blind" and incapable of either finding them or destroying them. Their behaviour is abnormal. And the dead neurons that cannot be eliminated build up and damage the neighbouring neurons further, which leads to an inflammatory response by the brain which harms and damages it even further. This discovery opens up a new channel for exploring therapies that could palliate the effects of brain diseases. In fact, the research group that authored this work is right now exploring the development of drugs to encourage this cleaning up process, phagocytosis.

Connecting Malfunctioning Glial Cells and Brain Degenerative Disorders

The DNA damage response (DDR) is a complex biological system activated by different types of DNA damage. Mutations in certain components of the DDR machinery can lead to genomic instability disorders that culminate in tissue degeneration, premature aging, and various types of cancers. Intriguingly, malfunctioning DDR plays a role in the etiology of late onset brain degenerative disorders such as Parkinson's, Alzheimer's, and Huntington's diseases. For many years, brain degenerative disorders were thought to result from aberrant neural death. Here we discuss the evidence that supports our novel hypothesis that brain degenerative diseases involve dysfunction of glial cells (astrocytes, microglia, and oligodendrocytes). Impairment in the functionality of glial cells results in pathological neuro-glial interactions that, in turn, generate a "hostile" environment that impairs the functionality of neuronal cells. These events can lead to systematic neural demise on a scale that appears to be proportional to the severity of the neurological deficit.

Swapping sick for healthy brain cells slows Huntington's disease

Researchers have successfully reduced the symptoms and slowed the progression of Huntington's disease in mice using healthy human brain cells. The research entailed implanting the animals with human glia cells derived from stem cells. One of the roles of glia, an important support cell found in the brain, is to tend to the health of neurons and the study's findings show that replacing sick mouse glia with healthy human cells blunted the progress of the disease and rescued nerve cells at risk of death. Conversely, when healthy mice were implanted with human glia carrying the genetic mutation that causes Huntington's, the animals exhibited symptoms of the disease. The researchers believe that the healthy human glia were able to essentially stabilize and perhaps even rescue neurons by restoring the normal signaling function that is lost during the disease.

Cerebrovascular disease linked to Alzheimer's

While strokes are known to increase risk for dementia, much less is known about diseases of large and small blood vessels in the brain, separate from stroke, and how they relate to dementia. Diseased blood vessels in the brain itself, which commonly is found in elderly people, may contribute more significantly to Alzheimer's disease dementia than was previously believed, according to new study results. The study analyzed medical and pathologic data on 1,143 older individuals who had donated their brains for research upon their deaths, including 478 (42 percent) with Alzheimer's disease dementia. Analyses of the brains showed that 445 (39 percent) of study participants had moderate to severe atherosclerosis - plaques in the larger arteries at the base of the brain obstructing blood flow - and 401 (35 percent) had brain arteriolosclerosis - in which there is stiffening or hardening of the smaller artery walls.

The study found that the worse the brain vessel diseases, the higher the chance of having dementia, which is usually attributed to Alzheimer's disease. The increase was 20 to 30 percent for each level of worsening severity. The study also found that atherosclerosis and arteriolosclerosis are associated with lower levels of thinking abilities, including in memory and other thinking skills, and these associations were present in persons with and without dementia.

Adult Neurogenesis and Gliogenesis: Possible Mechanisms for Neurorestoration

The adult brain has some ability to adapt to changes in its environment. This ability is, in part, related to neurogenesis and gliogenesis. Neurogenesis modifies neuronal connectivity in specific brain areas, whereas gliogenesis ensures that myelination occurs and produces new supporting cells by generating oligodendrocytes and astrocytes. Altered neurogenesis and gliogenesis have been revealed in a number of pathological conditions affecting the central nervous system, indicating that modulation of the processes involved in adult neurogenesis and gliogenesis may provide a plausible strategy for treatment. Compared to neurogenesis, gliogenesis occurs more prevalently in the adult mammalian brain. Under certain circumstances, interaction occurs between neurogenesis and gliogenesis, facilitating glial cells to transform into neuronal lineage. Therefore, modulating the balance between neurogenesis and gliogenesis may present a new perspective for neurorestoration. These processes might be modulated toward functional repair of the adult brain.

New clues about the aging brain's memory functions

Researchers have shown that the dopamine D2 receptor is linked to the long-term episodic memory, which function often reduces with age and due to dementia. This new insight can contribute to the understanding of why some but not others are affected by memory impairment. In this study, a PET camera was used to examine individual differences in the D2 system in a group consisting of 181 healthy individuals between the age of 64 and 68. All participants also had to take part in an all-inclusive performance test of the long-term episodic memory, working memory and processing speed along with an MRI assessment (which was used to measure the size of various parts of the brain). Researchers could see that the D2 system was positively linked to episodic memory, but not to working memory or to processing speed by relating PET registrations to the cognitive data. Researchers could also see that the D2 system affects the functioning of the hippocampus in the brain, long linked to long-term episodic memory.

Researchers here cast doubt on nuclear DNA damage as a primary cause of decline in the stem cell population that is responsible for creating immune cells and blood cells. All cell populations accumulate random mutations in nuclear DNA over the course of aging. It is well proven that this causes a rise in cancer risk, though as noted in the paper here that isn't a simple linear relationship. The consensus position is that this damage also contributes to degenerative aging in the form of increased disarray in cell operations, but there is no solid evidence to demonstrate that this is in fact so, nor to show the degree to which it is a cause of aging in comparison to other forms of damage. There are opposing viewpoints from those who suggest that nuclear DNA damage isn't in fact significant in aging beyond the matter of cancer, at least over the present human life span.

The mammalian blood system consists of many distinct types of differentiated cells with specialized functions like erythrocytes, platelets, T-and B-lymphocytes, myeloid cells, mast cells, natural killer cells and dendritic cells. Many of these mature blood cells are short-lived and need thus to be replaced at a rate of more than one million cells per second in the adult human. This continuous replenishment depends on the activity of hematopoietic progenitor cells (HPCs) and ultimately hematopoietic stem cells (HSCs).

HSCs numbers and HSCs potential are controlled via complex regulatory mechanisms involving tight molecular and cellular control of quiescence, self-renewal, differentiation, apoptosis, and localization as well as cell architecture. Under steady state conditions, HSCs are a largely quiescent, slowly cycling cell population, where only 8% of cells enter the cell cycle per day. However, in response to stress, HSCs exit quiescence and expand and differentiate. The mostly quiescent status of HSCs is thought to be a protective mechanism against endogenous stress caused by reactive oxygen species and DNA replication. In contrary to a common assumption that cell loss is tightly associated with aging, the number of phenotypic HSCs actually increases in both mouse and humans. In the aged bone marrow, there are two- to ten-fold more HSCs present when compared to young. Aged HSCs show under stress, like for example in serial transplantation assays, a diminished regenerative potential as consequence of a lower long-term self-renewal capacity. Aging-associated changes can be attributed at least in part to aging of HSCs. Aged HSCs are deficient in their ability to support erythropoiesis and show a markedly decreased output of cells from the lymphoid lineage, whereas the myeloid lineage output is maintained or even increased compared to young HSCs.

A controversially discussed cell-intrinsic factor driving HSC aging is DNA damage. HSCs are responsible for maintaining tissue homeostasis throughout a lifetime. It is therefore critical for HSCs to maintain their genomic integrity to reduce the risk of either BM failure or transformation. The paradigm of the DNA damage theory of stem cell aging states that aging-associated changes in the DNA repair system in HSCs, together with changes in cell cycle regulation due to increased DNA damage with age, are thought to result in elevated DNA mutations, which then causally contribute to the decrease in HSCs function with age. However, genetic engineering of mutations in most of the genes linked to DNA damage response so far did not result in the "aging-characteristic" initial expansion of the number of phenotypic HSCs, rendering a central role for these genes and the pathways they represent with respect to physiological aging of the hematopoietic system not likely.

Data confirms a mild 2-3 fold aging-associated increase in the mutation frequency in hematopoiesis, the increase though is linear and not exponential with respect to age, rendering a cause-consequence relationship to the exponential increase of leukemia upon aging unlikely. Modeling of aging of HSCs populations based on evolutionary theories also demonstrates that accumulation of genetic changes within HSCs are not sufficient to alter selectivity and fitness of HSCs, and identified non-cell autonomous mechanisms, aka changes in the stem cell niche, as the major selective driving force for aging-associated leukemia. Such conclusions are also supported by the observation that while a 22-fold increase in the mutational load initiated cancer, a modest 2-3 fold increase in mutational load did not result in leukemia initiation. Finally, novel data from our laboratory demonstrated that the quality of the DNA damage response in HSCs does not change upon aging.

Since the accumulation of DNA mutations in HSCs upon aging might not be directly linked to the functional decline of HSCs with age and an aging-associated exponential increase in the incidence of leukemia, what other mechanisms might contribute to these phenotypes? It could already be shown that aging of the HSCs niche and environment plays an important role in selecting and expanding normal and pre-leukemic HSC and HPC clones upon aging. Thus the concept of adaptive landscapes has been recently developed. In this concept, the niche environment of HSCs changes upon aging, influencing the functionality of HSCs. The mutations acquired over time might not influence the HSC per se. In addition to extrinsic factors also intrinsic alterations that are not mutations in DNA might ultimately contribute to HSCs aging. We have recently reported that HSCs change their polarity upon aging, both in the cytoplasm and the nucleus. It might thus be possible that also changes in the general architecture of the cell might contribute to HSC aging. Changes in the 3D arrangement of epigenetic marks and structural proteins might influence for example cell divisions in a way that reduces potential in daughter stem cells, contributing to intrinsic HSC aging. In summary, multiple mechanisms might contribute to aging of HSCs, and ultimately depend on the interplay between cell extrinsic and cell intrinsic factors.

Link: http://dx.doi.org/10.1016/j.exphem.2016.06.253

It is known that greater levels of education correlate with greater life expectancy, but the novelty in the research here is a matter of just how far back in history this correlation can be shown to exist - it isn't dependent on access to very modern medicine. This is a part of a web of correlations between social status, intelligence, wealth, and education, all of which associate with modestly greater longevity. The underlying mechanisms and their relative importance remain debated; it seems easy to argue for wealth to grant relatively greater access to medicine, for example, but there is also evidence to link intelligence with greater physical robustness. Ultimately the point of building rejuvenation therapies is to make all of this irrelevant, however: for everyone to be able to live for as long as desired in perfect health, regardless of the hand dealt by chance and genetics.

By using historical data on about 50,000 twins born in Sweden during 1886-1958, we demonstrate a positive and statistically significant relationship between years of schooling and longevity. This relation remains almost unchanged when exploiting a twin fixed-effects design to control for the influence of genetics and shared family background. This result is robust to controlling for within-twin-pair differences in early-life health and cognitive ability, as proxied by birth weight and height, as well as to restricting the sample to monozygotic twins. The relationship is fairly constant over time but becomes weaker with age.

Literally, our results suggest that compared with low levels of schooling (less than 10 years), high levels of schooling (at least 13 years of schooling) are associated with about three years longer life expectancy at age 60 for the considered birth cohorts. The real societal value of schooling may hence extend beyond pure labor market and economic growth returns. From a policy perspective, schooling may therefore be a vehicle for improving longevity and health, as well as equality along these dimensions.

Link: http://dx.doi.org/10.1007/s13524-016-0489-3

Today I'll point out a great open access paper on the evolution of human telomere dynamics: telomere length, how that length changes over time, and especially how it changes with aging. This makes a good companion piece to another paper from last week that covered the differences in telomere dynamics between mice and humans. This is quite important, since most of the work on this topic involves mouse studies, not human studies. As telomerase gene therapies continue to extend average telomere length and - in mice at least - also extend healthy life span, this is becoming a hot topic in the aging research community. It is increasingly a good idea to have a grounding of the basics and current scientific thinking on this portion of our biochemistry. Sooner or later someone will be selling telomerase gene therapies to the public as an alleged method to slow the progression of aging, and most likely selling these treatments well in advance of any comprehensive human studies or definitive answers as to their effectiveness. You will find yourself in the position of deciding whether or not to pay the price and undertake the therapies. Better to figure out your position and what would change your mind today rather than later.

Telomeres are repeating sequences of DNA that cap the ends of chromosomes. Their purpose is primarily to act as a part of the limiting mechanisms on cell replication: a little of the length is lost with each cell division, and when they become too short the cell self-destructs or becomes senescent, ceasing replication. For any given tissue the distribution of telomere length among cells is a function of how often new cells with long telomeres are created by stem cells, and how often cells divide. Stem cells maintain long telomeres through the use of telomerase, which adds more repeating sections to replace those lost to cell division. In humans only stem cells use telomerase, but in mice it has a much more widespread activity. Mice also have much longer telomeres than humans. All of this has everything to do with cancer, of course. The whole complicated arrangement of cells that are limited coupled to a much smaller number of cells that are privileged has evolved because it limits uncontrolled growth sufficiently well for evolutionary success. Without it highly structured and comparatively long-lived species such as our own couldn't exist.

Since stem cell activity declines with aging, it isn't surprising to see that measures of average telomere length also tend to do so - but this is a very poor measure of aging, and really only shows up in statistical studies across populations. There are too many other influences over the most commonly measured types of cell, such as immune cells. So average telomere length, much discussed this past decade, looks a lot like a measure of age-related damage, far removed from root causes. Given that, why does increased telomerase activity extend life in mice? Most likely for the same reasons that any method of spurring greater stem cell activity improves matters in an old individual: greater tissue repair and maintenance, a net benefit even if it is old and damaged cells that do the work. There are also other, less well explored activities undertaken by telomerase that might be beneficial, such as improvements in mitochondrial function. In mice at least it seems that these benefits come with no greater risk of cancer. It may be that improved immune function destroys more potential cancers than are created through greater activity in age-damaged cell populations, but that is pure speculation at this point. For humans the effects on cancer risk are much more of a question mark, though it is worth noting that stem cell therapies to date have exhibited far less risk of cancer than was expected at the outset.

Telomere Length and the Cancer-Atherosclerosis Trade-Off

Modern humans, the longest-living terrestrial mammals, display short telomeres and repressed telomerase activity in somatic tissues compared with most short-living small mammals. The dual trait of short telomeres and repressed telomerase might render humans relatively resistant to cancer compared with short-living small mammals. However, the trade-off for cancer resistance is ostensibly increased age-related degenerative diseases, principally in the form of atherosclerosis. Telomere length genetics should be considered in the context of evolutionary forces that have left their signature on the human genome. Inspection of the human genome reveals that of the approximately 22,000 currently annotated genes, 13,000 genes (about 60%) are linked to biological pathways of "cancer". These include genes engaged in growth, development, tissue regeneration, and tissue renewal, which heighten cancer risk due to increased cell replication, and genes that suppress cancer, including those that ultimately promote senescence and apoptosis. Central among cancer-protective pathways might be telomere-driven replicative senescence.

Stem cells are likely to undergo more replications in large, long-living mammals than in small, short-lived ones; this is because more replications are necessary for developing and maintaining a larger body size. More cell replication confers increased risk of cancer through accumulating de novo somatic mutations, which happen during successive DNA replications. This concept is supported by work showing that the risk of developing major human cancers is related to the number of stem cell divisions occurring in the tissues from which the cancers originated. Yet, large, long-living mammals generally display no increase in cancer risk compared to small, short-lived ones, a phenomenon known as Peto's paradox, suggesting that mechanisms have evolved to mitigate cancer risk in tandem with increasing body size and longevity. One such mechanism has been described in elephants. The elephant genome contains many more copies of TP53, a potent DNA damage response and tumor suppressor gene; p53-dependent apoptosis is thus triggered at a lower threshold of accumulating mutations, conferring cellular resistance to oncogenic transformation.

Similarly, a telomere-linked mechanism has been proposed in mammals based upon observations that telomerase activity in somatic tissues tends to be inversely correlated with body size while telomere length is inversely related to lifespan. Repressed telomerase and short telomeres would, therefore, limit replicative capacity in humans. In this way, short telomere length might curb the accumulation of de novo mutations and reduce the probability of oncogenic transformation in large, long-living mammals. Given the wide variation in telomere length across humans, might longer telomeres increase cancer risk? While initial studies were inconsistent (perhaps partially due to flaws in study design and small sample sizes), more recent studies show that in individuals of European ancestry, long telomeres, as expressed in leukocyte telomere length (LTL), are associated with increased risk for melanoma, adenocarcinoma of the lung, and cancers of the breast, pancreas, and prostate. Moreover, Mendelian randomization studies using leukocyte telomere length associated SNPs support the inference that having a longer LTL has a causal relation to cancer risk.

The cancer protection conferred by short telomeres could come with an evolutionary trade-off, namely, diminished proliferative activity of stem cells and consequently less regenerative capacity. This would manifest in age-dependent degenerative diseases. Some of the leading degenerative diseases in humans are related to atherosclerosis, and atherosclerosis is associated with short LTL. As cancer and atherosclerosis strongly impact longevity, the diametrically opposing roles of TL in these two disorders might be relevant to understanding the lifespan of contemporary humans and future trajectories in life expectancy. Notably, in evolutionary terms, this would probably have become more relevant when agrarian societies emerged over the past ten thousand years or so and lifespans increased considerably. In fact, evidence of atherosclerosis has been detected in ancient human Egyptian mummies.

Recent studies have used LTL genome-wide association study findings to generate "genetic risk scores" for cancers and for atherosclerosis insofar as it is expressed in coronary heart disease. These studies have shown that the same cluster of LTL-associated alleles is a risk indicator for melanoma, lung cancer, and coronary heart disease, such that when the joint effect of the alleles results in a comparatively long LTL, the risk for melanoma and lung cancer is increased, whereas the risk for coronary heart disease is diminished. The opposite holds when the joint effect of the alleles results in a comparatively short LTL, which engenders a higher risk for coronary heart disease and a lower risk for cancer. This cancer-atherosclerosis trade-off might principally apply to contemporary humans because they live so long, but not to ancestral humans. This trade-off has been principally established through the force of evolution. In contrast to cancer, which is associated with over ten thousand genes, only several hundred genes in the human genome have been shown to relate to atherosclerosis. Yet, atherosclerosis is a major determinant in the longevity of humans because of their relatively long lifespan, especially in high- and middle-income societies.

In transthyretin amyloidosis, also known as senile systemic amyloidosis when it occurs in the elderly, the protein transthyretin misfolds to precipitate into solid masses. This occurs to varying degrees over the course of aging for all of us, and it is becoming clear that these amyloid aggregates contribute meaningfully to the progression of heart disease, among other conditions. It also seems that transthyretin amyloidosis is what finally kills most supercentenarians, the oldest of people who evade every other fatal age-related condition.

There is a potential therapy to break down this form of amyloid that last year demonstrated very promising results in a human clinical trial, but it is currently locked into the slow regulatory path to availability; development has been ongoing for most of the last decade at a glacial pace. It is frustrating, given that this or a similar treatment should be used by pretty much everyone over the age of 40 every few years, and such a treatment should reduce the incidence of many fatal age-related conditions. Meanwhile, other research groups are continuing their investigations of the mechanisms of this form of amyloidosis and considering potential approaches to clearing transthyretin amyloid:

The tetrameric thyroxine transport protein transthyretin (TTR) forms amyloid fibrils upon dissociation and monomer unfolding. The aggregation of TTR causes life-threatening transthyretin amyloidosis (ATTR) associated with three conditions traditionally known as senile systemic amyloidosis, familial amyloidotic polyneuropathy, and familial amyloidotic cardiomyopathy. Senile systemic amyloidosis is a late onset disease in which Tafamidis, a TTR tetramer stabilizer, has been recently approved in Europe; it delays progression of the disease. Several other therapeutics are currently in clinical trials, including other tetramer stabilizers such as diflunisal and RNAi therapies that cause a decrease in the production of TTR protein. Additional approaches are needed to prevent ATTR, and here we explore the use of peptide inhibitors that block aggregation of TTR.

Several models of the TTR amyloid spine have been proposed, but the aggregation-prone segments of the protein remain uncertain. Based on the studies of crystal structures of amyloid-driving segments, our group has proposed that fibrils can form through intermolecular self-association of one to several fibril-driving segments. Identical segments from several protein molecules stack into steric zipper structures, which form the spine of the amyloid fibril through tightly interdigitated β-sheets. Here we identify two segments of TTR that drive protein aggregation by self-association and formation of steric zipper spines of amyloid fibrils. Based on the amyloid structure of these two segments, we designed two peptide inhibitors that halt the progression of TTR aggregation.

Link: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4661406/

I mentioned Project|21 in yesterday's announcement of Michael Greve's $10 million pledge to SENS rejuvenation research and development, but I think it merits its own post. Not so very long ago the SENS Research Foundation engaged a specialist in high-end medical non-profit fundraising, and Project|21 is the outgrowth of that relationship, a program to raise the millions needed to take the first SENS therapies to readiness for human clinical trials over the next five years. To get to the point at which such a program is possible and practical required the years of groundwork and grassroots support that we as a community have provided: large donations always follow the crowd, and high net worth donors require advocates and thousands of supporters to light the way - and to continue those efforts. In effect, this launch of Project|21, alongside the advent of the first startups working on senescent cell clearance, marks a transition to a new stage of development for rejuvenation research following the SENS vision of repairing the cell and tissue damage that causes aging. Congratulations are due all round.

SENS Research Foundation today announced its Project|21 campaign to secure $50 million in private support from individual donors, foundations, and corporations. The goal of Project|21 is for SRF to partner with a new generation of visionary philanthropists, build the Rejuvenation Biotechnology industry, and bridge the most challenging gulf between research and treatment by enabling human clinical trials by 2021. Aubrey de Grey, founder and chief science officer of SENS Research Foundation said, "Ending aging will require large-scale investment to flow into a globally-recognized industry for rejuvenation biotechnology. Since we began in 2009, SENS Research Foundation has been putting all the pieces in place - core research groups, key players, shared knowledge, underlying tools - for the creation of this industry. The key programs funded by Project|21 can create an environment where the first damage repair interventions addressing specific age-related diseases will be brought to human clinical trials within five years."

The programs funded under Project|21 focus on three major barriers to the development of truly effective rejuvenation therapies. First, funding to convert promising basic research programs into solid investment candidates remains far too scarce. Second, there are too few opportunities for dynamic collaborations with mainstream regenerative medicine. Finally, there is little understanding of the regulatory pathways and clinical infrastructure these technologies will require. Project|21 addresses these three areas by creating a $15 million bridge fund to support promising early stage technologies; a center of excellence to deliver better opportunities for collaborative development of early stage programs; and a Rejuvenation Biotechnology Alliance Program to address challenges in regulation, manufacturing, and investment. The first donation received for Project|21 is a commitment from German internet entrepreneur Michael Greve's Forever Healthy Foundation for $5 million in philanthropic support over the next five years. In addition Michael Greve's company KIZOO Technology Ventures will be committing seed investments of $5 million in startups focused on bringing rejuvenation biotechnology treatments to market.

Link: http://www.sens.org/outreach/press-releases/project21-announcement

Michael Greve is an internet entrepeneur turned venture capitalist with a long-standing interest in aging and longevity, and today he has pledged $10 million in support of SENS rejuvenation research: $5 million for the science, and a further $5 million to fund startups for clinical development. This money will help speed the development of therapies that can repair the forms of cell and tissue damage that cause aging, and thus prevent age-related disease, rejuvenate the old, and significantly extend healthy life spans. Michael Greve runs the Forever Healthy Foundation and the Kizoo venture fund, and has become ever more involved in the SENS rejuvenation research community over the past few years. If you attended any of the recent SENS conferences you might have met him. He was one of the generous matching fund donors for last year's Fight Aging! SENS fundraiser, and this year his venture fund has invested in companies Oisin Biotechnology and Ichor Therapeutics, both of which are carrying out the clinical development of biotechnologies relevant to the SENS approach.

I'm very pleased to see that Michael Greve has now joined the ranks of those who have committed a significant amount of funding to SENS research, alongside Aubrey de Grey, Peter Thiel, and Jason Hope. As more people in the venture community demonstrate their public, material support for this path forward, I think that we're going to see greater interest from that quarter. This is something that the SENS Research Foundation has been building towards since its inception, as it is no accident that the organization is headquartered in the Bay Area. The $5 million that Greve has pledged to research will be the founding donation for Project|21, which is the new SENS Research Foundation high-level fundraising program aiming to pull in exactly this sort of support: millions for specific programs, to complete the first prototype SENS rejuvenation therapies and push this industry into existence. You'll be hearing a lot more of this in the years ahead.

As you look at this important step forward in the movement to bring aging under medical control, consider that we all helped to make this happen, to persuade people like Michael Greve that this is the right place to invest in progress. Without the community of grassroots support and activism, without our voices and our own modest donations, without the writing and the crowdfunding and the discussions, without the simple step of talking to your friends about ending aging, we could never have gained the interest of people who can devote millions to the causes they believe in. A movement is a process, a collaboration. Today we can celebrate, and I think it is clear that this is but the start of far greater growth and success to come in the years ahead.

Michael Greve Commits $10 Million

German Internet Entrepreneur Michael Greve today announced that his Forever Healthy Foundation will be committing $5 million in philanthropic support over the next five years to the SENS Research Foundation (SRF), a non-profit organization focused on transforming the way the world researches and treats age-related disease. In addition Michael Greve's company KIZOO Technology Ventures will be committing seed investments of $5 million in startups focused on bringing rejuvenation biotechnology treatments to market.

"My goal is to provide support for the critical research of the SENS Research Foundation and to facilitate the development of the rejuvenation biotech industry and ecosystem. I think we should have more people contribute to the step-by-step creation of cures for the root causes of all age-related diseases. And we should have a whole rejuvenation industry based on the SENS treatment model including the self-accelerating feedback-loop of success stories and amazing opportunities for scientist, entrepreneurs and VC investors. This will truly accelerate both research and therapies. I have decided to lead by example and make this $10 million commitment," said Michael Greve.

Forever Healthy Foundation's initial donation will fund projects including Allotopic Expression of Mitochondrial Genes led by Dr. Matthew O'Connor at the SENS Research Foundation Research center and Pharmacological and/or enzymatic cleavage of glucosepane crosslinks led by Dr. David Spiegel at Yale University, SENS Research Foundation's Education Program led by Dr. Greg Chin and other SENS Research Foundation programs.

"Michael Greve's commitment shows that there is clear support for the critical work of the SENS Research Foundation. As the first donation in our Project|21 fundraising campaign, it will help enable us to build a bridge to the first human clinical trials of Rejuvenation Biotechnologies by 2021. This gift is an important cornerstone that we will be able to build upon," said Mike Kope, CEO, SENS Research Foundation.

SENS Project|21

Project|21 is a new initiative created by SENS Research Foundation to end age-related disease through human clinical trials, starting in 2021, through investment in rejuvenation biotechnology. We have all the pieces in place - core research groups, key players, shared knowledge, and underlying tools - for the creation of this industry.

Through three new programs, the Bridge fund, The Center of Excellence, and The Alliance Program, Project|21 will deliver the perfect environment for this fusion of opportunity and investment. With proper stewardship of this emerging industry, we can create an environment where the first damage repair interventions to address specific age-related disease will be brought to human clinical trials within five years.

$50 million in total funding is required for Project|21, at least half of which will come from the members of SENS Research Foundation's Group|21. Group|21 will bring together 21 philanthropists, each donating between $500,000 and $5 million. Grants, grassroots efforts, and matching-fund strategies will provide the remaining support.

The past decade of genetic research into natural variations in human longevity have made it pretty clear that there are no large effects. Where genes influence longevity, they do so in later life, when individuals are damaged and health is failing, and individual effects per gene are both small and vary widely between study populations. This has long suggested to me that comparative genetics, examining long-lived and short-lived people, is not the place to find any sort of meaningful basis for a therapy to extend healthy life. The open access research linked below reinforces this point in a well-studied human population by associating longevity with genetic variants related to a number of biomarkers thought to reflect better health in old age. The individual associations found can be shown to explain only a small fraction of the observed variation in longevity:

Genetic studies have thus far identified a limited number of loci associated with human longevity by applying age at death or survival up to advanced ages as phenotype. As an alternative approach, one could first try to identify biomarkers of healthy ageing and the genetic variants associated with these traits and subsequently determine the association of these variants with human longevity. In the present study, we used this approach by testing whether the 35 baseline serum parameters measured in the Leiden Longevity Study (LLS) meet the proposed criteria for a biomarker of healthy ageing. We have previously proposed four criteria for a quantitative parameter that, we think, need to be fulfilled before being considered a biomarker of healthy ageing. In short, a biomarker of healthy ageing should show an association with (1) chronological age, (2) familial propensity for longevity, (3) known health parameters, and (4) morbidity and/or mortality. Thus far, biomarker research has identified several potential biomarkers of healthy ageing, such as glucose and free triiodothyronine (fT3) serum levels, CDKN2A (p16) gene expression, leukocyte telomere length (LTL), and gait speed.

By testing the four previously proposed criteria for biomarkers of healthy ageing in individuals from the LLS, we identified parameters involved in carbohydrate (glucose and insulin) and lipid metabolism (triglycerides) as biomarkers of healthy ageing. In addition, we showed that a relatively high proportion of the genetic variants previously associated with these parameters are also nominal significant in the largest genome-wide association study (GWAS) for human longevity to date. However, even in the largest GWAS for these parameters to date the explained variance is only 4.8% (glucose), 1.2% (insulin) and 2.1% (triglycerides), indicating that there is still a lot to discover. Nonetheless, we were able to find an enrichment of significant genetic variants, previously indicated to be involved in glucose, insulin and triglycerides regulation, in the longevity GWAS dataset. This indicates that the genetic component underlying these traits may also contribute to human longevity.

Link: http://dx.doi.org/10.1016/j.exger.2016.06.013

In what seems an important incremental advance in nerve regeneration, researchers have demonstrated regrowth of damaged portions of the optic nerve in mice, and partial vision restoration as a result. Once past the initial point of provoking regeneration of nerve tissue, the challenge here is as much to identify the degree to which vision is restored as it is to actually repair damaged nerves. Mice cannot be walked through a standard eye exam, and they cannot tell you in detail just how good or bad their vision is. Determining how well they can see after the processes of damage and regeneration is a difficult undertaking, though clearly here there is a lot of room for improvement.

In experiments in mice, scientists coaxed optic-nerve cables, responsible for conveying visual information from the eye to the brain, into regenerating after they had been completely severed, and found that they could retrace their former routes and re-establish connections with the appropriate parts of the brain. The animals' condition prior to the scientists' efforts to regrow the eye-to brain-connections resembled glaucoma, the second-leading cause of blindness. Glaucoma, caused by excessive pressure on the optic nerve, affects nearly 70 million people worldwide. Vision loss due to optic-nerve damage can also accrue from injuries, retinal detachment, and other sources.

Retinal ganglion cells are the only nerve cells connecting the eye to the brain. Damage to mammalian retinal ganglion cells' axons spells permanent vision loss. Mammalian axons located outside the central nervous system do regenerate, though. And during early development, brain and spinal cord nerve cells abundantly sprout and send forth axons that somehow find their way through a thicket of intervening brain tissue to their distant targets. While many factors are responsible for adult brain cells' lack of regenerative capacity, one well-studied cause is the winding down, over time, of a growth-enhancing cascade of molecular interactions, known as the mTOR pathway, within these cells.

In the study, adult mice in which the optic nerve in one eye had been crushed were treated with either a regimen of intensive daily exposure to high-contrast visual stimulation, in the form of constant images of a moving black-and-white grid, or biochemical manipulations that kicked the mTOR pathway within their retinal ganglion cells back into high gear, or both. The mice were tested three weeks later for their ability to respond to certain visual stimuli, and their brains were examined to see if any axonal regrowth had occurred. Importantly, while retinal ganglion cells' axons in the crushed optic nerve had been obliterated, the front-line photoreceptor cells and those cells' connections to the retinal ganglion cells in the damaged eye remained intact.

While either visual stimulation or mTOR-pathway reactivation produced some modest axonal regrowth from retinal ganglion cells in mice's damaged eye, the regrowth extended only to the optic chiasm, where healthy axons exit the optic nerve and make their way to diverse brain structures. But when the two approaches were combined - and if the mouse's undamaged eye was temporarily obstructed in order to encourage active use of the damaged eye - substantial numbers of axons grew beyond the optic chiasm and migrated to their appropriate destinations in the brain. Tests of the mice's vision indicated that visual input from the photoreceptor cells in their damaged eye was reaching retinal ganglion cells in the same eye and, crucially, being conveyed to appropriate downstream brain structures essential to processing that visual input. In other words, the regenerating axons, having grown back to diverse brain structures, had established functional links with these targets. The mice's once-blind eye could now see. However, even mice whose behavior showed restored vision on some tests, including the one described above, failed other tests that probably required finer visual discrimination.

Link: http://med.stanford.edu/news/all-news/2016/07/first-ever-restoration-of-vision-achieved-in-mice.html

October 1st is the the UN International Day of Older Persons, and for the past few years the International Longevity Alliance has been campaigning to make it Longevity Day as well. This is an example of a longer-term, more subtle form of outreach to the public, most of whom never give much thought to aging, medicine, or what might be done at the intersection of those two fields in the near future. Improving the backdrop to the discussion is one way to help build greater support for treating aging as a medical condition to extend healthy life. A range of community events were held or started on Longevity Day last year, including the 2015 Fight Aging! SENS fundraiser. A number of conferences are held around that time of year, and in 2016 these include the Eurosymposium on Healthy Aging, hosted by the Healthy Life Extension Society, as well as the next conference of the International Society on Aging and Disease (ISOAD), both of which are scheduled for the end of September.

Longevity Day and Longevity Month - October 2016

Following the tradition of 2013, 2014 and 2015, as usual 3 months before October 1, there starts the organization of events and publications toward the "Longevity Day" (based on the UN International Day of Older Persons - October 1) in support of biomedical aging and longevity research. This has been a worldwide international campaign successfully adopted by many longevity activists groups. Last year, events, meetings, publications and promotions were organized in the framework of this campaign in over 40 countries. Some promotions reached hundreds of thousands of viewers. This campaign has also received factual endorsement and publicity from several internationally and nationally recognized scientific and advocacy associations.

Hopefully, this year, the campaign will be no less enriching, unifying and impactful. Though this year, it was suggested, while keeping the "longevity day" concept as would be desirable to particular groups and activists, rather to emphasize and organize the longevity promotion events in October in a new framework - as "The Longevity Month" - as usually the "longevity day" events spread through the entire month of October. Various "commemorative months" to support particular advocacy issues is a well established and effective practice, and a dedicated "month" can give people more flexibility and space to organize events and publications. This time it would even be endeavored to gain some official state-level recognition of this commemorative month campaign.

Eurosymposium on Healthy Aging

The Eurosymposium on Healthy Ageing (EHA) is a biannual conference organized for the first time in 2012. This meeting will highlight the cutting-edge of knowledge in the field of biogerontology and provide a unique opportunity for researchers, government officials, biotech executives, and advocates from around the world to meet, network, and forge new scientific collaborations.

The process of biological ageing is the root cause of all chronic age-related diseases and is inseparable from them. Worldwide, more than one hundred thousand people die every day from age-related diseases. So-called (healthy) or (normal) ageing should be seen as a presymptomatic stage for the appearance of severe and debilitating age-related conditions, such as Alzheimer's disease, most cancers, and cardiovascular disease. Ageing is a set of structural changes reducing the time until the individual suffers permanent functional decline and diminished health. Therefore, whether ageing in adults is viewed as a disease or a syndrome, it should be understood as potentially amenable to biomedical inteventions.

Addressing ageing-related debilitating processes through biomedical means should become a new and powerful approach to the prevention of non-communicable diseases which affect most people at the later stages of life. The purpose of preventive medicine for the elderly is to preserve the structure of an ageing individual so as to prevent functional decline.

International Society on Aging and Disease (ISOAD)

Despite dramatic improvement in average life expectancy, maximum documented lifespan in humans has remained at about 100-120 years throughout history. Most people do not live this long, however, because of disease (including age-related disease) and, perhaps also, physiological changes associated with "normal" aging. It has been proposed that such pathological and physiological factors may be interrelated, in that the aged are more prone to disease and have more limited adaptive capacity than younger adults. About 80% of older adults have age-related disorders like obesity, diabetes, hypertension, or heart disease, and 50% have at least two. Thus, aging has been described as a "risk factor" for various diseases, but the practical value of identifying such a non-modifiable risk factor - as opposed to modifiable risk factors like diet or hypertension - is unclear. Some have gone so far as to consider aging the "cause" of age-related diseases, although this does not explain why such diseases do not develop in everyone, nor why different individuals get different diseases. Aging (i.e., becoming chronologically old) is inevitable, but age-related diseases may not be.

A major goal of modern medicine is to preserve quality of life. Applied to the elderly, this translates into concepts like "successful", "healthy", or "optimal" aging, which are considered to comprise avoiding disease and disability, maintaining good cognitive and physical function, and remaining actively engaged in life. These objectives require the coordinated efforts and combined insights of scientists studying the basic biology of aging - gerontologists - and those focused on age related disease - geriatricians and others. The major goal of this society is to provide a platform that will help to fill the current gap between studies of the basic biology of aging and of aged-related disease.

It cannot be stated too many times that extended life will not produce overpopulation or the sorts of resource shortages constantly feared by Malthusians. Even if it did, that would be a prompt to solve both the resource problem and the aging problem, not a prompt to condemn billions to death by relinquishing the clear path ahead to widespread, cheap rejuvenation treatments. Malthusian visions of any form are simply incorrect, however. They are based on a static view of the world in which the nature of resources doesn't change. Humans, however, are ingenious and motivated by the prospect of future scarcity and increased prices to develop new resources and new technologies. This has happened over and again, yet for some reason we still have Malthusians. There is some flaw in human nature that makes it hard to see that the world is being changed for the better even while we are in the midst of radical progress in science and technology.

A classic objection to the radical extension of life is: "But such an extension will lead to an overpopulation crisis!" We think this is important to refute that idea that longevity equates to overpopulation, because it is not a harmless idea. Actually, this formula is so widespread that it is used to stop investment of public money in longevity research, because people making decisions have serious reserves: nobody wants to invest money in a project that would lead to an overpopulation crisis! Therefore, it is important to avoid turning longevity into a scapegoat. In addition, if we knew how to live much longer in good health, it would not be very humane to force people to die at 80 in order to avoid some hypothetical overpopulation problems.

The fertility rate is the average number of children per woman in a given population. When this rate is around 2, the population is considered stable. Being overly concerned about life extension, while easily accepting a fertility rate slightly greater than 2, is simply not rational. Even if death disappears tomorrow morning, the resulting population increase would be smaller than the one observed during the baby boom. And should it happen in Sweden, then after 50 years, the population increase would only be 30%, which is within the limits of the population increases observed during the last century. Therefore, even after such an unlikely event (and assuming that it is a problem), we should have more than enough time to adapt. But we are far from being at this point: living 50 more years would already be a major scientific advance! There is no good reason to ban or to refuse to finance longevity research.

Last but not least, keep in mind that the context can radically change before life expectancy increases significantly. This has already been the case during the industrial revolution. We could discover new ways to provide shelter and food to more people at a smaller price, make new zones habitable, and even, in the long-term, colonize new planets. It is evident that a radical increase in population is not a "goal" in itself. But, assuming that it happens, it's consequences may be far less dramatic than what we imagine today, because the context will have evolved. In the previous century, some people thought that London would eventually be entirely covered with horse manure. Today, this idea makes people laugh! In past predictions, we always underestimated the increase of life expectancy and always overestimated population growth. Are we not making the same mistake again? Two centuries ago, Malthus (the most famous thinker of overpopulation) was making apocalyptic predictions based on the scale of one century. Today, the population has been multiplied by 8 and instead of collapsing, the standards of life have significantly increased.

Link: http://ieet.org/index.php/IEET/more/longevity_overpopulation_the_erroneous_equation

Researchers here use some of the more recently sequenced mammalian genomes, of the majority eutherian branch that encompasses all of the mammals you might be familiar with, to investigate a potential role for gene duplication in the evolution of aging and longevity. This is a good example of much of the breadth of research into aging in that it is very far removed from any practical outcome: it is an unhurried process of mapping. Fundamental research is nonetheless essential despite - or arguably because of - the lack of a clear use for the knowledge gained.

One of the greatest unresolved questions in aging biology is determining the genetic basis of interspecies longevity variation. Within Eutherians, bowhead whales live more than 200 years, while short-lived rodents generally live up to 4 years. Gene duplication is often the key to understanding the origin and evolution of important Eutherian phenotypes. Many longevity-associated pathways evolved via gene duplication, and duplication can increase lifespan and impact the pathogenesis of various aging-related diseases. With the availability of genomes from long- and short-lived species and a set of hundreds of genes known to influence lifespan in model organisms, we thoroughly investigated the role that gene duplication played in the evolution of Eutherian longevity from a systematic perspective.

Longevity-associated gene families have a marginally significantly higher rate of duplication compared to non-longevity-associated gene families. Anti-longevity-associated gene families have significantly increased rate of duplication compared to pro-longevity gene families and are enriched in neurodegenerative disease categories. Conversely, duplicated pro-longevity-associated gene families are enriched in cell cycle genes. There is a cluster of longevity-associated gene families that expanded solely in long-lived species that is significantly enriched in pathways relating to 3-UTR-mediated translational regulation, metabolism of proteins and gene expression, pathways that have the potential to affect longevity. The identification of a gene cluster that duplicated solely in long-lived species involved in such fundamental processes provides a promising avenue for further exploration of Eutherian longevity evolution.

We can only speculate whether the inferred duplication patterns in this study could have impacted Eutherian longevity. In reality, longevity evolution is probably the result of many genes exhibiting small effect sizes, meaning that pinpointing the exact source of longevity determination will be extremely difficult to detect, even in large studies. Because we know that the environment and condition of an individual play a massive role on the proteins that are being expressed, perhaps the true meaning of the reason for duplicating these genes in long-lived species may not be fully understood from solely this perspective. However, subtle differences at the genomic level can exert a large phenotypic effect. It is possible that duplicating a small cluster of interrelated genes solely in long-lived species that have core functions involved in RNA and protein metabolism could have directly or indirectly impacted their longevity through their functions in gene and protein networks.

Link: http://onlinelibrary.wiley.com/enhanced/doi/10.1111/acel.12503/

The commentary linked below takes a look at some recent work on the topic of cellular reprogramming and the rejuvenation it appears to cause inside cells. In the grand scheme of things, it really hasn't been that long since researchers first discovered how to reprogram somatic cells into induced pluripotent stem cells. These artificially altered cell populations have the same characteristics as embryonic stem cells, able to generate any type of cell in the body given the right stimulus and environment. Reprogramming is so easy to carry out that it swept through the research community with great rapidity, and the improvements and further experimentation started almost immediately. Along the way, numerous researchers have found that reprogramming old cells in this fashion appears to revert a number of characteristic signs of cellular aging. Damaged mitochondria are removed, some epigenetic markers are altered in the direction of youthfulness, and so forth.

It is understood that cells are, in principle, capable of rejuvenation. Something must happen to repair the damage and epigenetic changes of aging in between that point at which aged germ cells get together and the point at which a young embryo is growing. Parents are old. Babies are young. A range of intriguing research on early embryonic development suggests the existence of a program of cleansing and repair that operates when the embryo is still only a handful of cells. It is not unreasonable to think that cellular reprogramming as it currently exists is triggering some fraction of those developmental rejuvenation mechanisms as something of a side-effect. The interesting question is whether or not there are useful near future medical applications that might result from a greater understanding and control of cellular rejuvenation of this nature.

The most obvious application is that any sort of cell therapy using the patients own cells is probably going to be improved if the cells are more rather than less youthful. Since reprogramming has this effect, and researchers are working towards using induced pluripotent stem cells in therapies, this will probably happen by default at the outset, and then be improved via degrees of optimization as the field of regenerative medicine progresses. On the other hand, safely inducing some form of rejuvenation-like repair or alteration of cell state in site in the body and brain sounds like a much more challenging proposition. It isn't at all clear that such an approach is even possible or plausible; a greater understanding is needed when it comes to exactly how rejuvenation is being achieved in reprogrammed cells. For example, it may well be the case that some of what appears to be rejuvenation is in fact a selection effect. Reprogramming typically has a low rate of success when you look at the number of cells in a sample that are converted, and perhaps those are all less damaged examples. But see what you think of this commentary and its references:

Stem cells for all ages, yet hostage to aging

Researchers showed that aging transcriptional changes in fibroblasts were reversed in induced pluripotent stem cells (iPSCs) derived from donors across the lifespan. Subsequently, when iPSCs were induced to form neurons by direct induction (iNS), the aging transcriptional signature was also absent. In contrast, when aging fibroblasts were directly programmed to iNS by a similar protocol, they maintained an aging transcriptional signature. Remarkably, much of this signature was not the original signature of the fibroblasts but a new age-associated signature more closely allied to neural related gene action. Thus, fibroblast-derived iNS retained an "aging state" on direct cell programming, but not a hard wired, age-related transcriptional signature. The potential for fibroblast rejuvenation extends to 'senescent cells': from the same 74 years old individual, iPSCs were derived from either primary fibroblasts or replicatively senescent fibroblasts after serial in vitro passaging: both differentiated into normal embryonic lineages. Surprisingly, given the huge attention to regulatory mechanisms underlying iPSC generation, there has not been extensive comparison of iPSCs by donor age.

How do pre-existing problems such as DNA damage relate to these processes? Mutations accumulate in aging skin as in all other mammalian tissues. Primary fibroblasts from breast skin of donors aged 20-70 showed exponential increases in double-strand DNA breaks against a linear doubling of chromosome structural abnormalities, 10% to 20% across the adult lifespan. Are their corrective mechanisms as part of the reprogramming process, and if so, how do these work? Alternatively, reprogramming may select against damaged cells within a mixed cell population, which might be estimated by the efficiency of reprogramming. Future studies may define a threshold level of DNA damage that is permissive for iPSC generation. It has been proposed that iPSC generation with extensive cell proliferation would "dilute any accumulated molecular damage" which could not occur during iNS generation under conditions that limited cell proliferation. While replicative processes may weed out protein damage, it is not clear how these would remove DNA damage. As well as selecting against damage to nuclear DNA, selection is also likely for mitochondrial function. Other groups have shown remarkable mitochondrial rejuvenation in iPSCs generated from aging donors.

These findings have broad ramifications for the field of regenerative medicine. Whatever the mechanisms at play, the loss of aging signatures in iPSCs is good news for autologous iPSC directed-cell therapies where the aging population will be the major target for personalized regenerative medicine. However, while iPSCs and their direct derivatives may be rejuvenated, the host's aging environment is problematic. For example, grafts of embryonic neurons into older Parkinson patients show donor cells acquire features of diseased host neurons. Inflammation related to Alzheimer disease, and to basic aging itself, can also attenuate grafted stem cell function. Thus, prospects for rejuvenation by iPSC may still remain hostage to the aged host.

Harmful actions on the part of senescent cells, whose numbers increase with age, is one of the root causes of degenerative aging. There is a growing interest in building therapies to clear out these problem cells and thereby postpone age-related disease and lengthen health life. Researchers here take the interesting step of protecting senescent cells from the usual array of evolved systems that try (and often fail) to destroy them, implanting these protected cells in mice, and then observing the results. This study provides evidence to suggest that the problem isn't just the senescent cells themselves, but that their presence also produces unwanted behavior in the immune system, and the development of a senescent-like class of immune cells.

Senescent cells (SCs) have been considered a source of age-related chronic sterile systemic inflammation and a target for anti-aging therapies. To understand mechanisms controlling the amount of SCs, we analyzed the phenomenon of rapid clearance of human senescent fibroblasts implanted into SCID mice, which can be overcome when SCs were embedded into alginate beads preventing them from immunocyte attack. To identify putative SC killers, we analyzed the content of cell populations formed around the SC-containing beads.

One of the major cell types attracted by secretory factors of SCs was a subpopulation of macrophages characterized by p16(Ink4a) gene expression and β-galactosidase activity at pH6.0 (β-galpH6), thus resembling SCs. Consistently, mice with p16(Ink4a) promoter-driven luciferase, developed bright luminescence of their peritoneal cavity within two weeks following implantation of SCs embedded in alginate beads. p16(Ink4a)/β-galpH6-expressing cells had surface biomarkers of macrophages F4/80 and were sensitive to liposomal clodronate used for the selective killing of macrophages. At the same time, clodronate failed to kill bona fide SCs generated in vitro by genotoxic stress. Old mice with elevated proportion of p16(Ink4a)/β-galpH6-positive cells in their tissues demonstrated reduction of both following systemic clodronate treatment, indicating that a significant proportion of cells previously considered to be SCs are actually a subclass of macrophages.

These observations point at a significant role of p16(Ink4a)/β-galpH6-positive macrophages in aging, which previously was attributed solely to SCs. They require reinterpretation of the mechanisms underlying rejuvenating effects following eradication of p16(Ink4a)/β-galpH6-positive cells and reconsideration of potential cellular target for anti-aging treatment.

Link: http://www.aging-us.com/article/XFECL8coa6th4i87b/text

Researchers have assembled a map of gene expression changes that occur with aging in human muscle, and here draw some first conclusions from their work:

Aging profoundly affects skeletal muscle, including loss of muscle mass and strength and increasing the levels of fat and connective tissue. This condition, often termed age-related sarcopenia, leads to a variety of physical conditions that reduce life quality and overall health in aging individuals. As we age, we lose approximately 1% of leg lean mass per year and approximately 2.5-4% in leg strength, men to a higher extent than women. This indicates that sarcopenia is not only a matter of loss of muscle mass but rather a concomitant loss of muscle mass and a decline of muscle quality. In order to efficiently delay the onset and severity of sarcopenia, it is crucial to more in detail describe the molecular mechanisms causing this physiological deterioration of muscle function.

Although high-throughput studies of gene expression have generated large amounts of data, most of which is freely available in public archives, the use of this valuable resource is limited by computational complications and non-homogenous annotation. To address these issues, we have performed a complete re-annotation of public microarray data from human skeletal muscle biopsies and constructed a muscle expression compendium consisting of nearly 3000 samples. In our meta-analysis, we find 957 genes significantly associated with aging. The data provides substantially more detail to gene-specific effects of the transcriptome and shows more widespread regulation of gene expression associated with aging than previously reported. We further study the pleiotropic associations of the 957 genes associated with aging and show for example that 20 out of the 21 aging genes are also associated with physical capacity but regulated in the opposite direction with increased physical capacity as compared to increased age. The skeletal muscle expression compendium is publicly available at ArrayExpress with accession number E-MTAB-1788.

Expression of genes in all the major complexes in the electron transport chain (ETC), as well as several genes in the PDH complex decreased with aging. These results together with those of others support the view that elderly subjects have a nearly 50% lower oxidative capacity per volume of muscle than younger subjects. At the cellular level, this decrease has been ascribed to a reduction in mitochondrial content and lower oxidative capacity of the mitochondria, i.e., this decrease of mitochondrial constituents could either reflect defective mitochondria or decreased number of mitochondria or both. Several potential regulators of mitochondrial mass and function were identified among the 957 age-associated genes in the current study. We also find that genes that have a function in glucose uptake and energy sensing are strongly affected by aging. For example, we see reduced expression of the γ1 regulatory unit of AMPK with increased age. AMPK is a major energy sensor in skeletal muscle, controlling crucial steps of both glucose and lipid metabolism through the ability to sense AMP levels.

Strikingly, we find that genes that are associated with both aging and physical capacity are largely counteracting. The presented data thereby support efforts to maintain high physical fitness in an aging population to counteract negative effects on mitochondrial function. In particular, we hypothesize that SOCS2 and FEZ2, which show significant associations with age, body mass index (BMI), and physical capacity and acting in the same direction for BMI and age but in the opposite direction for increasing physical capacity, have key regulatory functions in processes that link these three factors. SOCS2 interacts strongly with the activated IGF1R and may play a regulatory role in IGF1 receptor signaling. Age-associated difference in the mRNA level of SOCS2 has previously been demonstrated in muscle from rat, where it was suggested to reflect resistance to the effect of growth hormone. Also, an acute bout of resistance exercise is capable of upregulating SOCS2 in human skeletal muscle. FEZ2 is to our knowledge a novel age-associated gene, the expression of which was altered in the opposite direction with physical capacity.

Link: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4600214/

There is a lot of interest in telomeres and telomerase these days, and in particular the prospect of slowing some aspects of aging by increasing the gene expression of telomerase. Life span has been extended in mice through telomerase gene therapies, for example, and BioViva claims a human implementation. I suspect they are only the most vocal initiative, and I doubt that the patient there is the only individual to have undergone telomerase gene therapy, given how widely available gene therapy technologies have become in the past few years. I am cautious on this front, however, and one of the cautions I usually bring up is that telomere dynamics in mice are different from those in humans, and different in ways that are probably important in this matter. I'd want to see studies of telomerase therapies in mammals with more human-like telomere dynamics before taking the leap myself. But what do I mean by different? The open access paper I'll point out today is a review of telomeres and telomerase in our two species; if you want an overview the details, then take a look.

Telomeres are repeating DNA sequences tacked onto the ends of chromosomes. Every time a cell divides, a little of that telomere length is lost, and when it becomes short enough a suite of mechanisms ensure that the cell self-destructs or irreversibly halts replication. This is the basis for the well known Hayflick limit: that ordinary somatic cells that make up the bulk of our tissues only divide so many times and then stop. Stem cells, however, use telomerase to lengthen their telomeres as necessary, and thus can continually deliver a supply of new cells with long telomeres to support tissues by replacing cells that have reached the limit. This arrangement only really makes sense in the context of cancer: the setup in which only a tiny number of cells have privileged replication rights exists because it keeps the cancer rate low enough to allow for complex, structured species such as ourselves and our ancestors.

As I'm sure you're aware, average telomere length as presently measured in white blood cells tends to fall with aging, but this is a complicated number. It depends on a mix of (a) the rate of cell division, which in the immune system relates to health in a number of ways, and (b) the activity of stem cells as they deliver new daughter cells with long telomeres into the tissue they support. Stem cell activity declines with age, and this is probably enough to expect declines in average telomere length. Thus telomere length looks a lot like a marker of aging, not a cause. Even so, in immune cells there are so many environmental influences on cell division and replacement rates that it is a bad marker of aging - only useful over populations, in statistical studies, and not all that helpful for individuals.

Increasing the activity of telomerase will result in longer telomeres. The primary role of telomerase is to add new repeating sections of telomeric DNA at the ends of chromosomes. Longer telomeres produce cells that will divide more often, but it also means that more worn cells will survive rather than be destroyed, and more damaged cells will undertake more activity. If telomerase activity is increased in all or a majority of cells, the result might look somewhat like the effects of much greater stem cell activity, but with the addition that the extra cells are older and more damaged. In stem cell populations, more telomerase may also spur greater stem cell activity in and of itself. The consensus view is that all of this will likely increase cancer risk, but in mice telomerase gene therapy both slows aging and reduces cancer risk. This may be because immune function is improved, and thus more cancerous threats are defeated than are produced, but there is no assurance that the balance of changes will work out the same way in humans.

Human Specific Regulation of the Telomerase Reverse Transcriptase Gene

In humans, telomeres serve as an aging clock because most somatic cells lack telomerase (i.e., hTERT) expression and their telomeres progressively shorten upon successive cell division. Indeed, studies have shown that telomere shortening is a critical factor of human aging and its stabilization is essential for the development of most human cancers. Human TERT (hTERT) expression increases significantly during tumorigenesis, correlating with the increased proliferative potential of cancer cells. Telomere length regulation and mechanisms of proliferative senescence are not evolutionarily conserved, even among mammals. In a comparative analysis of telomere length and telomerase expression in cells of over 60 mammalian species, researchers concluded that the ancestral mammalian had human-like short telomeres and repressed telomerase expression. Cells in these animals undergo replicative aging, providing a barrier for tumor progression. On the other hand, many other mammals, especially some of the smaller and shorter-lived animals, such as rodents, telomeres become much longer, and telomerase is found in most somatic tissues. These studies provided a conceptual framework for understanding different telomere homeostasis in mammals and identified the need to use appropriate models for studying the role of telomere in human cancer and aging.

Laboratory mice are the most commonly used animal models for human development, aging, and diseases. While telomere length serves as a critical counting mechanism for cellular senescence in human cells, mice do not exhibit telomere-mediated replicative aging. Compared to humans, telomere homeostasis in mice is distinctive in two ways: Laboratory mice express ubiquitous telomerase activities in somatic tissues and possess long heterogeneous telomeres. There exist significant differences in telomerase expression between humans and mice. Unlike the hTERT, which is not expressed or expressed at extremely low levels in the most of human somatic tissues and cells, the mouse TERT (mTERT) expression is found in most adult tissues and organs. This difference likely results in, or at least contributes to, much longer telomeres (50-100 kb) in laboratorial mice, in comparison to human telomere (5-15 kb). As a result, telomere length is not apparently a limit to cellular lifespan in mouse cells.

Mouse models of human diseases have become a central part of biomedical research. Laboratory mice provide the most experimentally accessible mammalian models that share genes, organs, and systemic physiology with humans. However, many mouse models do not comprehensively mimic human disease progression, posing challenges in their exploitation to study human diseases. This may have contributed to the high failure rates of human clinical trials, particularly in oncology, predicating the need for improved preclinical data from mouse models. A principal difference between mice and humans relates to a longtime observation that murine fibroblasts grow in culture undergo spontaneous immortalization at a high frequency, owing to their long telomeres and constitutive telomerase expression. In conclusion, hTERT expression strictly limits telomerase activation in most of somatic cells, whereas mTERT expression is detectable in most of mouse tissue cells. The interspecies differences between human and mice suggest an improved mouse line, in which both telomerase regulation and telomere length controls are humanized, would considerably benefit the studies of human aging and cancer using mouse models.

Researchers have provided solid evidence to demonstrate that cartilage tissue does not renew itself in any meaningful way over the course of a life span. This implies that finding and encouraging existing tissue maintenance processes may not be a particularly useful strategy in regenerative medicine for cartilage - unlike the case for a number of other less regenerative tissues, where such maintenance exists, just at a very low level. These results suggest that engineering of new tissue sections, either in situ or for transplantation, will likely be a more important component of regenerative medicine for cartilage going forward into the near future.

Using radiocarbon dating as a forensic tool, researchers have found that human cartilage rarely renews in adulthood, suggesting that joint diseases may be harder to treat than previously thought. The technique, which dates tissues by tracing radioactive carbon and measuring it against levels of carbon-14 in the atmosphere from the nuclear bomb testing in the 1950's and 1960's, reveals that cartilage is an essentially permanent tissue in healthy and osteoarthritic adults alike. The findings may help explain the limited success of cartilage transplant and stem cell therapy for osteoarthritis, and may redirect treatment efforts to preventing cartilage disease and protecting joints from further damage.

Whether cartilage, the tissue lining the surface of joints, regenerates or remains "fixed" throughout life is a subject of debate. Less still is known about the effects of joint diseases on cartilage turnover. Researchers turned to the bomb pulse method, which exploits the fact that all living things through their diet incorporate carbon-14 from the atmosphere. During the Cold War, atmospheric levels of this carbon isotope spiked due to the testing of nuclear bombs, leaving a detectable imprint in all organisms living at the time. The technique has been used to estimate the age of fat, muscle, the eye lens, and other tissues. The researchers have now applied it to cartilage in knee joints from eight healthy and 15 osteoarthritic individuals born between 1935 and 1997. Across all individuals, the researchers detected virtually no formation of new collagen in cartilage, even in disease or under high loads, suggesting that the tissue is an essentially permanent structure. The findings help explain why human cartilage has poor healing capacity after injury and present new challenges for treating osteoarthritis and other joint diseases.

Link: http://www.eurekalert.org/pub_releases/2016-07/aaft-rds070516.php

Mitochondrial DNA, inherited from the mother, has a handful of varieties - known as haplogroups - in each species. Mitochondrial damage and function plays an important role in determining the natural progression of aging, and there is plenty of evidence to show that some haplogroups are a little better or a little worse than others when it comes to the mechanisms of aging, damage, and function. Here, researchers have produced a particularly clear example of this point in mice, in which the improved health observed likely results from hormesis, in that a small amount of damage is being generated within cells by increased oxidative molecule production in mitochondria, that results in greater cellular repair activities, and the result is a net benefit.

Mice bred such that their nuclear and mitochondrial DNAs derive from different strains tend to grow old in better health than mice whose mitochondrial and nuclear DNAs are ancestrally matched. These apparent health benefits occur despite signs of oxidative stress in the mismatched animals. Mitochondria, the energy-producing power stations of cells, have their own small genomes. And, compared with the human nuclear genome, these mitochondrial genomes are highly variable. But with the exception of known disease-causing mitochondrial DNA (mtDNA) mutations, he noted, "we always considered this variability just not relevant." The idea was that if the variants did somehow alter metabolic physiology, they would likely have been lost during evolution. But growing evidence suggests that normal non-pathogenic mtDNA variations could have more subtle effects on physiology than first thought. Such variations have been suggested to reflect mitochondrial and metabolic adaptations to different climates, for example. And in cells, mitochondria from different strains of mice have indeed been shown to exhibit different metabolic outputs.

Because mitochondria are only inherited maternally, the team crossbred female mice of the strain NZB/OlaHsd with male mice of the strain C57BL/6. For 20 generations, the researchers mated the resulting female offspring with C57BL/6 males, essentially diluting the nuclear DNA from the NZB/OlaHsd strain until it was practically non-existent. The resulting "conplastic" mice thus had mtDNA from NZB/OlaHsd, but nuclear DNA from C57BL/6. Compared with mice whose nuclear and mtDNA was of C57BL/6 origin, the conplastic animals had a longer median life span (although maximal life span was similar). They also showed better preservation of their ovaries in advanced age, fewer tumors at death, and maintained more steady cholesterol levels with age. In short the conplastic animals had better health spans. "We were surprised that the foreign DNA made the animals look healthier and age healthier."

And there were more surprises. The healthier disposition of the conplastic animals was - counterintuitively - associated with increased levels of potentially damaging reactive oxygen species (ROS), at least in young animals. "What they are seeing in the mismatched cases is basically an increase in oxidative stress. And that appears to be having generally a beneficial effect on health." One possible explanation is that because the mitochondrial enzyme complexes contain subunits encoded by both nuclear and mitochondrial genes, when the two genomes are mismatched these complexes may not function quite as efficiently, which would result in a mild stress response. And, "a mild stress response, as long as it's not too much, might be good for your overall health."

Link: http://www.the-scientist.com/?articles.view/articleNo/46483/title/Health-Effects-of-Mitochondrial--Nuclear-DNA-Mismatch/

Readers here probably recall the hype surrounding sirtuins in cellular metabolism, followed by the breathless marketing of compounds supposed to affect their expression such as resveratrol, all of which went to the usual destination for such things, which is to say nowhere. Some knowledge was added to the grand map of mammalian biochemistry, some people were fleeced, some people made a bunch of money on the backs of promises that never materialized, and that was that. This happens over and again. Every time a new link is uncovered in the complex chain of protein machinery relating to cellular repair mechanisms, upregulated in many of the ways to extend life in lower animals, or calorie restriction, a practice that extends life in short-lived mammals such as mice, and along the way alters near every aspect of the operation of metabolism, then the marketing begins for any supplement that can be linked, tenuously or otherwise, to that research.

If you recognize the general pattern, then you should be well placed to see how things will play out for nicotinamide riboside. This is yet another molecule that can be used as a supplement, and which influences some of the mitochondrial biochemistry associated with cellular maintenance processes. In mice it has been shown to modestly reduce some forms of age-related decline, either by spurring greater maintenance or greater stem cell activity. It is an open question as how much of this will be recapitulated in humans; short-lived species are much more readily influenced by this sort of thing. Their life spans are plastic, and so are their metabolic operations. Regardless, it is of course the case that a bunch of people got together to form a company in order to sell nicotinamide riboside as a supplement. That company is called Elysium Health.

The differences between this and past efforts of this nature are that (a) more reputable scientists from the aging research field are involved, more is the pity for their reputations, and (b) the whole affair is just a little closer to a sensible take on how to make progress in the field, rather than being an absolute money grab. In fact I agree with a fair bit of what cofounder Leonard Guarente has said in public on his motivations for doing this: that progress must be made more rapidly, that there is a space between the worthless supplement market and the highly regulated world of medicine in which good work can be done, and that it is important to put new approaches out there in the world to gather data. I just don't think that this particular approach has any merit in and of itself. Regular readers will know my position on tinkering with metabolism via drugs and found compounds in order to gain tiny and dubious benefits. It is a a waste of time and effort, and definitely not the road to meaningful outcomes in the treatment of aging. Further, even putting that to one side, the founders of Elysium haven't gone about this in the right way at all. They should have sold their product as an open trial of nicotinamide riboside wherein people pay for participation, doubled the price of the supplement, and used that extra money to collect data from participants. Instead they, as everyone is, are corrupted by the fiduciary duty that comes with running a company where the primary focus is selling a branded supplement - so now they are in the supplement business, not the science business. It should be an object lesson for the next group who are thinking of doing something like this.

The Weird Business Behind a Trendy "Anti-Aging" Pill

A renowned MIT aging scientist as cofounder. Not one, not two, but six Nobel prize laureates as scientific advisors. Oh, and a product that could just maybe help you stay feeling young. It's no wonder the dietary supplement company Elysium has attracted attention in an industry not exactly known for scientific rigor. One of the main ingredients in Elysium's supplement, Basis, is a chemical called nicotinamide riboside. It has, in fact, shown promise making mice healthier. No research has shown it to be effective in humans - a fact that Elysium's cofounders will readily admit. But they're also out to prove that NR isn't just snake oil. And so Elysium is currently running a human trial to suss out the effect of NR in older adults. Not that the company is waiting for those results. It's already touting NR's benefits for DNA repair and energy, which is perfectly legal under the Food and Drug Administration's (loose, sketchy) rules about dietary supplements. You can say almost anything you want as long as the claims aren't about specific diseases.

As others have pointed out, Elysium's supplements business is a savvy way of sidestepping the FDA's more onerous regulations around drugs. The agency doesn't even consider aging a disease. Why make a costly, time-consuming bet on FDA approval when you can start selling supplements for $50 a month right away? But another company, ChromaDex, actually is interested in getting FDA approval for NR right now. It wouldn't be an anti-aging drug - again, aging isn't a disease - but would instead get approved to treat a rare, genetic disease in kids called Cockayne syndrome. The point? While ChromaDex is waiting for that approval, it makes and sells raw NR to several companies, who repackage the supplement and sell it under their own brands - including, yes, Elysium.

Dozens of studies have sketched out a promising story: Levels of NAD decline with age. Boosting it seems to rejuvenate cells in mice. But does taking NR boost NAD levels enough to slow aging in humans? Nobody knows. Nevertheless, the mouse studies created demand for stable molecules that turned into NAD in the body. In 2011, ChromaDex licensed a patent for synthesizing NR in a lab - far cheaper than trying to purify it from milk. They named the product Niagen. You can buy it from several different consumer brands online, including Elysium. To boost future demand, ChromaDex has set up 70 research agreements with universities or research institutes to study nicotinamide riboside, putting up money and supplying scientists with the compound. Martens, the UC Boulder researcher, had been working with a different NAD precursor in mice when he found out about ChromaDex's NR. He reached out to the company, and they are now collaborating on a human trial that looks at NR's effect in healthy, older adults. That's independent of Elysium's trial.

Elysium is differentiating itself with Nobel prize winners and with savvy branding. Despite Elysium's pledged allegiance to scientific rigor, it is still selling a supplement unproven in humans - an expensive one, at that. Guarente told me he thought the nonhuman evidence was convincing, and he wanted to put the information out to let the customer decide. "You don't have to start now. If you want to wait, wait. We're taking it." I caught my self feeling that Elysium's pills, packaged in a sleek jar and backed by so many experts, seemed more legitimate than the bottles of NR online. But then why should I? It's all the exact same NR made by ChromaDex. Branding is a powerful thing.

I'm very much in favor of freedom. For my money, all of medicine should be as open as this: that anyone can invest the time and money to package and sell a product, that consumers can easily find all of the research online to read up on what the scientific community has to say, and that reviewers can take that information to provide digests for those who don't want to read the research. Freedom means the existence of marginal products as well as great products, and people doing things you personally think are a waste of time as well as people doing things you agree with, but you can always identify these as such. You just have to take a little time to read around the topic before you reach for your wallet. Freedom also means a far greater set of activity and greater experimentation and availability of new approaches than would take place if all of this was hammered flat beneath the cost of regulation, and that, I think, would be worth the price of admission. Successes will prove themselves by virtue of the fact that sellers will find it worth the cost of setting up formal trials to demonstrate effectiveness, for example.

Those people who live a very long time are typically much healthier than their peers, and spend a shorter period of their lives suffering from age-related disease and disability. Aging is a process of accumulating cell and tissue damage, and those people who are more resilient to damage, or who have suffered less of it though simple happenstance, will be less impacted in all aspects of aging. This is exactly what we'd like to achieve through the development of rejuvenation therapies that can repair this damage, which even in their early stages should produce a much greater difference in outcomes than the naturally occurring gap between long-lived and short-lived people.

Research has shown that the human lifespan has the potential to be extended. But would this merely mean people living longer in poor health? The upbeat findings from a new study indicate that those extra years could well be healthy ones. In a study of nearly 3,000 people, the onset of illness came decades later in life for centenarians than for their younger counterparts. "Most people struggle with an ever-increasing burden of disease and disability as they age. But we found that those who live exceptionally long lives have the additional benefit of shorter periods of illness - sometimes just weeks or months - before death."

The researchers looked at the health status of centenarians and near-centenarians enrolled in two ongoing studies: the Longevity Genes Project (LGP) and the New England Centenarian Study (NECS). The LGP recruits healthy, independently living Ashkenazi Jewish people 95 and older from the northeastern United States. For comparison, the LGP includes a group of Ashkenazi Jewish individuals who do not have a parental history of longevity. The NECS began in 1994 as a study of all centenarians living in eight towns near Boston and was later expanded to include participants from North America generally as well as England, Ireland, Australia and New Zealand. The NECS comparison group consisted of people aged 58 to 95.

This study compared (1) the health status of 483 long-lived LGP participants with 696 LGP comparison individuals 60-94 years old, and (2) the health status of 1,498 long-lived NECS participants with 302 NECS comparison subjects aged 58-95. For both sets of comparisons, the researchers looked at the ages at which individuals developed five major age-related health problems: cancer, cardiovascular disease, hypertension, osteoporosis and stroke. Analysis revealed a consistent pattern of delayed onset of illness in the LGP and NECS centenarian groups compared to their respective comparison groups. For example, for the long-lived NECS individuals, cancer didn't afflict 20 percent of men until age 97 and women until 99. In contrast, 20 percent of NECS comparison participants had developed cancer by age 67 in men and 74 in women. Results were similar for the LGP: for the long-lived LGP participants, the age at which 20 percent had developed cancer was delayed to 96 for both sexes. But cancer had affected 20 percent of LGP control-group males by age 78 and control-group females by 74.

Despite their genetic, social and cultural differences, the long-lived LGP and NECS participants proved markedly similar with respect to major illness: Compared to younger comparison groups, their onset of major age-related disease was delayed, with serious illness essentially compressed into a few years very late in life. The findings suggest that discoveries made in one group of centenarians can be generalized to diverse populations. And they contradict the notion that the older people get, the sicker they become and the greater the cost of taking care of them.

Link: http://www.einstein.yu.edu/news/releases/1189/living-longer-associated-with-living-healthier-study-of-centenarians-finds/

Researchers are making inroads into the biochemistry of age-related stem cell decline in muscles, the tissue most studied in this part of the field. Here, another protein is added to the list of those that change with age and seem to play an important role in this process, given that researchers can use it to restore the loss of muscle regeneration in old animals:

Muscle stem cells are the primary source of muscle regeneration after injury. These specialized adult stem cells lie dormant in the muscle tissue - off to the side of the individual muscle fibers, which is why they were originally dubbed satellite cells. When muscle fibers are damaged, they activate and proliferate. Most of the new cells go on to make new muscle fibers and restore muscle function. Some return to dormancy, which allows the muscle to keep repairing itself over and over again. Researchers determined that the function of integrins (or, more specifically, the protein called β1-integrin) is absolutely crucial for maintaining the cycle of hibernation, activation, proliferation, and then return to hibernation, in muscle stem cells. Integrins are proteins that 'integrate' the outside to the inside of the cell, providing a connection to the immediate external environment, and without them, almost every stage of the regenerative process is disrupted. The team theorized that defects in β1-integrin likely contribute to phenomena like aging, which is associated with reduced muscle stem cell function and decreased quantities of muscle stem cells. This means that healing after injury or surgery is very slow, which can cause a long period of immobility and an accompanying loss of muscle mass.

Researchers determined that the function of β1-integrin is diminished in aged muscle stem cells. Furthermore, when they artificially activated integrin in mice with aged muscles, their regenerative abilities were restored to youthful levels. Importantly, improvement in regeneration, strength, and function were also seen when this treatment was applied to animals with muscular dystrophy, underscoring its potential importance for the treatment of muscle disorders. Muscle stem cells use b1-integrin to interact with many other proteins in the muscle external environment. Among these many proteins, they found a clue that one called fibronectin might be most relevant. They discovered that aged muscles contain substantially reduced levels of fibronectin compared to young muscles. Like b1-integrin, eliminating fibronectin from young muscles makes them appear as if they were old, and restoring fibronectin to aged muscle tissue restores muscle regeneration to youthful levels. Their joint efforts demonstrated a strong link between b1-integrin, fibronectin and muscle stem cell regeneration. "Taken together, our results show that aged muscle stem cells with compromised b1-integrin activity and aged muscles with insufficient amount of fibronectin are both root causes of muscle aging. This makes b1-integrin and fibronectin very promising therapeutic targets."

Link: https://carnegiescience.edu/node/2058

The SENS Research Foundation's 2016 crowdfunded research initiative is focused on progress towards a universal cure for all forms of cancer, and needs our help to hit its goals within the next six weeks. Here is a poster to help spread the word:

Today's cancer therapies are both expensive and highly specific. There are hundreds of types of cancer, and many of them can evolve to defeat any one therapy as it is delivered. The research community can greatly improve this state of affairs, however, as it is possible to build a truly universal cancer therapy - one that cancers cannot evolve resistance to - by blocking telomere lengthening. All cancers rely on the abuse of ways to extend telomeres in order to grow without restraint. Telomeres become shorter with each cell division, a crucial part of the mechanisms that normally limit the number of times a cell can replicate. Since all forms of cancer bypass replication limits in this way, an effective method of safely shutting down telomere extension might be used to bring an end to all cancers. Even better, since there are only a few ways in which cells can lengthen telomeres, building such a universal cancer therapy will probably cost much the same as any one of the present generation of cancer therapies that can only be used on one or a few of the hundreds of types of cancer. If we want to defeat cancer in our lifetimes, this is the way to go: find the common mechanism and strike there. The SENS Research Foundation is building a crucial part of this technology, using philanthropic donations from people like you and I to pick up the slack where the research mainstream has thus far failed to build the needed tools.

The cancer patient advocacy community and the aging patient advocacy community overlap to some degree, but most cancer research advocates and supporters have never heard of this research. It is still comparatively new. Many of you reading this post will know people who are involved in the cancer establishment in one way or another: researchers, survivors, supporters, and more. Please do reach out. Point them to the SENS Research Foundation crowdfunding project, or the Fight Aging! interview with researcher Haroldo Silva, where the science is explained, and ask them where best to seek support for this important venture. The more people we can introduce to this research program, the better off we all are in the long term. The path to defeat cancer really is a matter of changing the economics and strategy of cancer research: a switch in to focus on universal therapies produced for the same cost as current therapies, but that are capable of effectively treating a far greater range of cancer types - or, as is the case here, all cancer types.

You are welcome to take the fundraising poster above and make good use of it. Since text resizes badly, there is a 4200px x 2800px version for printing and the 600px x 400px version above for other uses. If you want to improve upon the design yourself, then you might find it useful to know that the fonts are Mic32 New Rounded, for the SENS Research Foundation logo, and Tex Gyre Heros for the rest. You can also extract a usefully resizeable SENS logo from the 2012 annual report PDF if you are so minded. Everyone can make a difference! I encourage you to reach out to your communities, and tell them something that they didn't know about the possibilities for the future of cancer research, and how important it is to help make them a reality by donating today.

Both amyloid-β and tau aggregate in clumps and fibrils in aging brains, but much more so in the brains of Alzheimer's patients. The network of relationships and damage surrounding these aggregates is dense and still to be fully mapped. The progression of Alzheimer's disease is very complex at the detail level, as can be judged by the wide variety of theories proposed in just the past few years, as well as by the great diversity of efforts to determine how exactly the damage is done to brain cells and how to prevent it. The research noted here is an example of one particular class of efforts undertaken to better understand Alzheimer's, those involving the creation of models of the condition in animal lineages:

For decades, Alzheimer's disease, the most common cause of dementia, has been known to be associated with the accumulation of so-called neurofibrillary tangles, consisting of abnormal clumps of a protein called tau inside brain nerve cells, and by neuritic plaques, or deposits of a protein called beta-amyloid outside these cells along with dying nerve cells, in brain tissue. In Alzheimer's disease, tau bunches up inside the nerve cells and beta-amyloid clumps up outside these cells, mucking up the nerve cells controlling memory. What hasn't been clear is the relationship and timing between those two clumping processes, since one is inside cells and one is outside cells.

In humans, the lag between development of the beta-amyloid plaques and the tau tangles inside brain nerve cells can be 10 to 15 years or more, but because the lifetime of a mouse is only two to three years, current animal models that successfully mimic the appearance of beta-amyloid plaques did not offer enough time to observe the changes in tau. To address that problem, researchers genetically engineered a mouse model that used a tau fragment to promote the clumping of normal tau protein. They then cross-bred these mice with mice engineered to accumulate beta-amyloid. The result was a mouse model that developed dementia in a manner more similar to what happens in humans.

Prior studies of early-onset Alzheimer's disease have suggested that the abnormal accumulation of beta-amyloid in the brain somehow triggers the aggregation of tau leading directly to dementia and brain cell degeneration. But new research suggests that the accumulation of beta-amyloid in and of itself is insufficient to trigger the conversion of tau from a normal to abnormal state. Instead, it may set off a chain of chemical signaling events that lead to the "conversion" of tau to a clumping state and subsequent development of symptoms. "For the first time, we think we understand that the accumulation of amyloid plaque alone can damage the brain, but that's actually not sufficient to drive the loss of nerve cells or behavioral and cognitive changes. What appears to be needed is a second insult - the conversion of tau - as well." One implication of the new research, is to possibly explain why some drugs designed to attack the disease after the conversion of tau haven't worked. The work also suggests that combination therapy designed to prevent both the beta-amyloid plaque formation as well as pathological conversion of tau may provide optimal benefit for Alzheimer's disease.

Link: http://www.eurekalert.org/pub_releases/2016-07/jhm-gem063016.php

This open access paper is largely focused on type 2 diabetes, a condition that in most patients can be reversed even quite late through low-calorie diets and weight loss, but the principle of targeting senescent cells and chronic inflammation produced by an age-damaged immune system can be applied to many age-related conditions. While removing senescent cells is the most straightforward and practical approach to dealing with their bad behavior, and clinical development, there is a faction within the research community who would prefer to develop drugs that alter the behavior of senescent cells to be less damaging. This is a much more challenging undertaking, nowhere near any clinical application, but fits better with the prevailing scientific goal of mapping all of the biochemistry of such cells.

A chronic proinflammatory status is a pervasive feature of aging. This chronic, low-grade, systemic inflammation occurring in the absence of overt infection (sterile inflammation) has been defined as "inflammaging" and represents a significant risk factor for morbidity and mortality in the elderly. There is growing epidemiological evidence that a state of mild inflammation is associated with and predicts several age-related diseases (ARDs), including type 2 diabetes mellitus (T2DM) and its complications (e.g., cardiac death). The life expectancy of T2DM patients is about 6 years shorter than that of nondiabetic individuals of similar age.

Together with immunological factors, cellular senescence and the senescence-associated secretory phenotype (SASP) are currently held to be the largest contributors to inflammaging; however, a key role of senescence in patients with the most common ARDs (e.g., diabetes) has yet to be conclusively demonstrated. Significantly, at least two major molecular changes responsible for diabetes complications and also associated with physiological aging and T2DM, that is, oxidative stress and endoplasmic reticulum (ER) stress, have recently been related to senescence acquisition and/or SASP modulation. These findings suggest that the SASP can contribute to the endothelial dysfunction characterizing aging as well as T2DM.

Here we review the latest data connecting oxidative and ER stress with the SASP in the context of aging and T2DM, with emphasis on endothelial cells (ECs) and endothelial dysfunction. Moreover, since current lifestyle interventions and medications are unable to reduce the mortality of diabetic patients from cardiovascular disease, we also outline a gerontological, SASP-centered view of the vascular complications of diabetes that could provide a broader range of therapeutic options.

Link: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4908264/

As you might have noticed, the SENS Research Foundation is presently asking for your support in a crowdfunding campaign that aims to close in on a universal therapy capable of effectively treating all types of cancer, one based on blocking telomere lengthening. As is often the case, the SENS network is here using philanthropic donations to pick up necessary work that hasn't been taken on by the rest of the community, so as to unblock progress. The scientist who will lead the work is Haroldo Silva; he has been focused on this particular branch of cancer research for some years now, and below you'll find a short interview that covers some of his thoughts on the field and on this effort in particular.

I should emphasize that this SENS initiative is an important component in efforts to completely change the way in which the research community approaches the treatment of cancer. The cancer research community suffers from a high level strategy problem: the majority of treatments are only applicable to a small number of cancer types, out of the hundreds of known types, and the majority of new technology platforms under development will be just as expensive to adapt to a different type of cancer as to build in the first place. A much more efficient approach is needed, as there are only so many researchers and only so much funding in the world. As Silva describes below, blocking telomere lengthening is the most efficient of possible better approaches: all cancers must lengthen their telomeres in order to grow, and abuse a small number of target mechanisms in order to do so. These mechanisms, telomerase and alternative lengthening of telomeres (ALT), are very fundamental to cellular biochemistry. If they are turned off, it is expected that there is no way for a cancer to evolve around that dead end.

A cure for all forms of cancer is important today, but will become much more important in the future. Cancer stems from mutational damage to cells, and I believe that repair of random nuclear DNA damage scattered across all of our cells is going to be one of the more challenging operations to carry out on human biochemistry. So far no-one has come up with a methodology that is more plausible than the types of advanced nanorobotics requiring a mature molecular manufacturing industry: atomic-scale machinery to visit every cell, analyze, and repair DNA. All sorts of quite effective rejuvenation therapies are going to emerge long before it is possible to fix that problem: some are being worked on by startup companies even now. Thus the future of health in our lifetimes will involve partially rejuvenated people living actively for decades longer than they would otherwise have done, bearing a high load of mutational damage, and with much more active stem cell populations. This is a recipe for a lot of cancer, so the research community had better come up with something better than the present approach - and it is very much in our interest to aid the most promising efforts. To the extent that the SENS Research Foundation and allied researchers are supported in building ways to safely block telomere extension in cancerous cells, we can look forward to truly universal therapies that can be applied to all cancers.

You've been working with the SENS Research Foundation for a while now. How did you get involved in this grand endeavor? What drew you to the fields of aging and cancer?

Early in my college career I became interested in developing technologies that could substantially improve human health and so I majored in Biomedical Engineering with a particular focus on cardiovascular diseases. In graduate school at UC Berkeley, I became more directly involved in aging research by studying the behavior of stem cells from muscle tissue as a convenient model for understanding genetic and age-related diseases. While at Cal, I attended a seminar on campus by Aubrey de Grey on the SENS approach to combating the diseases and disabilities of aging, which drew me to the SENS Research Foundation. Since 2013, I have led the OncoSENS team on our project aimed at treating and preventing cancers that grow by relying specifically on the telomerase-independent Alternative Lengthening of Telomeres (ALT) mechanism. Of course my research endeavor is only one strand of the seven outlined by Aubrey de Grey in Ending Aging, but if we can tackle this major societal burden known as cancer we can potentially improve the health and life spans of millions of people worldwide.

Controlling cancer and ALT: could you outline your research, and how it fits into the bigger picture? Why is this important?

Cancer is truly a disease of the elderly. Both incidence and death rates grow exponentially with age. And as the population ages globally, according to estimates by the World Health Organization, there will be 21.4 million new cases of cancer worldwide in 2030, which is a whopping 52 percent increase over the 14.1 million cases in 2012. Unfortunately, during the same time span, the number of cancer-related deaths worldwide is expected to increase by 61 percent, from 8.2 million to 13.2 million. Therefore more than 34 million people could be alive and healthy in the year 2030 alone if we succeed in eradicating cancer from our lives!

To accomplish the noble goal mentioned above, our strategy is to attack the single characteristic that virtually all cancer cells have in common: The ability to maintain or elongate telomeres. Every time a cell divides its telomeres, or the DNA sequences at the very ends of each chromosome, get shorter and shorter until the cell is no longer able to replicate. At that stage a cell can either remain dormant or senescent or simply die. Cancer cells on the other hand are able to bypass this natural limitation by replacing telomeric sequences lost with every cell division. There are only two currently known ways for cancer cells to accomplish telomere maintenance. One of these mechanisms relies on expression of an enzyme called telomerase and the other is termed Alternative Lengthening of Telomeres (ALT), which is completely independent from telomerase activity. Our current efforts are focused solely on the ALT pathway.

Our collaborator in Australia, Dr. Jeremy Henson, discovered and published about 7 years ago that ALT cells contain a unique DNA structure that is circular, partially double-stranded and composed of telomeric DNA sequences and he named those structures C-circles. His pioneering work showed that the amount of C-circles in ALT cells correlates directly with the level of ALT activity performed by these cancer cells. However, the method used in the study to detect these C-circles was not amenable to automation and large-scale investigations. Through our collaboration with Dr. Henson, we have developed a high-throughput method to detect C-circles in ALT cancer cells, which enables us to screen thousands of small molecules very quickly and analyze their impact on ALT activity. Once we identify particular drugs in our screens that can inhibit ALT activity, these drugs can potentially be develop further into treatments for ALT cancers.

Given that you have developed a way to speed up all this testing, if you raised the stretch goal of $200,000 in the present fundraiser, what would that really mean for the science?

Raising $200,000 would allow us to test all of the 115,000 drugs in the diversity compound library. This particular drug library was specifically designed to include not only a broad range of chemical structures but also virtually every drug already approved for clinical use worldwide. Using this library will dramatically increase our chances of identifying a potential lead candidate for further testing and validation. Moreover, if one or more lead candidates comes from the pool of drugs already deemed safe and effective for other clinical applications, we can potentially re-purpose these drugs for the treatment of ALT cancers. The advantage here is that such compounds have already been through extensive clinical trials and have a history of use in patients, which significantly lowers the barrier for approval in other disease contexts.

In the short term, this amount of funds would help validate our assay as a bona fide tool for high-throughput screening of ALT-specific phenomena. Our approach could be applied to any other drug library as well as to investigate genes and molecular signaling pathways involved in the regulation of ALT activity. The field of ALT cancer research can definitely benefit from such enabling technologies. In the long term, the massive amount of knowledge as well as tangible strategies capable of tackling the ALT mechanism gained in the context of cancer will inevitably lead to novel therapies that will help millions of patients around the globe. We really mean it when we say we want to "Control ALT, Delete Cancer" so that society can finally be free from the burden of this terrible disease.

All things considered, shouldn't blocking telomere lengthening be a majority concern in the cancer research community? Why is that the SENS Research Foundation has to step in to get things done here?

The cancer research community does recognize the blocking of telomere lengthening as an important strategy for the treatment of cancer. The problem is that since the telomerase-based pathway is used by about 85% of all cancers, most of the community is concerned with therapeutic approaches aimed at disrupting telomerase-expressing cancer cells through a variety of methods. Thus it is not surprising that a lot of these approaches are already in advanced stages of clinical trials. On the other hand, ALT-specific anticancer therapies simply do not exist outside the realm of basic scientific research. This is why the SENS Research Foundation stepped in to bridge this gap by developing technologies that can advance the field of ALT cancer research as quickly as possible. Since the ALT mechanism is used by 15% of all cancers, any telomerase-based therapeutic approach would be ineffective for these patients, so there is a significant unmet clinical need here that definitely deserves more attention from the cancer research community, public and private alike. Moreover, there is an increasing amount of evidence suggesting that attacking telomerase-expressing cancers will lead to some of them switching to the ALT mechanism, rendering the antitelomerase therapy useless against the disease at that point. The SENS Research Foundation and our group in particular are working really hard to give cancer patients better treatment options that can potentially cure the disease or significantly improve its prognosis.

Most of us have no idea what a day's work in a molecular biology lab looks like. What sort of projects do you work on from week to week? What are the joys and frustrations?

Working in a lab whose sole purpose is fighting age-related disease in general and cancer in particular is very exciting and rewarding. However, not all of the work we do is the most glamorous since there are a lot of routine procedures needed day to day to keep the lab running smoothly. These include growing cancer cells in different cell culture dishes to generate enough cells to be able to perform many types of experiments, autoclaving all sorts of lab consumables to ensure sterility, washing glassware, and so on. Since our main focus is the high-throughput drug screening project, we are devoting a significant amount of resources towards optimizing our experimental protocols in our robotic liquid handler, the Biomek 2000. Automation is crucial to our work, especially when handling plates that have 384 tiny wells. We also have ongoing collaborations with other labs around the world that rely on our ALT-specific assays to analyze their samples. The incredible feeling of joy we get when a week-long experiment results in positive results that takes us a step closer to a potential life-saving cancer treatment is difficult to describe in words. On the other hand, when a long experiment fails is incredibly frustrating, but we often do learn something new or useful from both successes and failures in the lab. We need the frustrating moments to make the joyful ones that much sweeter!

The world sees cancer research as slow, incremental, and expensive. Can the SENS strategy for cancer treatment help bring an end to that?

I would say that biomedical research as a whole is slow, incremental, and expensive. Cancer research is therefore no exception. There are many factors involved in contributing to this current state of affairs that are well beyond the control of a small non-profit organization like SENS Research Foundation. Nonetheless, our technologies can potentially accelerate the pace of discovery in the field of ALT cancer research by allowing scientists to screen thousands of small molecules from a variety of libraries to pinpoint genes, RNA entities and drugs that are involved in the regulation of ALT activity. Such discoveries, combined with the advancements made in telomerase cancer research, can lead to a more dynamic pace of therapeutic development to address the societal burden of virtually all known cancer types. Our high-throughput research tools should also lower the cost of cancer research by reducing the time needed to identify potential candidates through complete automation of the procedure as well as by lowering the amount of reagents needed to run the assays.

If you were made benevolent ruler of the cancer research community today, how would you improve the present state of affairs?

I would donate a million dollars to our crowdfunding campaign at LifeSpan.io! All joking aside, I do encourage everyone to contribute to our campaign since every single dollar counts and gets us closer to a potential life-saving treatments to ALT cancer patients. As a benevolent ruler of the cancer research community I would divert more resources to the development of therapies for cancers that currently have the lowest long-term survival rates, such as brain cancer. Incidentally, about 15% of cancers in the central nervous system are positive for ALT activity. As with most cancers, the prevalence and death rates from brain cancer increase sharply with age, but this type of cancer is also the second most common among children. I am very excited about the prospect of changing a brain cancer diagnosis from a de facto death sentence to a treatable disease with long-term patient survival outcomes. Another decree as the community ruler would be to investigate in more detail the potential of combining different therapeutics to treat several types of cancer. In our case, we believe that the combination of telomerase and ALT inhibitors will potentially treat any type of cancer by completely hampering the ability of cancer cells to generate new telomeric DNA sequences at the ends of their chromosomes. This in turn will prevent cancer growth and dramatically improve patient outcomes. But even this combinatorial treatment could be boosted by adding another drug that inhibits a different molecular pathway involved in the growth of several types of cancer, such as the signaling pathways regulated by Ras genes.

Yeast cells share most of the interesting mechanisms relevant to aging with mammalian cells, but are very cheap to work with in comparison to mammals, which is why a lot of fundamental research starts with yeast. In the paper linked below, scientists use yeast to investigate the way in which cellular maintenance mechanisms in different parts of the cell react to one another's circumstances. This is of interest because the maintenance processes that remove damaged or waste proteins, as well as structures within the cell, are important determinants in the natural aging process. Many of the methods of somewhat slowing aging demonstrated in animal studies involve increased maintenance activities. This is also the basis for hormetic effects, in which exposure to a little damage can produce a net benefit because it provokes a larger and lengthy increase in cellular maintenance.

The intriguing portion of the results is this: because of the cross-talk between repair mechanisms in different parts of the cell, the researchers can make yeast cells live longer by very selectively disabling functions of cell maintenance in just one portion of the cell. The disabled portion might be broken, but maintenance activities in other parts of the cell pick up the slack, and the result is an extended functional lifetime for that cell.

Cells have acquired multiple mechanisms for the maintenance of protein structure and function. This implies an activity that would enable thousands of cellular proteins to fold, correctly and efficiently, under both optimal and challenging conditions. Molecular chaperones, including the heat-shock proteins (Hsps), are ubiquitously present cellular proteins, which display a wide spectrum of folding-oriented activities, coping with regular protein folding events as well as stress-induced protein misfolding. Naturally, such protein homeostasis (proteostasis) may decline in performance, as seen in numerous diseases and aging.

In compartmentalized eukaryotic cells, several independent pathways exist that ensure the integrity of the protein-folding environments in the cytosol, the endoplasmic reticulum (ER), and the mitochondria. The current knowledge posits that misfolded protein stress is sensed in a compartment-specific manner to induce the expression of compartment-specific chaperones. However, in this study we addressed the persisting question of cell-wide consequences of proteostasis failure in specific cellular compartments. We monitored the effect of loss-of-function of cytosolic, mitochondrial, and ER chaperones, each involved in protein input into different organelles, as well as protein folding. Our results show that the loss of each studied chaperone, regardless of the compartment of its residence and activity, induces a common cross-organelle response (CORE) that includes protein maintenance and antioxidant responses in the cytosol, mitochondria and the ER, without activating any of the canonical stress response pathways.

In order to induce protein stress in several different cellular compartments, we independently deleted a gene copy of three protein chaperones: cytosolic nascent polypeptide associated complex (NAC, EGD2), HSP70 chaperone from the endoplasmic reticulum (erHSP70, LHS1), and mitochondrial HSP70 (mtHSP70, SSC1). We set out to measure the replicative lifespan (RLS) of the studied chaperone deficient mutants. RLS is measured as the maximum number of generations that each mother cell goes through before the onset of senescence. The control strain produced a maximum of 19 buds during its RLS, which corresponds to the expected value for this strain. The largest effect on RLS with a 40% lifespan extension, in comparison to the control, resulted from the deletions of EGD2, encoding a subunit of the nascent polypeptide associated complex (NAC), as well as SSC1, mtHSP70. Finally, the deletion of LHS1, erHsp70, resulted in 30% lifespan extension relative to the control. Furthermore, we monitored the chronological lifespan (CLS) of the studied strains, measured as the mean and maximum survival time of non-dividing yeast populations. As with the replicative lifespan, we found that the chronological lifespan was extended in all chaperone deficient mutants, with the largest effect in the deletion of LHS1 (app 40%), followed by the deletion of EGD2 with 25% extension. As in the case of RLS, the smallest effect was observed in the deletion of the SSC1, with only 15% extension.

It is a feature of CORE that, regardless of the compartment in which the chaperone is deficient, the stress response seems to be cell-wide and unique in all studied strains. The response consists of changes in two groups of genes: (i) cellular maintenance, and (ii) metabolic changes, including a decline in respiration. The questions persist how the information on the folding environment status is communicated between the organelles and why none of the canonical stress responses have been activated by the deficiency of the three studied chaperones. At this point, we can only speculate that due to redundancy with other chaperones in each compartment, the cell perceives the absence of each of the three chaperones as mild proteotoxic stress. Therefore, specific signals needed to activate some of the canonical stress response pathways are likely to be missing during CORE, while the nature of signals generated to communicate the status of folding environment between cellular organelles will be a subject of further research.

Link: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4921836/

Transplantation of new retinal cells is one of the potential approaches to treat age-related loss of vision, such as that resulting from macular degeneration, in which photoreceptor cells die for a variety of reasons. The effectiveness of these approaches is so far limited, however, as most transplanted cells die. Researchers here investigate a means of improvement:

Regenerative therapies, based on cell replacement, hold promise for a wide range of age-related diseases, but efforts to bring the therapies to patients have not been very successful - in large part because the newly-derived replacement cells can't integrate efficiently into tissues affected by the ravages of aging. However, researchers have now harnessed a naturally-occurring and evolutionarily ancient anti-inflammatory mechanism that repaired the eye and significantly enhanced the success of retinal regenerative therapies in mice.

The group discovered a previously unknown immunomodulatory property of an evolutionarily conserved factor, MANF (Mesencephalic Astrocyte-derived Neurotrophic Factor). MANF converts inflammatory immune cells into repairing immune cells; in this study it profoundly improved the endogenous repair capacity of the retina in both flies and mice. Strikingly, when the researchers used MANF as a supplement while transplanting photoreceptors into congenitally blind mice, MANF increased the efficiency of integration and accelerated and improved the recovery of visual function. Even though researchers around the world have successfully transplanted retinal stem cells in mice that success has not benefited the millions of people who suffer from vision problems related to retinal degeneration, because only about 1 percent of the transplanted cells survive and integrate over time. "We are hoping to turn that statistic around."

The research also raises the possibility of using MANF as a treatment early in the disease process as a way of preventing further symptoms from developing, noting that they used MANF to protect photoreceptors in three mouse models of photoreceptor degeneration. "Our hope is that MANF will be useful for treatment of inflammatory conditions in many disease contexts. Focusing on immune modulation to promote a healthy repair response to tissue damage rather than a deleterious inflammatory response is a new frontier in aging research."

Link: http://www.buckinstitute.org/buck-news/harnessing-innate-repair-mechanism-enhances-success-retinal-transplantation

Most research programs that purportedly aim to extend human life by intervening in the aging process do not in fact have a good expectation of producing meaningful results. They typically involve searching the existing drug catalog for ways to alter the operation of metabolism so as to, for example, recapture some of the effects of calorie restriction, as lowering calorie intake is well proven to improve health and slow aging. This has turned out to be expensive, time-consuming, and challenging. So far very little of practical use has been achieved on this front after fifteen years of focus involving hundreds of scientists, at a cost of billions of dollars. Expense and difficulty are not the primary objection, however: it comes with the territory at the cutting edge of the life sciences. The primary objection to this branch of research is that even if these researchers achieved a perfect replication of calorie restriction, and so far they aren't close to achieving even a fraction of this goal, that wouldn't extend human life by more than a couple of years.

If all that the research community could do was this, then so be it. We would have to resign ourselves. But it isn't: much greater goals in extended health life span are possible with the same expenditure of time and funding, given a different research strategy. It is particularly frustrating to see this continued focus on slightly slowing aging at great cost when there is, in fact, a much better path forward. That better path consists of the research strategies described in the SENS vision for rejuvenation biotechnology, a package of approaches to aging and its causes drawn from the work of researchers across the breadth of the field. In short, the research community has a good catalog of the forms of cell and tissue damage that distinguish old tissue from young tissue, has had that catalog in a fairly complete state for more than two decades, and there exist detailed plans for treatments capable of repairing the damage. Repairing the damage that causes aging will be no more expensive and challenging than trying to alter metabolism to slow aging, but it has the possibility to create rejuvenation, to extend healthy life span indefinitely when the repair is comprehensive enough. Some of the technologies needed to create repair therapies to treat aging have been demonstrated in the laboratory, and a few are even at the stage of startup companies building treatments.

These days there is a lot of agitation for greater progress and greater investment in efforts to find drug candidates to alter metabolism in ways that may modestrly slow aging: calorie restriction mimetics, autophagy enhancers, exercise mimetics. This coincides nicely with the scientific urge to completely map the large blank regions in the grand map of human biochemistry. It is a huge project. But as Aubrey de Grey of the SENS Research Foundation points out below in a quite clear outline of his view of the field, metabolic adjustment to slightly slow aging is the wrong focus. The majority of the research community is forging ahead on a path that will produce only very small gains in lifespan and health, while ignoring what is known of how to repair the causes of aging completely. While there is certainly progress towards both repair therapies and persuading more of the research community to support that path to rejuvenation therapies, it is taking far too long and far too much effort to turn this ship. There is optimism in some quarters, but I fear that this process will remain slow and painful even after the first of the portfolio of SENS rejuvenation therapies, such as senescent cell clearance, are robustly demonstrated in human studies, as they have been mice. The inertia of large, heavily regulated research and development communities is a hard thing to wrestle with.

Future Trends in Aging Research

I'm going to make a claim that will outrage many of my colleagues, but which I think is robustly defensible: in the last 35 years we have not made one single discovery that has substantially changed what we think we know about mammalian aging. The last two discoveries that, in my view, reach that level of significance were made just around that time and were first published that year and the following year. Specifically, certain nonenzymatic changes were found to accumulate throughout life with potentially deleterious consequences in old age. Initially, such changes were found to affect long-lived proteins in the extracellular matrix; subsequently, they were found to affect the epigenetic state of the genome.

Is this a basis for consternation and despondency? Quite the opposite: it is a cause for unalloyed celebration. The analytical methods available to biologists have advanced beyond all recognition in those years, and the number of laboratories studying aging has also risen dramatically. Therefore, the lack of any major breakthrough in understanding aging constitutes extremely strong, albeit admittedly circumstantial, evidence that there is probably no such breakthrough yet to be made: in other words, that we really truly do already understand aging pretty well.

The modern restoration of biogerontology began with the discovery of simple genetic and pharmacological interventions that can greatly extend the lifespans of rodents. The implication that we will soon be able to do the same in humans is too obvious to ignore, especially since (at least in rodents) the extra life is added overwhelming to the healthy period before decline set in and not to the frail end of life. Since their very discovery (or very soon after, anyway), it was established that the most successful laboratory interventions I referred to above achieved, in one way or another, the same end. They tricked the organism into performing very much the same changes of gene expression and consequent metabolic activity that occur when it is starved.

So here's the problem. As biogerontology has become more intervention-friendly again, its translational research focus has centered overwhelmingly on this class of manipulations. Well, you may retort, so it should, since they are the things that work! But there's a catch-well, two catches. First, they don't work nearly so well when started in middle age as when lifelong, and second, they work far less well in long-lived species than in short-lived ones. In combination, these facts make the biomedical relevance of such manipulations very modest indeed. Unfortunately and inevitably, however, the field is spectacularly adhering to Upton Sinclair's aphorism that it is hard to make people understand something when their salaries depend on not understanding it, and is single-mindedly maintaining its intense focus on such interventions both in the lab and on camera, so as to similarly maintain its ability to keep funders convinced that they placed good bets in the past and to induce them to carry on funding the same people.

In the relative shadows, a few biogerontologists have been beavering away developing an alternative approach to maintaining health in old age-and though such work is at an early stage, its logic is steadily chipping away at the old-style thinking in the field and it is rising to bona fide orthodoxy. I speak, of course, of regenerative medicine for aging-a concept that I habitually refer to as rejuvenation biotechnology. There are many distinct avenues of research encompassed by this, but they have one thing in common: rather than manipulating our metabolism to slow the rate at which it inflicts accumulating damage on our tissues and organs, rejuvenation biotechnology is all about repairing that damage even after it has accumulated substantially. In the past few years, key proof-of-concept breakthroughs have been made in both realms, and highly respected and credentialed biogerontologists have endorsed a combined approach as a (or even the most) promising way forward, even to the extent of presenting it as if it were their idea. In conclusion, therefore, I can say with confidence that the future of aging research is extremely bright, both scientifically and medically. The pace of progress must now be sharply accelerated, via the injection of the funds that should for many years have been allocated at far higher a level than has actually occurred.

The work noted here is targeted at curing autoimmune conditions by removing the misconfigured immune cells that attack important infrastructure in tissues. This is good news for all autoimmunity in which the relevant biochemistry is fairly well understood - where the target immune cells can be well described in terms of their distinctive surface chemistry. However this is also very good news for the prospects of rejuvenating the aged adaptive immune system, wherein much of the problem is that the available capacity for immune cells is used up by an excess of cells uselessly specific to persistent viruses such as cytomegalovirus. There are too many of those cells and too little space left over for cells capable of responding to new threats. Clearing out the majority of those unwanted cells would go a fair way towards removing the contribution of the failing immune system to increased vulnerability to pathogens, cancer risk, and presence of senescent cells in aging. All that is needed is a good technology platform on which to build such a targeted therapy, and the work here seems like a sizable step in the right direction.

Researchers have found a way to remove the subset of antibody-making cells that cause an autoimmune disease, without harming the rest of the immune system. The key element in the new strategy is based on an artificial target-recognizing receptor, called a chimeric antigen receptor, or CAR, which can be engineered into patients' T cells. In human trials, researchers remove some of patients' T cells then engineer them in a laboratory to add the gene for the CAR so that the new receptor is expressed in the T cells. The new cells are then multiplied in the lab before re-infusing them into the patient. The T cells use their CAR receptors to bind to molecules on target cells, and the act of binding triggers an internal signal that strongly activates the T cells - so that they swiftly destroy their targets.

Since 2011, though, experimental CAR T cell treatments for B cell leukemias and lymphomas have been successful in some patients for whom all standard therapies had failed. B cells, which produce antibodies, can also cause autoimmunity. Researchers took an interest in CAR T cell technology as a potential weapon against B cell-related autoimmune diseases. "We thought we could adapt this technology that's really good at killing all B cells in the body to target specifically the B cells that make antibodies that cause autoimmune disease. Targeting just the cells that cause autoimmunity has been the ultimate goal for therapy in this field."

In the new study the team took aim at pemphigus vulgaris. This condition occurs when a patient's antibodies attack desmoglein (Dsg1 and Dsg3) molecules that normally keep skin cells together. When left untreated, PV leads to extensive skin blistering and is almost always fatal. To treat PV without causing broad immunosuppression, the team designed an artificial CAR-type receptor that would direct patients' T cells to attack only the B cells producing harmful anti-Dsg3 antibodies. The team developed a "chimeric autoantibody receptor," or CAAR, that displays fragments of the autoantigen Dsg3 - the same fragments to which PV-causing antibodies and their B cells typically bind. The artificial receptor acts as a lure for the B cells that target Dsg3, bringing them into fatal contact with the therapeutic T cells. Testing many variants, the team eventually found an artificial receptor design that worked well in cell culture, enabling host T cells to efficiently destroy cells producing antibodies to desmoglein, including those derived from PV patients. The engineered T cells also performed successfully in a mouse model of PV, killing desmoglein-specific B cells and preventing blistering and other manifestations of autoimmunity in the animals. "We were able to show that the treatment killed all the Dsg3-specific B cells, a proof of concept that this approach works."

Link: http://www.uphs.upenn.edu/news/News_Releases/2016/06/payne/

As we all well know, the adaptive component of the immune system deteriorates with age for a number of reasons. There is the toll of cell and tissue damage, there is a structural issue in which too many cells become uselessly devoted to persistent viral infections and can no longer respond to new pathogens, there is inflammaging, in which the immune system is constantly overactive, producing chronic inflammation to no good end, and there is the atrophy of the thymus where T cells mature, which greatly reduces the pace at which new T cells are generated. B cells, however, do not mature in the thymus, and here researchers provide evidence to suggest that the B cell population of the active immune system doesn't meaningfully age for much of life in our species. They didn't look at everything, however, and you might compare this open access paper with evidence from past years of a decline in B cell function.

We analysed the genome-wide expression profiles of naive and whole B cell populations from young and early aged healthy donors under 60 years. We revealed large homogeneity of all analysed genome-wide expression profiles but did not identify any significant gene deregulation between young (30-45 years) and early aged healthy donors (50-60 years). We argue that B cells avoid the aging program on molecular level until 60 years of age.

Genome-wide analyses have detection limits, which in turn could limit identification of age-specific genes. Only minor gene alteration might be hidden below the detection threshold and unrecognized in this study. Nevertheless, our genome-wide analysis homogeneity indicated result robustness and confident reliability. We summarize surprising observations that human B lymphocytes remain almost identical at the molecular level during 30 to 60 years of age. As the immune system declines, the predispositions to B cell lineage malignancy manifested in some individuals below 60 years of age could not be addressed to natural healthy aging of B lymphocytes. Rather, other aspects might be involved including compromised body environment, declined cell stimulation, immune cell population disorders, clonal accumulations, infection history, life style and other individual behaviour contributing to early onset of aging.

The molecular identity of young and early aged B cells demonstrated potential of hematopoietic stem cells to generate uncompromised progenitor lymphocytes, naive and mature B cells in early elderly. These are very encouraging findings for general health, because the immunity maintenance does not seems to needed artificial intervention to keep B cells uncompromised in the early elderly.

Link: http://www.impactjournals.com/oncotarget/index.php?journal=oncotarget&page=article&op=view&path%5B%5D=10146&path%5B%5D=31928