Fight Aging!

Another year is over, and we're all that much closer to both the ugly declines of aging and the advent of rejuvenation therapies. For those fortunate enough to be in a younger demographic, which of those two items wins out depends entirely on the pace of progress. We are in a race. The results matter greatly. Every effort made to help will shift the odds to be that much better.

A Year of Ups and Downs in Fundraising

Insofar as fundraising goes, this has been a mixed, interesting year of ups and downs. On the one hand it has been a struggle to raise funding for smaller non-profit projects, such as the MouseAge and AgeMeter initiatives at Lifespan.io. At the same time companies working on rejuvenation biotechnology have obtained angel and venture investments, and new venture funds are entering the longevity science community. Ichor Therapeutics announced a series A for their SENS-based Lysoclear technology, and later in the year their other spin-off Antoxerene was funded. Oisin Biotechnologies expanded their technology to target cancerous as well as senescent cells, and are also raising more funding. Other companies involved in senescent cell clearance have done well; SIWA Therapeutics pulled in new funding for their antibody approach, for example, and CellAge was seed funded to work on better assays for senescence. Unity Biotechnology continues to have enough of a war chest to buy the rest of the nascent industry should they so choose. AgeX Therapeutics launched, with Aubrey de Grey on their staff - that should be interesting. LIfT Biosciences seems to be doing well in their efforts to bring leukocyte transfer therapies for cancer to the clinic.

On the other side of the fundraising fence, the Methuselah Fund launched this year, taking a mixed non-profit/for-profit approach, and from the funds raised from our community invested in Leucadia Therapeutics, supporting a new approach to clearing aggregates that cause neurodegeneration. Larger monied interests arrived in the form of Jim Mellon's Juvenescence venture, who have initially invested in Insilico Medicine, but have indicated support for the SENS research agenda. As this is a vocal group, we can expect to see them influencing public and investor opinion rejuvenation research and development in the years ahead.

Despite all of the challenges faced by non-profit fundraisers over the course of much of 2017, the year ended on a high point: the SENS Research Foundation year end fundraiser pulled in $1 million more than the target of $325,000 or so in pledges, as the anonymous principal of the Pineapple Fund donated $1 million in bitcoins in December. The Fight Aging! SENS Patron component of that year-end fundraiser came to a successful conclusion: Josh Triplett, Christophe and Dominique Cornuejols, and Fight Aging! put up a $36,000 challenge fund to match the next year of monthly donations, and that target was reached. Many thanks are due to all who supported SENS rejuvenation research over the course of the year: this funding makes a real difference, especially now that multiple lines of research are closing on the point at which commercial development can begin. You might take a look at the SENS Research Foundation annual reports and the state of progress in SENS addition to the Fight Aging! FAQ for a sense of how things are going.

Finally, with all of the hype surrounding blockchain initiatives this past year, it was inevitable that some of the adventurous souls in our community would make the effort to run initial coin offerings and see whether or not this was a viable path to pull in funding. The Open Longevity organization set out to give it a try, and so did Youthereum. It is a little early to say where this will all go; it is a very rapidly changing area of effort.

Expanding Efforts in Advocacy

Discussion of advocacy for the cause is a usual feature of our community, as we try things and attempt to make progress in persuading the world that rejuvenation research is plausible, practical, and necessary. There are more people engaged in advocacy now than at any time in the past decade, and so discussions of strategy come up often. New ventures kicked off in 2017 include the Geroscience online magazine, and among the existing ventures the LEAF / Lifespan.io volunteers seem to be hitting their stride. The mainstream media continues to be as much a hindrance as a help, and where it is a help you will usually find Aubrey de Grey involved in the article somewhere - which is not to mention the recent /r/futurology AMA.

In the broader question of strategy in advocacy, questions abound. Do we continue to spend a lot of time tearing down arguments against treating aging as a medical condition, such as the naturalistic fallacy and unfounded fears of overpopulation? Should we be avoiding talk of immortality and radical life extension? Or focusing on ethical arguments? Or correcting mistaken views of aging and the underlying biology? Trying harder to persuade people that rejuvenation therapies are a near future possibility? Or trying to address some of the unhelpful behavior from some members of the research community? Or continuing to hammer on the costs of failing to address aging, the worldwide toll of death and suffering? Or continue to hammer on the benefits of success? Do we talk less and strive to engage with structural problems in the funding of research? Or endeavor to find more funding for advocacy rather than sending it all to research? Given the fact that we have to keep making the same arguments for incremental gains, are we bad at this advocacy business, or is it a tough challenge? Should we switch some of this non-profit activity to for-profit activity?

We must keep making the case, of course - the benefits of success are enormous. There were some sizable wins in advocacy this year, such as a series of YouTube videos from popular channels that covered the prospects for the treatment of aging and were viewed by hundreds of thousands of people.

Topics in Longevity Science from the Past Year

Is genetics important in longevity? Some researchers think that most of the observed variation in human life span is chance, not genes. There has been plenty of other research this year on human genetics that are related to longevity, and there are a number of large commercial ventures working in the space, but it is going to be hard to top the discovery of human PAI-1 mutants who appear to enjoy a seven year gain in life expectancy. Since this mutation is closely connected to cellular senescence, it seems plausible that we should read this as support for the benefits of senolytic therapies. A similar discovery was made for a growth hormone variant, with a much smaller effect, of course. That aside, analysis of genetics doesn't look like a fast road to sizable results for a variety of good reasons.

Cellular senescence research continues apace, of course, alongside the commercial efforts to bring senolytic therapies to the clinic. The research community has now well and truly woken up on this topic, and many researchers are increasingly optimistic that senolytic treatments will be transformative for medicine. New work now implicates cellular senescence in kidney disease, macular degeneration, osteoarthritis, cardiac hypertrophy, sarcopenia, lung diseases, vascular calcification, immune system aging, fibrotic diseases, fatty liver disease, skin aging, declining regenerative capacity, the accelerated aging effect of chemotherapy, the effects of visceral fat on health, and more.

Some groups are trying to find ways to reverse senescence, sabotage harmful signaling by senescent cells, or prevent cells from entering this state - though it is unclear as to whether or not these classes of approach will be significantly helpful, given that the cells are damaged. The more direct and definitively effective approach of destroying senescent cells continues to gather more potential methods. This past year, the very intriguing method involving FOXO4-DRI was demonstrated in mice - we can hope it holds up in human studies, as this looks considerably better than the current crop of repurposed chemotherapeutic senolytic pharmaceuticals. Those chemotherapeutics expanded to include HSP90 inhibitors quite recently. Meanwhile exploration continues in search of better ways to assess the number of senescent cells in tissues; current approaches just aren't all that useful for human clinical applications.

Beyond clearance of senescent cells, other lines of SENS research are progressing. This year, glucospane research turned to the creation of monoclonal antibodies to aid in building a therapy to break cross-links in aged tissues. Gensight continues to find success in their implementation of allotopic expression of mitochondrial genes, proving out the technology platform that will ultimately become a rejuvenation therapy.

Given the advanced state of senolytics, it is only natural that our community is starting to think about trials and how to run them - in addition to whatever the various companies in the space might put together over the next couple of years. Paid trials are a good idea, but there is an unaccountable amount of hostility towards them from the scientific community. Groups such as Betterhumans and the Society for the Rescue of Our Elders are running small, independent senolytic pilot studies. Responsible self-experimentation is another time-honored way forward. Some people are trying it for senolytic treatments. I have put some thought into the logistics and what tests one might use in order to determine whether or not a particular treatment is useful.

Self-experimentation in the broader community nowadays extends to comparatively crude gene therapies, with a number of organizations offering the tools or running the trials. These technologies are too cheap and too easily used to be more than inconvenienced by regulators. A few companies are headed in the same direction, such as Libella Gene Therapeutics, with a plan for human telomerase gene therapy trials, following in BioViva's footsteps.

Lines of research emerging from parabiosis studies, in which old and young individuals have their circulatory systems linked, continue to expand. The core questions regarding whether beneficial factors in young blood or harmful factors in old blood are responsible for the observed effects on aging, or both and to what degree, continue to be debated. While the weight of evidence leans towards "bad old blood" with a few specific candiates for the factors causing that effect, it is still the case that new studies with evidence for beneficial factors in young blood continue to arrive. The contradictions will eventually be resolved, but for now it is an area of research in flux. Meanwhile, human trials of plasma transfusion from young to old continue; Ambrosia and Alkahest reported results that are ambiguous enough to resolve nothing.

Cryonics remains an important and underappreciated technology. Not all of us are going to make it; the progression of rejuvenation technology won't happen fast enough. We will need the backup plan of cryonics. This year marks the fiftieth anniversary of the first, comparatively crude cryopreservation, and that individual, unlike most of those from of that era, remains preserved. The technologies of preservation today are far more advanced, and the organizations more reliable in the face of various failure modes, as noted in an interview from earlier in the year. One line of work that has made considerable progress of late is safe and rapid thawing of vitrified tissues. In community news, the International Longevity and Cryopreservation Summit took place in Spain earlier this year.

Is Google's large investment in aging research, the California Life Company, Calico, at all relevant to the goal of defeating aging? The more we find out, the less likely it appears. Researchers are increasingly willing to go on record as saying that the efforts funded there are just not helpful in the near term. Calico looks like pure curiosity-driven scientific research into understanding the very fine details of aging, which is not what we need at this stage in order to push forward to the range of effective therapies that can be built in the near future.

Amyloid accumulation is one of the causes of aging, and transthyretin amyloid is one of the types of amyloid with more research interest. It is connected to heart disease and osteoarthritis, and may be the majority cause of death in supercentenarians. Covalent Bioscience is one of the companies looking at ways to remove this amyloid. A variety of new research was published this past year, including a better approach to assessing the amount of amyloid present, and RNA inteference and antibody based therapies.

On the topic of biomarkers of aging, there are many various lines of work taking shape. The research community agrees that having effective, reliable biomarkers for a rapid assessment of biological age is very necessary to speed up progress towards treatments for aging. Among efforts noted this year include gene expression of glia, metrics based on neuroimaging, or on microRNA expression, various attempts to assemble a compound biomarker from a collection of standard lab tests and measures. People are setting up online databases to hold the various prospects. DNA methylation tests based on one or more of the existing epigenetic clocks have now reached the consumer marketplace. They can be ordered from Osiris Green and Zymo Research. The research community continues to refine and expand further epigenetic clocks and related assessments.

Calorie restriction is ever a popular research topic, despite this being unlikely to produce very large effects on human lifespan. This is really the core of the geroscience view of the treatment of aging: slow it down a bit, but don't try for more. Researchers now claim that human studies show a slowing of aging via a collection of biomarkers. The final consensus on long-running primate studies appears to be that, yes, calorie restriction does modestly slow aging in our near relatives. Near all specific measures of aging are similarly slowed, such as the fibrosis leading to kidney disease, the early stages of cancer, the epigenetic changes of aging, the decline of the immune system, the accumulation of metabolic waste in cells, and the accumulation of amyloid in aged tissues. Researchers continue to find new mechanisms by which calorie restriction produces its effects, such as a slowing of ribosomal activity. Sense of smell continues to surprise the research community in the degree to which it is important in determining response to calorie intake. A number of researchers have gained traction in pushing forward intermittent fasting as an alternative approach, particularly the fasting mimicking diet. Meanwhile, ever more candidate drugs and protein targets are found that might act as a basis for potential calorie restriction mimetic therapies - though given the lack of concrete progress on this front over the past decade, I wouldn't hold my breath waiting for results.

Another rising topic in aging research is the contribution of gut microbes and other microbial populations in the body; these may be as influential over aging as, say, exercise or calorie intake. Researchers have noted influences on amyloid accumulation, something that is attracing greater interest from the Alzheimer's research community. It is also interesting to see studies demonstrating extended life as a result of transplantion of gut bacteria from young animals to old animals in zebrafish and in mice, or showing that healthier older individuals have microbial populations more like those of younger individuals. Moving beyond observations, candidate mechanisms are being discovered to explain exactly why changes in gut bacteria are good or bad. The next step is therapies that target those mechanisms. Researchers appear close to being able to sabotage the detrimental effects of oral bacteria, for example.

A few interesting views on aging and its origins surfaced in the past year: aging as a consequence of complexity in cellular life, for example, or that aging is an inevitable consequence of competition between cell types in multicellular life. Another group argued for selection to decline with age even in hypothetical immortals, thus ensuring that no species would become so exceptionally long lived. Others have looked for explanations for the present state of stem cell populations, in that they are not as effective as they could be, especially in later life.

Work on addressing dysfunction in the immune system by destroying near all immune cells and then repopulating them via cell therapy, shown to cure severe autoimmune disease is progressing on a number of fronts. The most important thing here is to find a safer, less damaging way to kill the unwanted parts of the immune system. Currently it is too risky to be applied to older people, so as to clear out the issues in an aged immune system. Researchers recently discovered a promising lead here.

Regenerative medicine, cell therapies, and tissue engineering are energetic fields. Far too much is going on to note all of it, but a few things caught my eye. The Methuselah Foundation continues to be in the thick of it with their initiatives to promote progress, for example. Decellularization continues to be an important line of research, and that will be the case until someone figures out a reliable means of producing blood vessel networks. Bioprinting of tissue proceeds apace, and is driving a lot of the advances in reduced cost and increased capabilities. Researchers are building ever more and better organoids: fully functional ovaries, stomach, skin that is fully and completely structured, lungs, thymus, bile ducts, inner ear, and more. Organoid production is on the verge of scaling up, and use of multiple organoids may work well as an alternative to full organ transplant for some organs. In other parts of the tissue engineering field, mass production is also an ongoing interest. Organ factories are not so very far ahead. Teeth are similarly moving forward; tooth regrowth has moved up from rodents to canines. Researchers are also making inroads into the manufacture of blood to order.

Will regenerative medicine make the leap soon from cell therapies that do little but suppress inflammation, to actual methods of rejuvenation and repair? That is hard to say, and the final form of such therapies is also uncertain. Consider induced cell turnover or artificially increased cell replication strategies for example, a novel approach where the implications have yet to be fully explored, or the variety of cell therapies that appear to produce quite sizable changes despite using only incremental advances in methodology, or very novel processes such as reprogramming skin cells into stem cells in a living individual. Comparative biology continues to deliver intriguing findings from lizards, spiny mice, zebrafish, and the like. Related work is finding that adjusting the balance between populations of macrophages with different polarizations can spur greater regeneration in mammals, and the same may be true of microglia.

2017 Short Essays

You'll find a number of short essays at Fight Aging! each year. Here is a selection from 2017:

• Why Rejuvenation Research Startups Go Quiet Following Launch
• Will Senescent Cell Clearance Therapies Sink the Pensions and Annuities Industry?
• The Million Year Life Span
• If Much Older than 30, Save More Aggressively Over the Next Decade or Two
• What Next for Unity Biotechnology?
• The Problem with Focusing on Healthspan
• Advocacy for Rejuvenation Research is as Much a Process of Documentation as it is a Process of Persuasion
• The Fall into Nihilism
• Success in Rejuvenation Research to Date is Partial: Many Projects Still Need Our Philanthropic Support to Flourish
• Wolf has been Cried So Very Many Times When it Comes to Anti-Aging Therapies
• Patient Paid Clinical Studies are a Good Plan for Rejuvenation Therapies

Looking Ahead to 2018

Next year should see the first published results from senolytic trials - and if the effects of the first drug candidates translate well from mice to humans, that should wake up everyone not yet aware of the enormous potential of this field. I expect that this will probably overshadow everything else achieved in the field for a while, at least in the public eye. There will be more startup companies launched to work on SENS rejuvenation biotechnologies, and that will hopefully be an ongoing story for the next few years. This period of transition, handing off from laboratory to clinical development, is critical to the future of human rejuvenation therapies. The more we can do to help, the better.

Average telomere length is currently usually measured in leukocytes obtained from a blood sample. When considering the statistics of a sizable population, average telomere length tends to trend downwards over a lifetime. Telomeres form a part of the complex mechanism that limits somatic cell replication: they shorten with each cell division, and cells with very short telomeres self-destruct or become senescent, ceasing to replicate in either case. Stem cells deliver a supply of new somatic cells with long telomeres to make up the numbers. So average telomere length is a blurred measure of stem cell activity and pace of cellular replication - and in the immune system the latter is highly variable, depending on the current state of health and presence of threats. Telomere length thus varies considerably between individuals of a similar age and health status, and also over quite short periods of time for any given individual. Even in smaller groups, the statistical association with aging can be weak to non-existent. All of this means that telomere length isn't all that helpful as a guide for medical decisions or as a way to evaluate the state of aging.

The associations between mortality and traditional biomarkers such as blood pressure, cholesterol, and body mass index (BMI) weaken with age. The search for a definitive aging biomarker is encumbered by the heterogeneity of cellular aging. Post-mitotic cells are not subjected to the replicative stresses experienced by mitotic cells; therefore, some tissues exhibit greater biological aging than others. The highly variable human lifespan highlights that the mere passage of chronological time is not an effective, isolated measure of aging. Biological aging refers to processes that proceed independently of chronological aging that reduce organismal viability and increase vulnerability. Telomeres are regarded by many as the heir apparent of aging biomarkers, recording both chronological and biological age.

A growing body of evidence also indicates that telomeres are responsive to habitual physical activity (PA). Despite the telomere's popular designation as a mitotic clock, the relationship between telomere length and aging is inconsistent and does not meet the requisite biomarker criteria. Closer examination of the association with PA also reveals inconsistencies and methodological confounders. The clinical and public interest in the PA-telomere association is predicated upon several tacit assumptions: (i) mean telomere length is causally associated with biological aging and age-related pathologies and (ii) PA can lengthen mean telomere length and that in doing so; (iii) PA will reduce biological aging and disease burden.

The proposed associations with aging and exercise are biologically plausible. Telomere length holds tantalizing promise as a biomarker; however, a host of evidential inconsistencies and paradoxes must be addressed. Leukocyte telomere length (LTL) is highly variable at birth, a metric influenced by genetic inheritance and paternal age at conception. It reflects lifelong exposure to oxidative and inflammatory burden yet childhood LTL has more predictive fidelity than LTL in adulthood or old age. Oscillating throughout the lifespan, even inexplicably lengthening despite advancing age, mean LTL differs between genders. Attrition rates also differ between genders and appear dependent upon initial telomere length. Shortening trajectories can be further influenced by variable exposure to a wide range of environmental stimuli. The association between PA is more questionable with 50% of studies failing to find a significant association.

Investigations into plausible mechanisms have returned promising yet inconsistent findings. The prevailing consensus is that exercise-induced reductions in oxidative stress and inflammation likely mediate the effect. The possibility that LTL is a physiological epiphenomenon cannot be excluded. Changes in LTL may simply be coincidental processes that reflect, without directly influencing, the primary mechanism. It is likely that telomere length per se is significant only in so much as it reflects the resultant phenotype via pathways such as senescence-associated inflammation. It has been proposed that evolutionary pressures have fine-tuned telomere length to reduce the risk of short and long telomere pathologies, namely atherosclerosis and cancer. The long-term consequences of manipulating telomere length are not well understood and should therefore be approached with equal measures of enthusiasm and evidence.

Link: http://dx.doi.org/10.3390/ijms18122573

Here, researchers investigate the role of the VCP gene in producing cardiac hypertrophy as a response to hypertension, or high blood pressure. Blood vessels become stiff with age, the result of cross-linking, calcification, and dysfunction in the smooth muscle that controls contraction and dilation. This causes hypertension by breaking the finely balanced feedback systems that regulate blood pressure in response to environmental circumstances. Hypertension in turn causes cardiac hypertrophy: heart tissue expands inappropriately to become both larger and weaker. At the end of this road lies death due to heart failure or structural failure of critical blood vessels in a high pressure environment. Addressing the root causes would be the best way forward, but most research groups are more interested in controlling mechanisms at later stages of the process, such as VCP. Therapies based on this sort of work have the potential to produce some benefits, but nowhere near as comprehensively as reversal of vascular stiffness.

Pressure overload-induced cardiac hypertrophy, such as that caused by chronic hypertension, is a major independent risk factor for heart failure. Accumulating evidences from studies in patients and animal models suggest that cardiac hypertrophy induced by chronic pressure overload is not a compensatory but rather a maladaptive process. Despite intensive research efforts over several decades, the molecular mechanisms of hypertrophic heart failure are not fully understood. Therefore, it has become compulsory to identify novel targets involved in the pathogenesis of cardiac hypertrophy and its transition to heart failure.

Our previous studies identified valosin-containing protein (VCP) in the heart and showed that it is a critical mediator of cardiomyocyte survival under ischemic stress both in vitro and in vivo. However, the role of VCP in cardiac growth or hypertrophy under stress conditions was completely unknown. We observed that VCP expression was significantly down-regulated in the hypertrophic left ventricle (LV) tissues of both hypertensive rats and transverse aortic constriction (TAC)-induced pressure-overloaded mice. These findings demonstrated a strong link between down-regulation of VCP expression and hypertensive cardiomyopathy. Reciprocally, cardiac-specific overexpression of VCP in a transgenic (TG) mouse significantly attenuated the pressure overload-induced cardiac hypertrophy. These data together suggested that VCP plays a critical role in pressure overload-induced cardiac hypertrophy.

Direct evidence of VCP's cardioprotective effect was shown in an in vitro study where VCP was downregulated in AngII-induced hypertrophic cardiomyocytes in a dose- and time-dependent manner, whereas the overexpression of VCP prevented AngII-induced cardiomyocyte hypertrophy. In addition, we also found that VCP plays a dual role on the regulation of the mechanistic target of rapamycin (mTOR) signaling in the heart: activating the survival-promoting mTORC2 but repressing the stress-induced growth-promoting mTORC1. These data suggested that VCP acts as a negative regulator of mTORC1 under stress of pressure overload. These selective effects of VCP on mTORC1 and mTORC2 are different from that of other mTOR regulators identified in the heart, such as rapamycin, and also distinct from the function of VCP observed in other tissues. Moreover, VCP suppressed mTORC1 signaling only under the stress of TAC but not at the baseline condition.

Our data collectively concluded that pressure overload reduced VCP expression in the heart which attenuated the inhibitive effect of VCP on mTORC1 signaling, subsequently promoting the pro-growth pathway and resulting in cardiac hypertrophy. These findings bring new insights to the regulatory effects of VCP in the heart and also lead to a new therapeutic target for pressure overload-induced cardiac pathogenesis.

Link: https://doi.org/10.18632/aging.101357

Arguably the most robust and reliable of currently available stem cell therapies, though still varying widely in outcome between sources of cell, methods of delivery, and patients, judging by the studies conducted to date, are those involving mesenchymal stem cells. They are now widely used for all sorts of musculoskeletal and joint issues that might benefit from less inflammation and more regeneration. The transplanted cells typically don't live for long, but they do generate signals that produce a sizable temporary change in the local environment, including suppression of chronic inflammation.

It is an interesting question as to the degree to which the observed results of modestly enhanced regeneration following mesenchymal stem cell therapy are secondary to reduced inflammation, versus being caused by pro-regenerative signaling that doesn't relate to inflammation. It is becoming clear that chronic inflammation degrades the normal processes of regeneration and tissue maintenance, all of which involve an intricate dance of stem cells, immune cells, and various other cell populations specific to each tissue type. When immune cell behavior is running off the rails because of constant inflammatory signaling, regeneration is diminished.

Here, I'll point out a small open access study on the use of mesenchymal stem cell therapy for the common age-related joint issue of osteoarthritis, in which cartilage and bone break down. It differs from most earlier studies in tracking patient outcomes for a longer period of time following the procedure, something that is probably needed in order to provide a more definitive answer as to which of the various methodologies of treatment are effective. Osteoarthritis is an inflammatory condition, though the inflammation is localized to the problem joints. Given the results from recent studies, it is beginning to look likely that senescent cells are the major cause of this condition. Since these errant cells are known to generate a potent mix of inflammatory signaling, this all fits together quite nicely.

Mesenchymal stem cell therapies don't address the cause of the issue, but they do appear to damp down inflammation and perhaps issue other regenerative signals for long enough to allow tissues to accomplish some repair of the structural damage despite the presence of senescent cells. It will be interesting to see how senolytic therapies to remove senescent cells compare, as that should provide a good answer to the question above regarding the split of benefits between reduced inflammation versus increased regenerative signaling.

Intra-articular injection of expanded autologous bone marrow mesenchymal cells in moderate and severe knee osteoarthritis is safe: a phase I/II study

Knee osteoarthritis (KOA) is a common condition affecting the adult population causing pain and dysfunction of the knee joint. Subsequently, there is a negative impact on the quality of life of these patients. A recent meta-analysis of the 11 trials with 558 patients using mesenchymal stem cells (MSCs) was published. There was an improvement in various clinical scores. The authors concluded that there was no significant difference in the comprehensive evaluation index after stem cell treatment, despite the significant improvement in clinical symptoms and cartilage morphology. A recent phase I-II of expanded autologous bone marrow stem cells has been published. It reported the safety and effectiveness of this modality. There is one published work using allogeneic bone marrow-derived MSCs in advanced KOA in humans showing clinical improvement but no significant MRI improvement.

In this paper, we report on the results of 13 patients who were treated by expanded autologous bone marrow mesenchymal stem cells (BM-MSCs) in an open-label phase I prospective study and followed for 2 years for any adverse events and for efficacy by normalized Knee Osteoarthritis Outcome Score (KOOS) and by MRI.

Knee cartilage has limited regenerative capacity. Mesenchymal stem cells (MSCs) are known to have paracrine and differentiation properties. They can produce extracellular matrix within the joint. These properties make them good target for use in the regeneration of knee cartilage. Whether MSCs stimulate the proliferation and differentiation of resident progenitor cells or they differentiate into chondrocytes remains to be clarified. Rabbit and goat models of osteoarthrosis suggest that the repair occurs through paracrine effects by stimulation of endogenous repair mechanisms.

This work shows that the use of BM-MSCs is safe with only minimal early pain in some patients in the injected joint which resolved quickly without any intermediate or long-term clinical or biochemical adverse events. Bone marrow is attractive since it can easily be harvested as an outpatient procedure and without the need for patient hospitalization. Patients were followed up for 2 years. The work provides preliminary evidence that BM-MSCs are effective in KOA, as judged by the significant improvement in KOOS and by MRI. Mean knee cartilage thickness measured by MRI improved significantly. All symptoms significantly improved conferring significant improvement in the quality of life of these patients with grade II and III KOA. However, we wish to emphasize that the small number of participants in this study prohibits generalization of efficacy, and further work is warranted.

We suggest that next trials should also explore the dose of MSC and the source of MSC. There is a need to establish the safety of allogeneic MSC for KOA. The use of allogenic MSC can be standardized and the dose can be better controlled, and the cell variability can be reduced to the minimum. We believe that MSCs are potential definitive therapy for KOA.

Debate continues over the mechanisms responsible for the outcomes observed in parabiosis studies, in which a young and an old individual have their circulatory systems linked. The young individual shows a decline in measures of health, while the old individual shows an improvement - a modest reversal in some aspects of aging. That there must be harmful factors in old blood seems a solid conclusion, but are benefits to the older individual mediated by the presence of beneficial factors in young blood, or by dilution of harmful factors in old blood? There is evidence for both sides. Here, researchers outline some of the support for eotaxin-1 to be one of the harmful factors present in larger amounts in the bloodstream of older individuals, and consider possible implications for the blood transfusion industry.

High blood levels of the chemokine eotaxin-1 (CCL11) have recently been associated with aging and dementia, as well as impaired memory and learning in humans. Importantly, eotaxin-1 was shown to pass the blood-brain-barrier (BBB) and has been identified as crucial mediator of decreased neurogenesis and cognitive impairment in young mice after being surgically connected to the vessel system of old animals in a parabiosis model. It thus has to be assumed that differences in eotaxin-1 levels between blood donors and recipients might influence cognitive functions also in humans. However, it is unknown if eotaxin-1 is stable during processing and storage of transfusion blood components.

In this study, we show for the first time that ready-to-use transfusion blood components contain CCL11 at a physiological concentration. Importantly, in both blood components eotaxin-1 expression did not differ between males and females, but significantly increased with the donor's age in both sexes. Of note, eotaxin-1 levels detected in these processed, transfusible blood products are comparable with those found in unprocessed plasma of healthy individuals. We demonstrated that eotaxin-1 is subject to only minor donor-specific changes over 15 measurements within a 3-months period of time, even when samples have been taken at different times of day. Taken together, our findings and the available literature prove that eotaxin-1 is a relatively stable factor in fresh or processed blood components of one individual over a longer period of time, but significantly rises with increasing age.

Eotaxin-1 was found increased in Alzheimer's disease patients compared to age-matched controls. Eotaxin-1 correlated with impaired verbal and visual memory, and other conditions associated with cognitive decline, such as recurrent depression have also been associated with increased levels of the chemokine. Moreover, it was demonstrated that, among a range of cytokines and chemokines, eotaxin-1 correlated most strongly with reduced hippocampal neurogenesis and aging in mice, and importantly, artificially increasing eotaxin-1 levels in young mice resulted in decreased neurogenesis as well as in impaired memory and learning. Using mouse parabiosis models further proved that exposure of a young animal to the systemic milieu of an older mouse is sufficient to induce severe cognitive impairments and reduced neurogenesis after 2-5 weeks, and identify blood-borne eotaxin-1 as one of the responsible factors.

It has to be considered that a direct impact of short-term eotaxin-1 exposure on neurogenesis and mental factors has only been assessed in mice so far. It is unclear whether a single transfusion of high-eotaxin-1 containing blood components to recipients with very low levels will indeed change total eotaxin-1 levels in the recipient, if this elevation is transient or durable, and if it does indeed influence cognitive functions in humans. Future studies require a prospective study design to carefully resolve these questions.

Link: https://doi.org/10.3389/fnagi.2017.00402

The research community continues to improve their ability to build structured and functional organ tissue from the starting point of a patient cell sample. The challenge of constructing blood vessel networks to support large tissue structures remains to be solved, but by the time it is, there will be a direct path to the manufacture of entire organs on demand. Work on kidney tissue is one of the leading areas from the point of view of technical capabilities in tissue engineering, as this research news demonstrates.

In the embryonic kidney, three types of precursor cells, nephron progenitor cells, ureteric buds, and interstitial progenitor cells, interact to form three-dimensional structures of the kidney. Methods to induce nephron structures via nephron progenitor cells from mouse pluripotent stem cells (PSCs) have already been established. However, since other progenitor cells were not included, the "higher-order" structures of the kidney (the state in which differentiated nephron structures are organically connected to each other by branching collecting ducts) were not reproduced. Now, a research group has developed a method of using PSCs to induce production of ureteric buds, the progenitors of branched collecting ducts, and has succeeded in reproducing the higher-order structure of the kidney.

Unfortunately, opportunities for kidney transplantation are limited, but the 2006 discovery of induced pluripotent stem cells (iPS cells) has elevated the expectation for regenerative medicine to "build" fully functioning organs. However, the process of reproducing a whole organ structure continues to be a common and challenging theme for any organ regeneration study. Researchers are working toward the goal of producing a fully functional kidney. To do so, it is important to reconstruct higher-order kidney structures from PSCs.

The researchers first discovered that mouse Wolffian ducts (WDs), precursors of ureteric buds, gradually matured and gained branching capacity between embryogenesis day (E) 8.75 and E11.5. They were then able to culture WD cells in vitro and determined the growth factors necessary to produce mature ureteric buds. Finally, they developed a protocol to induce E11.5 ureteric bud-like cells from mouse ESCs via E8.75 WD-like cells. It was revealed here that nephron progenitor cells and ureteric buds require individually optimized conditions for successful induction.

Functionality of mouse ESC-derived ureteric buds was further verified by co-culturing a single bud with embryonic kidney precursors, or with a mixture of ESC-derived nephron progenitors and embryonic stromal progenitors. In the reconstructed kidney organoid, researchers observed the formation of branching ureteric epithelium, differentiated nephrons, and nephron progenitors on the surface of the ureteric bud tips, thereby confirming the functionality of induced ureteric buds and the reconstruction of higher-order kidney structures. With a slight modification of the protocol, the researchers were able to induce ureteric buds from human iPSCs, and confirmed their branching capacity when cultured with growth factors.

Link: https://www.eurekalert.org/pub_releases/2017-12/ku-rhe121817.php

Physical exercise is good for long term health, and thus the research community is interested in finding ways to recreate its benefits without the need for exertion. The prospect of exercise mimetic drugs should sound like a familiar sort of goal, and it is. This line of development almost exactly recapitulates earlier years of the long-running effort to find ways to recapture the beneficial response to calorie restriction via pharmaceuticals. Both are immensely challenging projects, consuming enormous effort and funding with little to show for it but incremental progress in mapping slices of cellular biochemistry. The search for calorie restriction mimetics is going on for two decades old at this point, and has cost something like a billion dollars to date. It remains the case that there is no credible drug in the clinic, and a lot more of the relevant portions of cellular metabolism are yet to mapped.

The same process of mapping and initial drug evaluation that has been underway for many years for calorie restriction has really only just started in earnest for exercise, despite a few threads of research stretching back just as far, so we shouldn't be holding our breath waiting for pharmaceuticals to enable cardiovascular fitness without the physical exertion. At the present pace, advanced rejuvenation therapies that can turn back aging by reversing its causes will be contemporary with methods of tinkering with the operation of metabolism to somewhat improve health. It makes you wonder why the effort - but the answer to that is probably the as yet incomplete detailed map of cellular biochemistry. The true scientific goal is knowledge, not application of knowledge. If you want application, technology, and consideration of which paths forward might be more effective than others when it comes to health, then the pure science community is probably not the right place to be looking.

The research here is illustrative of the point. Given an age-related condition where exercise has been shown to be helpful in specific ways, is it possible to chase down exactly why exercise helps? The answer is that, given a few years, a research group can make some inroads, and then come to a stage at which a lot more work will be needed to progress further. Cellular biochemistry is enormously complex, and exercise influences nearly every aspect of the way in which cells work. Chasing the relationships between regulators and actors and systems and cellular behaviors, all of this in an environment of great complexity, is laborious and time-consuming. In the long run there is no such thing as useless knowledge, and the scientific aim of complete knowledge is correct and noble, but other strategies are needed if we want to achieve sizable gains in human health and longevity in the near term.

Researchers shed light on why exercise slows Parkinson's

While vigorous exercise on a treadmill has been shown to slow the progression of Parkinson's disease in patients, the molecular reasons behind it have remained a mystery. Now, for the first time in a progressive, age-related mouse model of Parkinson's, researchers have shown that exercise on a running wheel can stop the accumulation of the neuronal protein alpha-synuclein in brain cells. Clumps of alpha-synuclein are believed to play a central role in the brain cell death associated with Parkinson's disease.

The mice in the study, like humans, started to get Parkinson's symptoms in mid-life. At 12 months of age, running wheels were put in their cages. "After three months the running animals showed much better movement and cognitive function compared to control transgenic animals, which had locked running wheels." Researchers found that in the running mice, exercise increased brain and muscle expression of a key protective gene called DJ-1. Those rare humans born with a mutation in their DJ-1 gene are guaranteed to get severe Parkinson's at a relatively young age. The researchers tested mice that were missing the DJ-1 gene and discovered that their ability to run had severely declined, suggesting that the DJ-1 protein is required for normal movement. "Our results indicate that exercise may slow the progression of Parkinson's disease by turning on the protective gene DJ-1 and thereby preventing abnormal protein accumulation in brain."

Running wheel exercise reduces α-synuclein aggregation and improves motor and cognitive function in a transgenic mouse model of Parkinson's disease

DJ-1 is one of the Parkinson-associated genes in which mutations lead to early-onset, autosomal recessive disease. Because the loss of gene expression causes disease, the DJ-1 gene can be seen as protecting nearly everyone from developing Parkinson's disease. DJ-1 or its homologs are present in all life forms that use oxygen including all animals, all plants that perform photosynthesis, and all aerobic bacteria. This critical gene protects cells by antioxidant mechanisms such as stabilizing Nrf2 (nuclear factor erythroid 2-related factor) and thereby upregulating a family of antioxidant response element (ARE) genes. DJ-1 is also involved in regulating HIF1 transcriptional activity under hypoxic conditions. We have shown that DJ-1 also protects cells from abnormal protein aggregation by upregulating Hsp70.

Because Parkinson's disease leads to disabling bradykinesia and rigidity, exercise and physical therapy are often prescribed by physicians. The hope has been that exercise will enhance mobility, preserve muscle tone, and prevent medical complications such as pneumonia that are associated with immobility. Several clinical trials have found that regular exercise or physical therapy may improve motor function in Parkinson patients. In acute, drug-induced animal models of Parkinson's disease, exercise can partially protect dopamine neurons from neurotoxicity.

We have discovered that a functional DJ-1 gene is required for normal, voluntary running wheel performance in mice. In young wild-type mice as well as in aging transgenic mice expressing mutant human α-synuclein in all neurons, running wheel exercise can increase DJ-1 protein levels in muscle, plasma, and brain. We have found that long term running wheel exercise has a neuroprotective effect in our transgenic mice. Exercise significantly improves motor and cognitive function while dramatically reducing α-synuclein oligomer accumulation in brain while increasing plasma concentrations of α-synuclein. The mechanism by which exercise leads to these beneficial effects appears to be related to upregulation of DJ-1 and other neuroprotective factors such as Hsp70 and BDNF in the brain.

Because exercise produces sweeping changes in all aspects of physiology from sensorimotor activity to lipid metabolism in muscle, it is difficult to define a hierarchy of beneficial effects on brain function. Since mice which lack the DJ-1 gene cannot perform on running wheels with the same intensity as wild-type animals, DJ-1 appears to be essential for dealing with the physiological stress created in muscle by sustained motor activity. Because DJ-1 knockout animals have the same cognitive performance as wild-type mice, the DJ-1 deficit does not appear to influence cognition nor low intensity motor activity. To precisely define the role of muscle verse brain derived DJ-1, organ-specific DJ-1 knockouts would have to be developed.

Our study gives insight into the mechanism by which exercise prevents α-synuclein oligomer accumulation in brain. While oligomer formation was reduced in brains of mice with access to running wheels, the same animals showed increased plasma concentrations of α-synuclein monomers and dimers. α-Synuclein is known to be present in plasma of humans and other mammals, but the exact source of plasma α-synuclein remains uncertain. While it is possible that red blood cells may release α-synuclein into plasma, the protein may come from central and peripheral neurons.

In summary, we have found that voluntary exercise on a running wheel can upregulate DJ-1 in muscle and brain of a transgenic mouse model of Parkinson's disease and can prevent the age-related decline of motor and cognitive abilities normally seen in this transgenic strain. Since we have described similar beneficial effects with the drug phenylbutyrate in these transgenic mice, we hypothesize that patients with Parkinson's disease might be able to slow or stop disease progression from either an intensive exercise program or treatment with the drug phenylbutyrate.

Elizabeth Parrish of BioViva, you might recall, has made every effort to publicize the follistatin and telomerase gene therapy that she underwent. This is a strategy intended to accelerate progress; I suspect she was not the first, and that others were just more circumspect. The technology exists, it is not expensive in the grand scheme of things, and at the very least hundreds of people have the laboratory access and the knowledge to carry out such an operation. BioViva's efforts, and those of other ventures such as the Odin and Ascendance Biomedical illustrate the tension between desire for progress and desire for regulation. As a general rule, the majority of people who are not suffering significantly at the present time are just fine with heavy-handed regulation that holds back progress towards cures and enhancements. The minority of people who are suffering want the option to undergo treatments that they have researched and chosen, that appear to have a good chance of working, but are not going to be approved by regulators in the foreseeable future. Unfortunately they are largely ignored by the powers that be, and vitriol is heaped upon anyone who flouts medical regulation.

You can see how this plays out against a backdrop of technological progress by looking at the history of stem cell therapies. The primary goal of regulators is to avoid poor publicity, and they achieve this by putting as many roadblocks as possible in the way of new medical technology. Blocking new technologies causes a lot less bad publicity than is the case when something that causes harm slips though. Since medicine is uncertain and conditional, near every useful medical technology can, in some context, cause harm - or appear to cause harm in a naive view of the circumstances - so regulators become strongly biased against any form of progress.

Look at how costs of FDA approval have doubled in the past decade - ever more is required of petitioners in the effort to reduce bad publicity for regulators by any and all means possible. The media is ever ready to broadcast any failure in medicine, but generally reluctant to talk about the very real cost of suppressing progress in medical technology. Regulators will continue to hold back new technologies until the widespread availability of said technologies in other regions makes them look like clowns for doing so. This is exactly what happened for first generation stem cell therapies, and is exactly what will happen for gene therapy technologies. Making new medicines available via experimentation and medical tourism is the only reliable path forward to faster general availability.

Elizabeth Parrish is a proponent of controversial ideas. Rankled by barriers to trials on potential life-enhancing treatments, she used herself as a guinea pig and says the results have borne fruit - but she has irked the science community in the process. The CEO of Seattle-based BioViva, a biotechnology company that focuses on developing gene therapies to slow the ageing process, revealed that in September 2015 she flew to Colombia and tried two experimental gene therapies on herself. Six months later, BioViva claimed the experiment was a success against ageing and that the treatment lowered the biological age of Parrish's immune cells by 20 years.

Parrish's actions caused a stir within the industry, mainly because BioViva had not done the pre-clinical work needed to progress to human studies or testing. Neither did the US Food and Drug Administration authorise Parrish's rogue experiment - hence the trip to Colombia. But Parrish denies her actions were reckless. "As a matter of fact, not intervening in one's health is more reckless because we already know how we'll die. We can actually use this powerful technology to treat many of the diseases of childhood and ageing. We studied a couple of gene therapies that had the most promise to treat not only adult diseases, but also childhood diseases, and I took them to prove they were safe to the world."

Parrish's foray into longevity science began when she stumbled upon a SENS Research Foundation conference in Cambridge, UK, and discovered how gene modifications had extended the normal lifespan of worms and mice. It was there she learned ageing ought to be classified as a disease, a collection of conditions including cancer, heart disease, stroke, and dementia and that everyone will suffer. She wanted to tell the world and get people to put money behind finding a cure. "Ageing is the biggest killer on the planet - by 2050 it will be the biggest killer in every small pocket of the world. To think that ageing is a problem of industrialised countries is just not correct. In countries that are developing right now we see most of the causes of death are associated with ageing - cancer, heart disease and various other things."

Since her personal experiment, Parrish says people have contacted her to ask if they can try her anti-ageing gene therapy. She admits this is not enough to expedite the official sanction for use of such therapies in humans. Instead, she is interested in asking countries to re-regulate. While the "EU has passed through regulations for a couple of gene therapies and the US FDA is following," Parrish wants to set up partnerships with governments, universities and paid-for trials (for those who can afford the hefty price tag). Scientific rigour in Parrish's work is the massive snag in her efforts to peddle gene therapies to the world. Many scientists, including those that are and have been a part of BioViva's scientific advisory board, have told the media that bypassing preclinical studies and trials raises serious ethical questions about how quickly such treatments can be tested on people, and whether medical regulators can be dodged.

Parrish's goal of bringing gene therapies to thousands of people could well be a pipe dream, but her sense of urgency about solving the world's ageing crisis is real. "By 2050 there'll be ten times more people living over the age of 100. It's fantastic news that we're living longer, but we need to live healthy longer. Right now, if you're running a drug through innovation through the US Food and Drug Administration it's 15-plus years and costs at least a billion dollars. It's too slow. We lose 40 million people a year to ageing."

Link: http://www.scmp.com/lifestyle/health-beauty/article/2125406/biotech-boss-backing-gene-therapy-solve-ageing-crisis-seeks

Researchers have found that fibrosis in the lung can be controlled via levels of FOXO3. This dovetails nicely with recent evidence for increased levels of cellular senescence to be a cause of lung fibrosis, as loss of FOXO3 triggers greater senescence in cell populations. This relationship might explain the observed associations of FOXO3 with longevity, though these are not as large as one might expect if it did have a strong effect on senescence. Other FOXO proteins also play a role in the determination of senescence versus self-destruction in cells that are damaged or have reached the end of their replicative life span, as demonstrated by the use of FOXO4-DRI as a senolytic compound that can trigger senescent cell apoptosis. All of this is interesting, but probably somewhat secondary to the goal of destroying senescent cells - it seems likely that FOXO3 is either moderating the bad behavior of senescent cells, preventing their influence from generating fibrosis, or perhaps preventing new cells from becoming senescent without much affecting existing senescent cells.

Idiopathic pulmonary fibrosis is currently an incurable lung disease, in which sufferers lose the ability to absorb adequate oxygen. Although the word 'idiopathic' means that the cause is unknown, the disease primarily affects former and active heavy smokers from the age of 50. An important role in idiopathic pulmonary fibrosis is played by connective tissue cells called fibroblasts. These cells provide structure to the air sacs (alveoli) in the lungs. During development of the disease, characteristic changes to these fibroblasts are observed. "The fibroblasts undergo a kind of personality change. In patients with pulmonary fibrosis, these cells contain increased amounts of contractile proteins, like those involved in muscle cell function." These modified cells, known as myofibroblasts, are responsible for the changes in connective tissue structure. As the disease progresses, the air sacs increasingly degenerate, resulting in damage to the blood vessels in the lungs. This results in shortness of breath.

Researchers decided to look for a factor which might be responsible for the fibroblast changes. Such a factor could hold the key to a possible treatment. The team first compared connective tissue cells from healthy individuals and patients with pulmonary fibrosis. "We noticed a transcription factor called FoxO3. Cells from patients with pulmonary fibrosis contained less of this protein than cells from healthy controls. The results were even clearer once we looked at FoxO3 activity - it was much lower in fibroblasts from patients with pulmonary fibrosis than in cells from healthy people." The researchers then turned their attention to animal research and develped a mouse model of the disease. They found that mice with pulmonary fibrosis also had reduced FoxO3 activity. The effect was much greater in mice which had been genetically modified to lack FoxO3.

Reactivating FoxO3 in patients with pulmonary fibrosis might, therefore, offer a way of treating the disease. This approach proved successful in mice: treating mice with pulmonary fibrosis with UCN-01 resulted in a reduction in symptoms and improved lung function. This effect was not observed in mice that lacked FoxO3. UCN-01 is a substance which activates FoxO3 and is currently undergoing clinical trials as a tumour therapy. Further studies will examine this link more closely, in the hope of eventually being able to start trials on patients.

Link: https://www.mpg.de/11868863/pulmonary-fibrosis-foxo3

A shift in the character of rejuvenation research has taken place over the past couple of years. Greater attention is being given to this work, and the most advanced lines have made - or will soon make - the leap from non-profit laboratory and philanthropic funding to for-profit startup company and venture funding. A growing community of angel investors and a fair few venture funds are now interested in supporting startup companies whose founders implement approaches to rejuvenation that follow the SENS model of repairing fundamental damage. A brief selection includes Kizoo Technology Ventures, Methuselah Fund, the Longevity Fund, Mann Bioinvest, and Apollo Ventures. Others will join them in the next year or two - it is a growing area of interest.

The point to be made here is that there is more than enough funding waiting in the wings to power any credible rejuvenation-focused company through its first few years. It is in fact much, much easier at this point to raise that funding than it is to obtain philanthropic funding for early stage research in the laboratory. The message for those with technologies that can make the leap is to go ahead and do it. Don't wait around; reach out to the venture community and take a look at the present state of play. Many different and interesting approaches to the treating of aging as a medical condition are on the verge of viability for commercial development, and what follows is a list of those I'd like to see emerge sooner rather than later, in no particular order of priority. If you are working on something that looks a lot like any of the following, then please do reach out; there are many in our community who would like to hear from you.

Better Approaches to Assessing the Outcome of Senolytic Treatments

Senolytic therapies that destroy senescent cells are going to be a very big deal in medicine. But how to determine whether or not they are working, and how well they work? One can measure all the usual metrics of disease, but that is a poor second best to understanding the actual load of senescent cells, and therefore the degree of impact. Currently all of the useful ways to count senescent cells involve tissue samples, and since wounding creates senescent cells there is some question as to the viability of biopsy-based approaches. We need some better: approaches that will lead to non-invasive or minimally invasive tests that quantify cellular senescence. A couple of years from now there will be a dozen companies putting forward various senolytic treatments, but next to no-one appears to be thinking about viable commercial assays for senescence. In such an important space, there is currently a single startup and perhaps one or two research groups with interesting ideas. This needs to change.

Make Medical Tourism Work for Enhancement Therapies

If any of the first generation senolytic drug candidates prove useful in humans, that will result in a tremendous market opportunity for medical tourism. The same is true when, in the next few years, CRISPR-based approaches to gene therapy become capable of reliable transfection of a large fraction of target cells. There are four or five gene targets, such as myostatin and follistatin, that make for very interesting enhancement therapies. There are many, many more healthy people who might want to undergo rejuvenation or enhancement therapies than there are patients seeking treatments for specific medical conditions. A number of groups related to the longevity science community have been gnawing away slowly at various aspects of the challenge of making medical tourism work, such as BioViva, Ascendance Biomedical, and Libertas Biomedical, and all have found it harder than one might suppose it to be. Somewhere in here there is a recipe that works, a way to make overseas clinical trials and treatments transparent, cost-effective, safe, and attractive, building a growth market that works in synergy with the advent of practical rejuvenation therapies and enhancement technologies.

Rejuvenating the Immune System

The immune system touches on so very many processes and aspects of aging that turning back its age-related dysfunction will be enormously influential on health in later life. There are potentially viable approaches for each of the various parts of this puzzle, and most of them are within striking distance of commercial development. Selective destruction of errant immune cells, or even the entire immune system, if it can be done without the present working approach of high dose, damaging immunosuppressants. Periodic infusion of patient-specific immune cells in bulk. Addressing the failing activity of the bone marrow stem cell populations responsible for creating immune cells. Restoring activity to the thymus, where T cells mature, to increase the supply of new T cells. Immune dysfunction is a sizable component of age-related frailty, and any of these items should move the needle.

Glucosepane Cross-Link Breaking and Supporting Technologies

At some point in the near future, the Spiegel Lab staff will uncover enzymes to break glucosepane cross-links, and then no doubt roll that effort into a startup company. There are probably numerous other approaches that will work, however, such as suitable small molecule drugs. As cross-link breaking will reverse blood vessel stiffening and skin aging, it will be an enormous market with plenty of room for competition. Drug screens are not massively expensive, though getting set up to work with glucosepane is still a specialty concern; there is a real opportunity here for any group that can adapt to the developing infrastructure for glucosepane research and make some progress. Further, this field has the same challenge in measurement of outcomes as senolytics: while companies will start by forging ahead with therapies, how do we tell how greatly a specific individual is affected by glucosepane cross-linking without cutting chunks out of them for analysis? Non-invasive or minimally invasive means of assessment will be important, and very much in demand as the first therapies roll out.

Better, Faster, Cheaper Amyloid Clearance

Current immunotherapy approaches to the amyloid-β of Alzheimer's disease are characterized by their enormous expense, both in development and implementation. Unless the cost is crushed down quite radically, and unless the pace of progress towards something that actually works speeds up to the same degree, this will be a poor platform for the future clearance of the other twenty or so types of amyloid that build up in aged tissues. We need to do better than this. More thinking outside the box is needed, such as the cerebrospinal fluid drainage focus of Leucadia Therapeutics or the catabodies of Covalent Bioscience, both approaches that could be far more economically viable if successful. More similarly inventive biotechnologies are called for.

Clearing Out as Yet Untouched Forms of Lysosomal Garbage

Companies such as human.bio and Ichor Therapeutics are working on some of the first implementations of biotechnologies to break down specific problem forms of metabolic waste, those that clog up the lysosomal recycling mechanisms, or otherwise cause cells to become dysfunctional. This is a small start on a sizable challenge: there are a great many problem compounds, and thus a great many opportunities to make meaningful inroads in removing these contributing causes of age-related disease. The Ichor Therapeutics model of picking one compound strongly tied to a specific disease is a strategy that can probably sustain a dozen companies for a variety of targets given the current state of knowledge.

Components of an Ecosystem for Targeted Blockade of Telomere Lengthening

Defeating all cancer with one single form of therapy, based on blockade of telomere lengthening, is a very plausible solution to the problem of too many types of cancer, too few researchers, and the current mainstream focus on overly specific forms of cancer treatment. If we want to see meaningful progress to an end to cancer in our lifetimes, the existing research and development model must change. The scientific path forward to this class of universal cancer therapy is well defined: selectively block the effects of (a) telomerase and (b) the alternative lengthening of telomeres (ALT) mechanisms, and couple that with a targeted delivery mechanism. It is unlikely at this stage that any one company could move directly to the full unified approach as a product, but a solution for even part of the overall problem, the portion of the final ecosystem, should be valuable in and of itself. That is likely to start with one of the demonstrated means of sabotaging telomerase activity, but we shall see.

Bringing Cell Therapies into the Rejuvenation Space

Today the overwhelming majority of cell therapies used in clinics do not produce rejuvenation. They achieve temporary benefits in patients largely through reductions in inflammation, accompanied by modest increases in regeneration and tissue maintenance that would not otherwise have taken place. The transplanted cells die quickly, and achieve these results through signaling in the period of time that they remain alive. The next generation of more sophisticated cell therapies is still waiting in the wings, approaches that can actually replace lost or damaged cell populations for the long term, with transplanted cells that survive and integrate into tissues, in order to restore function to specific organs and biological systems. Further, there are a range of other less immediately obvious possibilities that may also prove useful, such as induction of pluripotency in vivo, the aforementioned infusion of patient-matched immune cells, and accelerated cell replacement strategies. All in all, stem cell based regenerative medicine is a field that has reached a comfortable point, a box, and now needs to break out of it to reach the next level.

Reliable, High-Coverage Gene Therapy Platforms

The big stumbling block for moving the most promising genetic edits direct to human access via medical tourism is the reliability and cell coverage of the delivery methods when used in adult individuals. They are not consistent enough, and they are not delivering the payload into a large enough fraction of cells - and particularly stem cells, needed to make any change truly permanent for the recipient. Success here would be transformative for medicine and human enhancement technologies, and it appears that the research community is on the verge of solving this challenge in a number of different ways. Any one of these methods, carried forward to the clinic, should be enough to unlock an explosive growth in the size and capabilities of the gene therapy marketplace.

The open access review paper here provides a summary of the present scientific understanding of immunosenescence, the name given to the declining function of the immune system with advancing age. Some researchers consider this a separate phenomenon from inflammaging, the increased levels of inappropriate inflammatory activation of the immune system found in older individuals, and also distinct from some other kinds of immune cell failure found in old people, such as cellular senescence or immune cell exhaustion. Others consider all of these line items to be aspects of immunosenescence. Further, when it comes to the roots of age-related immune failure, the degree to which various potential causes are responsible is open to debate, and there will likely remain considerable uncertainty until such time as the research community can reverse those causes one by one to observe the results.

In our era of rapidly improving biotechnology, it is frequently the case that building therapies to address the causes of age-related dysfunction is the fastest path to an understanding of which of those causes are important. In the case of immunosenescence, there are a number of obvious paths forward, some of which should also help to treat autoimmune conditions: reversing atrophy of the thymus to increase the supply of new immune cells; destroying damaged or overspecialized immune cells to free up space for effective replacements; using cell therapies to deliver a large number of new immune cells; restoring function of the hematopoietic stem cells that generate immune cells.

Immunosenescence correlates with the linear extension of average life span that began in the nineteenth century and is still in progress. The aging phenotype, including immunosenescence, is the result of an imbalance between inflammatory and anti-inflammatory mechanisms with the consequence of a state defined by some authors as inflammaging. The most important feature of immunosenescence is the accumulation in the "immunological space" of memory and effector cells as a result of the stimulation caused by repeated clinical and subclinical infections and by continuous exposure to antigens. This state of chronic inflammation that characterizes senescence has a significant impact on survival and fragility. In fact, the condition of frail elderly occurs less frequently in situations characterized by low contact with viral infections and parasitic diseases. Furthermore immunosenescence is characterized by a particular remodelling of the immune system, induced by oxidative stress.

Apoptosis, a complex mechanism of programmed cell death, allows the maintenance of a physiological homeostasis mechanisms between survival and removal of damaged cells. Apoptosis is a strategic mechanism for the manifestation of the clonotypic diversity during lymphocyte selection, permitting to control the clonal expansion after antigenic stimulation. Changes in apoptosis, together with inflammaging and the up-regulation of the immune response with the consequent secretion of pro-inflammatory lymphokines, represents the major determinant of the rate of aging and longevity, as well as of the most common diseases related with age and with tumors. Other changes occur in innate immunity, the first line of defence providing rapid, but unspecific and incomplete protection, consisting mostly of monocytes, natural killer cells, and dendritic cells, acting up to the establishment of an adaptive immune response, which is slower, but highly specific, which cellular substrate consists of T and B lymphocytes.

The markers of inflammaging in adaptive immunity in centenarians are characterized by a decrease in naive T cells. The reduction of CD8- cells may be related to the risk of morbidity and death, as well as the combination of the increase of CD8+ cells and reduction of CD4+ T cells and the reduction of CD19+ B cells. The immune function of the elderly is weakened to due to the exhaustion of CD95 T cells, which are replaced with the clonal expansion of CD28- T cells. The increase of pro-inflammatory cytokines is associated with dementia, Parkinson's disease, atherosclerosis, type 2 diabetes, sarcopenia, and a high risk of morbidity and mortality. A correct modulation of immune responses and apoptotic phenomena can be useful to reduce age-related degenerative diseases, as well as inflammatory and neoplastic diseases.

Link: https://doi.org/10.1186/s12948-017-0077-0

Commensal microbes are the largely helpful populations that live inside us, usually meaning the gut microbiota, but there are others, such as the bacteria found in the mouth. Among these largely helpful microbes are a range of species that cause us harm over the years, however - consider the bacterial origins of gum disease, for example. Researchers are increasingly interested in the ways in which the swarming microbial life inside us, and particularly in the gut, might influence the progression of aging; to what degree are gut bacteria a cause of the observed natural variations in pace and outcome of aging in mammals? This is an open question.

In the case of neurodegenerative conditions such as Alzheimer's disease, microbial life may contribute by generating some fraction of the amyloid deposits or chronic inflammation known to be associated with the condition. In this context, some scientists are focused on invading microbes such as spirochetes, while others, like those noted here, are more interested in the commensal microbes that normally live inside us. There is a fair amount of evidence for either of these two classes of microbe to be involved.

Research in the past two decades has revealed that microbial organisms in the gut influence health and disease in many ways, particularly related to immune function, metabolism, and resistance to infection. Recent studies have shown that gut microbes also may cause or worsen Parkinson's disease, Alzheimer's disease and other neurodegenerative conditions. Researchers now propose the term "mapranosis" for the process by which amyloid proteins produced by microbes (bacteria, fungi and others) alter the structure of proteins (proteopathy) and enhance inflammation in the nervous system, thereby initiating or augmenting brain disease. The term is derived from Microbiota Associated Protepathy And Neuroinflammation + osis (a process).

Research into the multitude of microbes that inhabit the human body has expanded considerably in recent years. Genomic analysis has begun to reveal the full diversity of bacteria, viruses, fungi, archaea, and parasites living in and on the body, the majority of them in the gut. Even more recently, researchers have begun to explore how the proteins and other metabolites produced by microbes inhabiting the gut influence functions in other parts of the body, including the brain. However, we do not yet have a full understanding of how these systems work. The relationship between the microbiota and the brain has been called the "gut-brain axis."

It is understood that the clumping of misfolded amyloid proteins, structures produced by neurons in the brain, are associated with neurodegeneration and conditions such as Alzheimer's disease, Parkinson's disease and amyotrophic lateral sclerosis (ALS). "It is well known that patterns of amyloid misfolding of neuronal proteins are involved in age-related brain diseases. Recent studies suggest that similar protein structures produced by gut bacteria, referred to as bacterial amyloid, may be involved in the initiation of neurodegenerative processes in the brain. Bacterial amyloids are produced by a wide range of microbes that inhabit the GI tract, including the mouth. Our work suggests that our commensal microbial partners make functional extracellular amyloid proteins, which interact with host proteins through cross-seeding of amyloid misfolding and trigger neuroinflammation in the brain."

Link: http://uoflnews.com/releases/uofl-researcher-refining-understanding-of-the-role-of-microbiota-in-neurodegeneration-with-a-new-term-mapranosis/

There is still time to sign up for the Undoing Aging event in Berlin, coming up in March 2018. This scientific conference will focus on rejuvenation research in the same manner as the SENS conference series that ran from 2003 to 2013 under the auspices of the Methuselah Foundation and, later, the SENS Research Foundation. Undoing Aging is a collaboration between the SENS Research Foundation and Forever Healthy Foundation, the latter being the organization founded by SENS patron Michael Greve. You might recall that in 2016 Greve pledged $10 million to fund rejuvenation research and resulting startup companies, becoming the first donor to the SENS Project|21 initiative.

As the first rejuvenation therapies near human trials and clinical availability, it becomes ever more important to expand the size of the research community presently working on ways to repair the causes of aging. As Aubrey de Grey has pointed out, there is a great deal left to accomplish on the way to a toolkit of therapies capable of turning back aging and extending healthy life spans by even a few decades. That work requires funding, and interested researchers, public support. That in turn requires networking, persuasion, and a showcasing of promising work currently in progress. In years to come, everyone will say that the strategy of repairing the cell and tissue damage of aging was obvious in hindsight - but we need their support now, when it matters, when there is work yet to accomplish, not after the fact. It is the eternal challenge of bootstrapping a movement, an industry, a research community. Conferences play an important role in this process.

Undoing Aging 2018 Conference Announces Program and Speakers

The SENS Research Foundation and the Forever Healthy Foundation today announced the 2018 Undoing Aging Conference program and speakers. Undoing Aging will take place March 15 - 17, 2018 at the Umspannwerk Alexanderplatz in Berlin, Germany. Undoing Aging 2018 is focused on the cellular and molecular repair of age-related damage as the basis of therapies to bring aging under full medical control. The conference, a joint effort of SENS Research Foundation and Forever Healthy Foundation, provides a platform for the existing scientific community that already works on damage repair and, at the same time, offers interested scientists and students a first-hand understanding of the current state of this exciting new field of biomedical research.

Undoing Aging 2018 Program

I have regretted not having thought of the title "Undoing aging" for our 2007 book "Ending Aging", ever since a reader accidentally used that name for it in an email to us. I am thus delighted to have this opportunity to use it now. It perfectly encapsulates the nature of the approach to maintaining youthfulness in old age that SENS Research Foundation pursues: the repair of the self-inflicted damage that the body generates as side-effects of essential metabolic processes. This conference will, accordingly, mirror the structure of SENS, with sessions devoted to each strand and to the enabling technologies that multiple strands will rely upon. Those of you who attended any of the conferences we organised in Cambridge, from 2003 to 2013, will notice the similarity - and indeed, the similarities will not end there!

Two of the seven SENS damage categories consist of the elimination of cells that we have too many of: either because they are dividing too much (which is essentially the definition of cancer) or because they are not dying when they should. The most promising truly general anti-cancer therapies each merit multiple talks, so we have a session for each, as well as one for the "death-resistant cells" category. Russell and Hawthorne will present novel methods for weakening the ability of cancer (or indeed any) cells to render themselves invisible to the immune system, while Silva and Gorbunova will update us on ways to manipulate telomere elongation and thereby limit proliferation capacity. Kirkland, Lewis, and de Keizer will then discuss the range of methods currently under development for selectively eliminating cells that are doing us more harm than good: small molecules, suicide genes, and engineered peptides.​​

The two SENS categories that have, arguably, seen the greatest contribution from research funded by SRF are those relating to damage within cells: mitochondrial mutations and "garbage". Our in-house team has made immense progress recently in rendering mitochondrial mutations harmless by installing "backup copies" in the nuclear genome, and O'Connor will provide updates on where that work stands. Honkanen and Moody will describe the state of play in relation to elimination of the two best-characterised types of intracellular garbage that drive major age-related diseases, namely atherosclerosis and macular degeneration.​

Extracellular changes play a major role in mediating the loss of function of cells and tissues. Talks in this part of the conference will cover a variety of such problems. Paul and Graef will present novel approaches to the removal of aggregated material, notably the protein transthyretin which misfolds particularly easily and may be the main factor responsible both for important diseases and for mortality in very old age. Spiegel and Clark are both researching the stiffening of the extracellular matrix, a process that contributes both to life-threatening and to cosmetic aspects of aging. Wagers' focus will be the role of circulating proteins in mediating and counteracting age-related deleterious changes of gene expression in a wide range of tissues.​

In an ideal world, the whole of SENS would be viewed as regenerative medicine, since it is all about restoring structure to restore function; but that term has too much history to be broadened in such a way, so we adhere to its standard usage covering just stem cell therapy and tissue engineering. The manipulation of stem cells to generate safe and effective therapeutic reagents has advanced by leaps and bounds recently, and West, Sen, and Loring are among the absolute leaders in this burgeoning area, especially where age-related conditions are concerned.

The replacement of entire organs from a variety of sources may soon be far more practical than hitherto, and Atala, Lemaitre, and Jones will describe three radically new approaches to addressing the still-acute shortage of organs for transplant. Finally, the restoration of organ function can in principle be achieved not only via one-for-one replacement of a malfunctioning organ, but through more distributed means where a single "organoid" only partially substitutes; Lagasse will present one highly novel approach along these lines.​

Most of SENS is still at a pre-clinical stage of development, where evidence of safety and efficacy can be obtained via short cuts that would not be available when treating humans. SRF has, therefore, always set its priorities both near-term and long-term, funding proof-of-concept research alongside work that will only have clear utility further downstream. The latter tend to cross the boundaries between SENS strands. First, it is crucial to be able to measure efficacy across the full range of metabolic markers, and Horvath, Fortney, and Csordas will address three complementary "omics" domains in which changes with age - and therapeutic manipulations of those changes - can be monitored: epigenomics, metabolomics, and proteomics. Then we will hear, from Young and Zhavoronkov, how drugs can be discovered and repurposed using state-of-the-art computational techniques. Finally, how are therapeutics delivered? The conference's closing session will feature Calos, Scholz, and Hebert telling us about new ways to get nucleic acids, proteins, and cells (respectively) into places that standard methods can only inadequately reach.

The field of aging research could do with more of its scientists choosing to write for laypeople; the more outreach the better. This short column by researcher Steven Austad illustrates one way of looking at aging - that it is all about the mortality rate at a given age, and the inexorable rise of that mortality rate over time, caused by the accumulation of cell and tissue damage. By this metric an individual at age 40 or 50 is already significantly impacted by the processes of aging in comparison with an individual at age 20, manifesting as an increased mortality rate. Given this, there is every chance that a half-way decent first generation rejuvenation therapy would be of some benefit to people at age 40, those the medical establishment currently designates as being in perfect health, but who nonetheless have a mortality rate that is considerably higher than is the case for people at age 20.

I have a pill. If you decide to take my pill, you immediately stop aging and are preserved in your current physical state from this day forward. This hypothetical pill that stops aging, call it the Methuselah pill, will not make you immortal. Immortality does not exist in this world. Whether or not you age, you can still step in front of a bus, eat a contaminated hamburger, catch a stray bullet, or be struck by lightning. In fact, if you lived long enough one of these things would almost be guaranteed to happen to you.

One way that scientists define aging is that it increases the chance that you will die in the coming year. In America, your chance of dying doubles every 8 years after about age 35. But with the Methuselah pill that no longer happens. You have the same chance of dying, you look the same, you feel the same, as the age at which you took the pill, forever. Would you want to be frozen in time with the physical looks, the energy, strength and agility you had when you were 20? Give this some careful thought because half of you - the male half - may remember 20 as the testosterone-soaked age at which you were more than a little crazy. Maybe you'd like to be preserved at age 50, when people will take you more seriously. You would be more settled in life, a bit more thoughtful, a bit less swift.

One thing to consider. The age you choose to stop aging has a great deal to do with how much longer you can expect to live. A little simple algebra with U.S. government statistics shows that with a 20 year old male survival rate lasting into infinity, your life expectancy is another 600 years rather than the 57 years it is in reality. Not a bad bargain for staying a little crazy. If you're a woman, you're not so crazy at that age and you are also better designed for survival than your male counterparts. That's a sad fact of biology, men. You could expect to survive another 1700 years rather than 62 years you can expect in reality, nearly three times as long as those crazy men. I know it doesn't sound fair, fellows, but age 20 is when the survival advantage of women over men is close to its greatest.

If you decided to stop aging when you are a dignified and mature 50 year-old, you will have sacrificed a lot of future years to achieve that dignified look. Fifty year olds are about 6 times more likely to die in a given year than 20 year olds. Not only that, but you could expect to live with some aches and pains that you didn't anticipate. You won't hear as well and will probably be holding the newspaper or your smart phone at arm's length, but at least that testosterone problem will no longer be so pressing. Your life expectancy, however, has dropped to a mere 140 years if you're a man and a little over 200 years if you're a woman. Ladies, that decision to stop aging at 50 rather than 20 has cost you 1500 years of life expectancy and a considerable amount of pain. You suspected it was a bad decision, didn't you?

The point of this exercise, I suppose, besides having a little fun and stimulating a little thought is to give readers a visceral feel for the toll that aging exacts on us. Back here in the real world, there has been only one confirmed 120 year old person, a woman naturally, in the history of our species. No one yet has approached even 130 years, although some of us researchers are working to change that.

Link: http://www.al.com/opinion/index.ssf/2017/12/the_cost_of_aging.html

Aubrey de Grey of the SENS Research Foundation needs little introduction to the audience here. His efforts and those of his allies have gone a long way towards ensuring that we will benefit from the first generation of rejuvenation therapies to emerge over the years ahead. The interviewer here is focused on the science of SENS, the Strategies for Engineered Negligible Senescence, a recipe for the control of aging through periodic repair and reversal of its root causes. I encourage you to read the whole interview rather than just the snippets below; it is fairly long.

Feinerman: The past five years have been remarkable. Now every day I read new articles and news about age reversal. I believe we will remember 2016-2017 as the most important years. Do you share this feeling?

de Grey: Yes and no. Yes, in the sense that there are indeed more and more exciting breakthroughs being made in the lab - and of course I am very proud that SENS Research Foundation is responsible for some of them. But no, in the sense that there is still a terribly long way to go; we need to fix a lot of different things in order to get rid of ageing, and for some of them we are still at a very early stage in the research.

Feinerman: Your famous book "Ending Ageing" was published 10 years ago. Would you like to make a new version?

de Grey: I probably should, at some point, but it's not a priority, because the overall approach that we described in that book has stood the test of time: we have made plenty of progress, and we have not come across any unforeseen obstacles that made us change course with regard to any of the types of damage.

Feinerman: You look for bacteria who feed on dead animals to find enzymes capable of breaking glucosepane. How do you find useful bacteria?

de Grey: We are using a "metagenomic" strategy for identifying enzymes that can break glucosepane: we take standard E. coli bacteria, we break one or two of their genes so that they become unable to synthesise one or another chemical (in this case typically arginine or lysine) so that they need to take it up from their surroundings. Then we add random DNA from the environment, which could come from any bacteria, even unculturable ones, and add bits of it to the E. coli. Very occasionally the new DNA may encode an enzyme that breaks glucosepane, and if so, the bacteria will grow even without any arginine or lysine in the environment, if (but only if) we give them glucosepane instead and they break it to create arginine and lysine.

Feinerman: In your book you proposed Whole-body Interdiction of Lengthening of Telomeres (WILT) - the removal of telomerase in all cells in order to prevent cancer and reseeding stem cell populations regularly. Has there been any success in that?

de Grey: We are making progress there, yes; in particular we have shown that telomerase-negative stem cell reseeding works for the blood. However, no, the problem with non-integrating telomerase is that it will extend cancer telomeres just as much as normal cells' telomeres. I support that research, though, not least because there may be breakthroughs in combating cancer in other ways (especially with the immune system), in which case it would be much safer to stimulate telomerase systemically.

Feinerman: Now we have very precise CRISPR, and removing genes is easier than inserting ones because you can target the same cell more than once. When we solve delivery problems will we be able to apply WILT?

de Grey: Yes, certainly.

Feinerman: Why can't we remove telomerase locally in compromised tissue?

de Grey: It's being tried, but it is very difficult to make the removal selective.

Feinerman: There is growing evidence that epigenetic changes are highly organized and may be one of the causes of ageing. What do you think? Maybe should we consider epigenetic changes as another type of damage in SENS model, calling EpiSENS?

de Grey: We need to be much more precise with definitions in order to answer your question. Epigenetic changes can be classified into two main classes: shift and noise. Shift means changes that occur in a coordinated manner among all cells of a given type and tissue, whereas noise means changes that occur in some such cells but not others, increasing the variability of that type of cell. Shifts are caused by some sort of program (genetic changes to the cell's environment), so yes, they can potentially be reversed by restoring the environment and putting the program into reverse. Noise, on the other hand, is not reversible. And we have for several years worked on determining whether it happens enough to matter in a currently normal lifetime. We have not got to a definitive answer, but it's looking though no, epigenetic noise accumulates too slowly to matter, other than maybe for cancer (which, of course, we are addressing in other ways).

Feinerman: Should we use reprogramming factors to reverse the epigenetic program?

de Grey: Probably not. There may be some benefits in doing so, as a way to restore the numbers of certain types of stem cells, but we can always do that by other methods (especially by direct stem cell transplantation), so I don't think we will ever actually need to dedifferentiate cells in vivo.

Feinerman: What do you think of the idea of Whole-body Induced Cell Turnover (WICT)?

de Grey: The general idea of accelerating cell turnover is definitely a good one. It is a bit like the idea of replacing whole organs: if you replace the entire structure, you don't need to repair the damage that the structure contains. However, also like replacement of organs, it has potential downsides, because evolution has give us a particular rate of turnover of particular cells, and the function of each of our cell types is optimised for that. So it may end up being complicated, with many pros and cons.

Feinerman: Won't it be easier to print or grow new organs instead of rejuvenating the old ones?

de Grey: That's absolutely correct. I expect that in the early days of implementing SENS, some organs will be easier to replace than to repair. However, of course replacing an organ requires invasive surgery, so we will want to develop repair eventually.

Feinerman: What in your opinion will be the order of arrival of rejuvenating therapies?

de Grey: Well, a lot of the stem cell side of things is in clinical trials already, and removal of amyloid is there too in the case of Alzheimer's. Next on the list will probably be senescent cell ablation, which Unity Biotechnology are saying will be in the clinic next year, and removal of intracellular garbage for macular degeneration will also be, courtesy of our spinout Ichor Therapeutics. The other three are harder but they are all chugging along!

Feinerman: There are about twenty various types of amyloids, we can see some success in removing transthyretin and beta-amyloid. What is about others? Can we scale success in removing the above two on the others?

de Grey: I'm very confident that the removal of other amyloids can be achieved using more or less the same methods that have worked against those two. The next one on my list would be islet amyloid, which contributes to diabetes.

Feinerman: When I ask people to donate to SENS Research Foundation they often say that their a few bucks don't matter. What can you say to our readers to encourage them?

de Grey: One way to say it is to calculate how many dollars it would take to save a life by donating to SENS. I estimate that a budget of $50 million per year would let us go three times faster than now and would bring forward the defeat of ageing by about a decade. About 400 million people die of ageing in a decade, so that means donating to SENS has a bang-for-the-buck of roughly one life per dollar. No other cause comes anywhere near that.

Link: https://medium.com/@arielf/wake-up-people-its-time-to-aim-high-b0c2bcac53f1

Below you will find a paper on advanced glycation end-products (AGEs) and their contribution to degenerative aging, with a focus on the vascular system. AGEs are the result of various chemical reactions involving sugars, many of which occur both inside the body in the normal course of metabolic operations and outside the body during food preparation. There are many different types of AGEs, most well-known to chemists, but the tools for working with AGEs and their precursors in a biological context are not that great in comparison to the rest of the biochemistry field, and as a consequence their study has lagged. You will still find many papers hedging or being carefully agnostic on the question of which AGEs are important in mammalian aging, and on their relative amounts and relevant mechanisms. That is the case here.

As is true of mitochondrial damage, there are two quite distinct ways of looking at AGEs in aging, two collections of processes, one of which offers worse prospects when it comes to producing gains in health and longevity, but is nonetheless the point of greatest mainstream research focus. This is, sadly, the story for much of the young field of rejuvenation research. We have a lot of work left to accomplish when it comes to driving the necessary interest and funding to make meaningful progress towards addressing the causes of aging. Not least of this is the matter of steering more of the research community in the right direction, towards high-yield rather than low-yield strategies.

The first, minority area of AGE research is focused on persistent cross-links formed by AGEs in the extracellular matrix. AGEs can bind to the matrix proteins, linking them together. Since the physical properties of tissue are determined by the arrangement of these proteins and their ability to move relative to one another, this process of cross-linking can corrode elasticity and strength. It makes bone brittle, skin wrinkled, and blood vessels stiff. The last of those starts the cascade leading to hypertension, heart disease, and death: even if there were no other processes in aging, it would kill you eventually.

Few AGEs are persistent, however. Most are like the sugars that formed them: here today, gone tomorrow, with current levels very dependent on the diet. It is thought that glucosepane makes up the overwhelming majority of all persistent cross-links in human tissues, but there is next to no funding for research into this compound and its role in aging. The SENS Research Foundation has been funding near all of the work aimed at the production of necessary scientific infrastructure and then AGE-breaker pharmaceuticals that can destroy cross-links. This is hopefully nearing fruition. That this is just a single type of target makes it a very promising line of work, hopefully soon to join senolytics as a rejuvenation therapy moving from theory to practice. Reversing blood vessel stiffness alone would have a profound effect on health for older individuals.

The second, majority area of AGE research is more focused on chronic inflammation, metabolic dysfunction characteristic of type 2 diabetes and obesity, and dietary intake of sugars and AGEs. It encompasses the short-lived AGEs, which are a much larger fraction of the AGE population than the rare, persistent AGEs that linger to accumulate slowly in tissues. A primary point of interest here is the interaction between AGEs and RAGE, the receptor for AGEs. RAGE is a mediator of inflammation, and high levels of AGEs trigger it relentlessly; it also has a number of other roles that are poorly cataloged, but the general consensus is that these probably don't benefit from continual activation either. This is thought to be one of the ways in which diabetes and excess fat tissue result in high degrees of chronic inflammation, and all of the downstream consequences of that inflammation. That means higher rates of age-related disease, greater immune dysfunction, more tissue damage, and so forth. At least until quite late in old age, much of this is the result of lifestyle choices, and can be avoided or reversed through choice in diet and weight.

The paper here is focused on a future of therapies that interfere in the interaction between AGEs and RAGE. The author dismisses AGE-breakers due to past failures, which I think is an incorrect conclusion. The past failures were failures because they targeted forms of AGE that are noteworthy in short-lived rodent species, but unfortunately not all that relevant in humans. The types of AGE that cause pathology vary considerably by species and species life span. No past initiative ever targeted glucosepane. Meanwhile, efforts to target the AGE / RAGE interaction are probably best thought of as belonging to the same class of strategy as other attempts to block the inflammatory consequences of fat tissue or diabetes. It is an effort to compensate for a problem, not repair the cause of the problem.

The AGE-RAGE Axis: Implications for Age-Associated Arterial Diseases

Changes in the components of large arteries due to advancing age have been described in humans and animals. Age-associated blood vessel remodeling includes such features as dilation of the lumina, intimal and medial thickening, changes in the extracellular matrix (ECM), and augmented stiffness. In addition to these structural changes, other mechanisms contribute to the overall consequences of aging to the arterial wall, including such phenomena as inflammation, endothelial dysfunction, and oxidative stress. Fibroblasts and smooth muscle cells (SMC) contribute to aging in the vasculature, in part by increasing ECM; macrophages contribute by increasing inflammatory factors that have a wide range of possible consequences. These pathobiological events adversely affect the vessel wall and all of its components, potentially contributing to arterial aging.

It has been shown that the aged human arterial wall exhibits a more proinflammatory signature, with increased expression and activity of matrix metalloproteinases (MMPs) and chemokines. Atop these considerations is the effect of co-morbid conditions in aging, which may augment production of inflammatory mediators and exacerbate the impact of arterial aging, examples of which include diabetes mellitus (types 1 or 2 or the rarer forms of diabetes); chronic renal disease; and chronic immune/inflammatory disorders.

Advanced glycation endproducts (AGEs) are a diverse group of macromolecules and at least 20 different specific AGEs have been described to date. Among the major groups of AGEs are carboxymethyl lysine (CML), carboxyethyl lysine (CEL), pentosidine, glucosepane, methylglyoxal lysine dimer, glyoxal lysine dimer, and glycolic acid lysine amide. AGEs form throughout life via the process of non-enzymatic glycation of proteins and lipids, and this process is accelerated during hyperglycemia, oxidative stress, aging, advanced renal disease, and inflammation. Humans and animals are also exposed to exogenous sources of AGEs ingested through food-derived AGEs and tobacco products. It has been shown that restriction in dietary AGE intake may increase the lifespan in animals.

AGEs accumulate in aging tissues and on vulnerable plasma proteins. Higher levels of circulating AGEs have been linked to chronic diseases in aging subjects. The accumulation of AGEs is increased and accelerated in hypertensive subjects and is also associated with diabetes. In fact, aged subjects, even though healthy, may have higher AGE accumulation compared to younger subjects with diabetes and its complications, thus underscoring that AGE production and accumulation accompanies the normal aging process. Therefore, multiple factors such as the rate of accumulation of AGE ligand, the absolute concentration of the ligand, and individual susceptibility to AGE formation may be important in determining an individual's AGE burden.

Numerous studies have confirmed the correlation between AGE accumulation and increased artery stiffness. Arterial stiffness is associated with greater risk for aging-associated cardio- and cerebrovascular diseases and mortality. AGE accumulation causes upregulation of inflammation and destruction of collagen and elastin, along with other proteins of the ECM. It is noteworthy that despite testing of multiple classes of anti-AGE agents, none have obtained, at least to date, approval for anti-AGE indications. Although there are many possible reasons for this, we propose that one reason is that solely targeting AGEs fails to capture the pathobiological effects of distinct RAGE ligands. Therefore, it is not surprising that attempts are underway to directly target RAGE as a therapeutic strategy.

RAGE is expressed on a number of important cell types implicated in arterial aging and vascular pathology. Once AGEs are formed, albeit by diverse intrinsic and environmentally-triggered mechanisms, their interaction with RAGE on endothelial cells, SMCs, and immune cells such as macrophages, results in upregulation of inflammatory and oxidative stress-provoking factors, thereby providing a mechanism to link AGE-RAGE to arterial aging and its consequences.

Approaches to limit RAGE ligand AGEs have been accompanied by efforts to block RAGE itself and these have been tested in vitro and in vivo; in addition, human clinical trial testing is also underway. In vitro, pre-treatment of AGE-stimulated endothelial cells with anti-RAGE antibodies or anti-oxidants blocked cellular perturbation. Another RAGE blocking agent currently in Phase III clinical trials in Alzheimer's disease is the small molecule Azeliragon, which inhibits the receptor for advanced glycation endproducts and prevents RAGE ligands from interacting with RAGE. Certainly, more research is required to understand the entire scope of RAGE signaling and the extent to which blocking AGEs/RAGE interaction may intercept the full pathobiology of RAGE activation.

The media throws around the term "immortality" when talking about efforts to extend healthy life, with little concern for the dictionary definition. Advocates for radical life extension have in the past used physical immortality as a alternative term for the concept of agelessness, in which aging is controlled but all other causes of death still exist - which is another change of meaning. Some people find this a distraction, an annoyance, something that makes it harder to conduct advocacy and fundraising for current and prospective longevity science. Convincing the world that rejuvenation therapies are a viable near term prospect, given sufficient funding, is challenge enough without the peanut gallery.

It isn't clear whether or not dictionary definition immortality is possible in this universe, and if it was the entities enjoying it would be very different from the present human model of existence. Even scaling up to a reliable life expectancy of a million years would require considerable technology-assisted change and expansion. Such long-lived beings would probably be something akin to distributed collections of hardened, space-faring, automated computational factories. In that sense, we stand a long way removed from even the lesser challenges of living for a very, very long time. The problems of today, in which we take the first steps towards treating aging as a medical condition, so as to add the first few additional decades of healthy life, are those of the first rung on an extremely long ladder - and they are hard problems. If we don't focus on them, there is every chance of failure to progress soon enough to matter for most of us.

It's not uncommon, especially for outsiders of a given field, to use an inappropriate word to indicate a more complex concept than the word itself conveys - maybe because they think that the two are close enough or possibly because they just don't see the difference. For this reason, it's likely that each field has its own unspeakably profane word; in the field of rejuvenation, that word is the dreaded I-word: immortality.

Whether or not immortality is possible is an intriguing question, but it is decidedly off-topic in the field of rejuvenation, because rejuvenation is not immortality. If a universal antiviral drug existed, able to wipe the floor with every conceivable virus, you wouldn't call it an immortality drug, because right after leaving the doctor's office where you got your miracle shot, a grand piano might happen to crush you after a 50-story free fall, and the antiviral drug wouldn't be especially effective against that particular cause of death. Similarly, rejuvenation would save you from death by age-related diseases, but again not by falling grand pianos.

Yet, both people and the media keep talking about "curing death" and "immortality pills" when the actual topic is rejuvenation biotechnology; this is a cause of particular annoyance to Dr. Aubrey de Grey, whose pioneering work is constantly called an "immortality quest" and similar things. Since immortality reasonably seems a pipe dream, this results in a gross misrepresentation of the entire field and a lot of unwarranted bashing of completely legitimate medical research whose only fault is that it aims to prevent the diseases of aging rather than just coping with them.

The same story is true of negligible senescence. If a successful rejuvenation platform were implemented, people would still age biologically, but we would have therapies capable of undoing such aging. Through periodic reapplication of these therapies, the hallmarks of aging would always be kept well below the pathology threshold. In other words, we would still senesce (that is, age), but our level of senescence would stay negligible - that's where the term comes from. Yet, many people keep calling negligible senescence immortality just like they do rejuvenation biotechnology, whether deliberately or by genuine mistake, thereby providing an excellent strawman for needy critics to beat.

Negligible senescence is the expected result of truly comprehensive rejuvenation biotechnologies, and yes, if we got there, our healthspan would be vastly increased, and consequently, so would our lifespan; if you were in perfect health for longer than, say, 100 years, it is a disarmingly trivial consequence that you would live for longer than 100 years. However, whether a negligibly senescent person then lives on forever or not, or ten thousand years from now, someone beats the odds and comes up with a fancy immortality switch, is an entirely different matter that is beyond the scope of the field of rejuvenation biotechnology.

Link: https://www.leafscience.org/for-the-last-time-rejuvenation-is-not-immortality/

We see the current survivors of the relentless evolutionary process of winnowing and change all around us, and near all are examples of the point that greater life span is all too rarely a winning trait. Look at how easy it is for our early biotechnology to engineer longer lives in near all animal species. Small genetic tweaks suffice in most cases. Why were those genetic alterations not selected for long ago, given that longer-lived individuals can produce more progeny than their shorter-lived rivals? The study here provides one example of the many reasons for the current state of life span in most species: the present outcome for any given species is a balance between resistance to stress and ability to live longer, in this case mediated by the way in which the immune system acts in response to circumstances.

A shorter life may be the price an organism pays for coping with the natural assaults of daily living, according to researchers. The scientists used fruit flies to examine the relationship between lifespan and signaling proteins that defend the body against environmental stressors, such as bacterial infections and cold temperatures. Since flies and mammals share some of the same molecular pathways, the work may demonstrate how the environment affects longevity in humans.

The research identified Methuselah-like receptor-10 (Mthl10), a protein that moderates how flies respond to inflammation. The finding provides evidence for one theory of aging, which suggests longevity depends on a delicate balance between proinflammatory proteins, thought to promote aging, and anti-inflammatory proteins, believed to prolong life. These inflammatory factors are influenced by what an organism experiences in its every day environment.

Mthl10 appears on the surface of insect cells and acts as the binding partner to a signaling molecule known as growth-blocking peptide (GBP). Once Mthl10 and GBP connect, they initiate the production of proinflammatory proteins, which, in turn, shortens the fly's life. However, removing the Mthl10 gene makes the flies unable to produce Mthl10 protein and prevents the binding of GBP to cells. As a result, the flies experienced low levels of inflammation and longer lifespans. "Fruit flies without Mthl10 live up to 25 percent longer. But, they exhibit higher death rates when exposed to environmental stressors."

When the project started in 2013, scientists did not know what cell-surface protein was working with GBP to promote inflammation. So they began testing 1700 compounds that could individually suppress the production of every known cell-surface protein in the fruit fly. They looked for the protein that prevented GBP from binding and activating inflammation. They found several candidates, but all were eliminated during further testing, except Mthl10. The study proposes that the human counterpart to GBP is a protein called defensin BD2, but the nature of its binding partner is currently unknown.

Link: https://www.laboratoryequipment.com/news/2017/12/defending-against-environmental-stressors-may-shorten-lifespan

Today I'll point out a fairly readable review paper that walks through the high points of what is known of the mitochondrial contribution to degenerative aging and the common, well-studied age-related diseases that cause the greatest amounts of suffering and death. Every cell has a few hundred mitochondria swarming inside it, evolved descendants of ancient symbiotic bacteria that are now fully integrated components of the cell. They are highly active components: they replicate and fuse, pass molecular machinery between one another, are destroyed by cellular quality control mechanisms when they become damaged, and can even transfer between cells, all conducted at a rapid pace. Most of their DNA has moved into the cell nucleus, but a small number of genes remain to form the circular mitochondrial DNA. Mitochondria are primarily responsible for generating chemical energy stores, providing the power for cellular operations, but they also participate in many other fundamental cellular processes in one way or another.

There are two ways we might think of mitochondria in the context of aging. The first is the SENS view of the mitochondrial contribution to aging. The mitochondrial DNA becomes damaged, either through replication or because building energy store molecules is a process that generates potentially damaging, reactive molecules as a side-effect. Sometimes that damage cuts out an important part of the energy generation machinery, creating a mitochondrion that both runs hot, producing many more harmful molecules, but is also more competitive than its peers when it comes to replication within the cell. Perhaps it can evade quality control, perhaps it replicates more rapidly; whatever the cause, whenever this rare form of damage occurs, the descendants of the damaged mitochondrion very quickly take over the entire population within that cell.

The result is a pathological cell that churns out harmful reactive molecules in large amounts into the surrounding tissue. This can, for example, cause atherosclerosis through oxidative damage of lipids that end up in the bloodstream. There the damaged molecules irritate blood vessel walls, resulting in the lesions that will become atherosclerotic plaques and eventually rupture. This could be avoided via any reliably means of sabotaging this chain of events. The proposed SENS Research Foundation approach is to use gene therapy to copy mitochondrial DNA into the cell nucleus to provide a backup supply of protein machinery; if carried out, then it won't matter how ragged the mitochondrial DNA becomes. The mitochondria will still function correctly, and cells will remain unharmed.

The second way to think of mitochondrial in aging is given far more attention in the scientific mainstream. It is a sort of general malaise found in all cells in aged tissue, in which mitochondrial dynamics are altered, the size of mitochondria changes, and their ability to generate energy stores falters. The processes of cellular quality control responsible for destroying problematic mitochondria start to fail as well. This is well studied by researchers who specialize in neurodegenerative diseases, as the brain requires a great deal of energy to function, and lack of that energy is a real problem. Why does this happen? That remains a question; which of the forms of damage that drive aging lead to this reaction, and what exactly is the chain of cause and effect? Researchers are making some inroads in tinkering with this mitochondrial malaise, speeding it up and slowing it down somewhat, but the roots remain obscure.

The Mitochondrial Basis of Aging and Age-Related Disorders

Mitochondrial dysfunction is linked to various aspects of aging including impaired oxidative phosphorylation (OXPHOS) activity, increased oxidative damage, decline in mitochondrial quality control, reduced activity of metabolic enzymes, as well as changes in mitochondrial morphology, dynamics, and biogenesis. Mitochondrial dysfunction is also implicated in numerous age-related pathologies including neurodegenerative and cardiovascular disorders, diabetes, obesity, and cancer.

The role of mitochondria in aging was first proposed more than 40 years ago in the free radical theory of aging, suggesting that accumulation of cellular damage with increasing age results from reactive oxygen species (ROS) and mitochondria are one of the most important sources and targets of ROS that could function as an 'aging clock'. Since then, a growing body of evidence has shown that mitochondrial dysfunction contributes to aging in multiple model organisms and that several factors cause increased mitochondrial dysfunction with chronological age including accumulation of somatic mtDNA mutations, enhanced oxidative damage, decreased abundance and quality of mitochondria, as well as dysregulation of mitochondrial dynamics.

Mitochondria are unique as they harbor their own genome (mtDNA). Point mutations and deletions are the two most frequent types of mutations that arise in mtDNA genome with age mainly due to spontaneous errors during mtDNA replication or damage repair. A wealth of supportive evidence demonstrates that mitochondrial dysfunction occurs with age due to accumulation of mtDNA mutations; however, the causative role of mtDNA mutations in aging remains controversial. Various mtDNA point mutations have been shown to significantly increase with age in the human brain, heart, skeletal muscles and liver tissues. Increased frequency of mtDNA deletions/insertions have also been reported with increasing age in both animal models and humans. The strongest evidence to date that favors a causative role of mtDNA mutations in aging comes from the study of mtDNA mutator mice that exhibit significant accumulation of mtDNA mutations as well as a premature or accelerated aging phenotype.

Mitochondria are highly dynamic structures as they continuously undergo fission and fusion processes that shape their morphology and regulate mitochondrial size, number and function. Mitochondrial dynamics is essential for mitochondrial viability and response to changes in cellular bioenergetic status. Mitochondrial fission is vital for mitotic segregation of mitochondria to daughter cells, distribution of mitochondria to subcellular locations, and mitophagy. Unopposed fission leads to mitochondrial fragmentation, loss of OXPHOS function, mtDNA depletion and ROS production, which are associated with metabolic dysfunction or disease. Mitochondrial fusion is essential for maintaining mitochondrial membrane potential, ATP production, and maximal respiratory capacity. Unopposed fusion generates a network of hyperfused mitochondria associated with increased ATP production, reduced ROS generation and which exhibit an ability to counteract metabolic insults, protect against autophagy as well as apoptosis.

In the past decade, several studies have shown that mitochondrial dynamics plays a crucial role in the regulation of mitochondrial function and metabolism. Studies suggest that dysregulation of mitochondrial dynamics could contribute to aging and age-related pathologies. However, there are several outstanding questions that yet remain to be addressed regarding the link between mitochondrial dynamics and aging. For example, which factors cause altered expression of mitochondrial fission and fusion proteins during aging, and are these factors genetic or affected by environmental stimuli? Is altered mitochondrial dynamics a major cause of mitochondrial dysfunction in aged cells or tissues? Can proteins involved in mitochondrial dynamics serve as promising candidates for promoting healthy aging and/or alleviating various age-related pathologies? Future experimental studies that are designed to address these questions would help to better understand the role of mitochondrial dynamics in aging and age-related pathologies.

NRF2, or SKN-1 in the nematode worm Caenorhabditis elegans, is one of the many coordinating stress response genes activated by calorie restriction or a range of other forms of mild cellular stress. Part of the way in which this results in improved health and extended life span in a range of species is through activating cellular protection and repair mechanisms. Researchers are interested in ways to recapture this reaction to stress via pharmaceuticals rather than diet, and so are working their way through the drug databases in search of prospects. The results here are an example of the sort of thing they are looking for: a drug already approved for use that might be adapted as a calorie restriction mimetic treatment.

Sadly this is marginal work; calorie restriction does have very positive effects on human health, but only small effects on human life span. Short-lived species have a much greater plasticity of life span in response to environmental circumstances than is the case for long-lived species such as our own. So calorie restriction is worth pursuing as something that is free, but it is not worth billions in research and development investment when there are other, potentially far more effective ways forward. Why tinker with adjusting metabolism for tiny gains when we could follow the SENS rejuvenation research road and add decades of health life with the same investment in time and funding? The real battle in aging research these days is shifting from convincing people it is worth doing at all to convincing people to adopt strategies that will produce large results: human rejuvenation, the reversal of aging, not just a modest slowing of the underlying processes.

An FDA-approved drug to treat high blood pressure, hydralazine, extended life span about 25 percent in two strains of C. elegans, one a wild type and the other bred to generate high levels of a neurotoxic protein called tau that in humans is associated with Alzheimer's disease. "This is the first report of hydralazine treatment activating the NRF2/SKN-1 signaling pathway. We found the drug extends the life span of worms as well as or better than other potential anti-aging compounds such as curcumin and metformin. The treatment also appeared to maintain their health as measured by tests of flexibility and wiggling speed."

The NRF2 pathway protects human cells from oxidative stress. The body's ability to protect itself against damaging oxygen free radicals diminishes with age. One of the hallmarks of aging and neurodegenerative diseases such as Alzheimer's and Parkinson's is oxidative stress, which is believed to result cumulatively from inflammatory and infectious illnesses throughout life. SKN-1, a C. elegans transcription factor, corresponds to NRF2 in humans. Both play a pivotal role in their respective species' responses to oxidative stress and life span.

The researchers performed in vivo (in a living creature) and in vitro (in a lab dish) studies on the worms. Compared with untreated controls, roundworms treated with the drug showed about a 25 percent increase in life span (from 15-18 days to about 20-23 days), the team reported. The results of a series of biochemical experiments indicated that the hydralazine-linked life span extension was dependent on the worms' SKN-1 pathway via a mechanism that appeared to mimic caloric restriction. "Based on these results, we suggest that hydralazine may be a good candidate for clinical trials for the treatment of age-related disorders in humans as it may also offer general health benefits to the aging population."

Link: http://www.utsouthwestern.edu/newsroom/articles/year-2017/hbp-drug.html

There are many issues that might be solved by destroying a sufficiently large number of immune cells. Take autoimmune disease, for example, in which the immune system attacks tissues. This is a configuration problem, and that configuration is entirely contained in immune cells. If those cells are removed, autoimmunity is cured. The age-related decline in the immune system, similarly, is in part a problem of too many unhelpful, over-specialized, or damaged, senescent, and exhausted immune cells cluttering up the body.

The only currently working approach involves high doses of harsh immune suppressant drugs to clear out near all immune cells, accompanied by some form of cell therapy to speed replenishment. It has been used to cure multiple sclerosis and type 1 diabetes in trials, but is hard on the patients. This isn't something that would be risked in anything other than a severe condition, and is probably too dangerous for older, less robust individuals. Better, safer methods of shutting down or destroying the unwanted parts of the immune system are needed.

In the research noted here, the authors have identified IRF4 as a single target protein that can disable active T cells, and thus potentially shut off many forms of autoimmunity. Quite aside from that, it has the look of a suitable target for the Oisin Biotechnologies cell-killing gene therapy that is triggered by the presence of specific proteins inside a cell, as IRF4 only occurs in immune cells. The researchers will no doubt pursue a pharmacological option for inhibition, but it is worth keeping in mind that this is only one of an expanding number of options nowadays.

Researchers have identified a critical switch that controls T-cell function and dysfunction and have discovered a pathway to target it. T-cells, which are a type of white blood cells that protect the body from infection, play a central role not only in infections, but also autoimmune diseases and transplant rejection. Understanding how T-cells work is of critical importance for treating these diseases. Researchers are doing this by systematically deleting different molecules in T-cells to check which ones are required for the T-cells to function.

What they have found is that one of the most critical molecules controlling gene expression in T-cells is the transcription factor IRF4, which is usually only found in the immune system and not expressed in other cells. IRF4 is what needs to be targeted to solve the problem of transplant rejection or to develop an autoimmunity cure. "If we delete IRF4 in T-cells they become dysfunctional. In doing so, you can solve the issue of autoimmunity and have a potential solution for organ transplant rejection. You need them functional, however, to control infection. If we can find an IRF4 inhibitor, then those issues would be solved. That's big."

The way they will be able to do this is by only targeting active T-cells that have already been exposed to antigens, leaving the so-called naïve T-cells - those that have never seen antigens and produce no or little IRF4 - alone. These naïve T-cells produce IRF4 only when needed to fight infections. It's the activated T-cells armed with IRF4 that are responsible for organ transplant rejection and autoimmunity. These are the ones that are a potential target, thereby leaving other T cells in the immune system still armed against infection.

Their initial results were promising. By inhibiting IRF4 expression for 30 days - the usual timeframe required for transplant patients to remain infection free - the T-cells became irreversibly dysfunctional. In practice, this could mean prolonging a patient's ability to tolerate a transplanted organ. "How to therapeutically inhibit IRF4 is the Nobel-prize winning question. If we can find a way to inhibit IRF4 as desired in activated T-cells, then I think most autoimmune diseases and transplant rejection will be solved."

Link: https://www.eurekalert.org/pub_releases/2017-12/hm-rfk122017.php

The research noted here improves the understanding of how inflammation acts to drive the progression of Alzheimer's disease, despite being secondary to the well-known deposition of amyloid-β observed in the condition. Alzheimer's disease is considered to be in part an inflammatory condition. Rising levels of chronic inflammation occur with aging, in the brain and elsewhere in the body, and there is plenty of evidence for inflammation to contribute to a good many age-related conditions. The ordering of cause and effect in Alzheimer's is still somewhat up for debate, but there is evidence for the cascade to begin with amyloid-β, that then produces inflammation as the immune cells of the brain react to it, which in turn leads to tau aggregation. The paper here adds nuance to that possible ordering, suggesting that amyloid-β and inflammation form their own feedback loop, spurring one another forward.

The immune system of the central nervous system is its own creature, quite different in its details from the immune system of the rest of the body, and arguably much more integrated and necessary for the correct function of the brain than is the case in other organs. Nonetheless, similar classes of age-related dysfunction arise, and inflammation is one of the results regardless of protein aggregation such as the formation of amyloid deposits. Immune cells become overly active, but at the same time less effective at carrying out their assigned tasks. Inflammation is a necessary part of the immune response to many of the issues it might have to deal with, typically those that involve destruction, as as removal of senescent or potentially cancerous cells, and mounting attacks upon the pathogens that constantly try to invade the body and brain. If permanently switched on, however, inflammation begins to disrupt all of the other necessary tasks of the immune system, such as those relating to regeneration or shepherding the correct function of brain cells.

For a number of years now, some researchers have departed a little way from the mainstream focus on removal of amyloid-β to consider an anti-inflammatory approach to building therapies for Alzheimer's, but this line of research hasn't made a sizable impact yet. Reducing inflammation in a usefully targeted way is still quite challenging, as the immune system is very complex, though promising noises are emerging from research groups investigating NLRP3 as a target. That also happens to show up in the research here as a part of the connection between immune cells, amyloid, and inflammation.

Inflammation drives progression of Alzheimer's

A new study shows that inflammatory mechanisms caused by the brain's immune system drive the progression of Alzheimer's disease. In recent years, studies revealed that deposits of amyloid-β, known as "plaques", trigger inflammatory mechanisms by the brain's innate immune system. However, the precise processes that lead to neurodegeneration and progression of pathology have thus far not been fully understood. Previous work had established that the molecular complex NLRP3, which is an innate immune sensor, is activated in brains of Alzheimer's patients and contributes to the pathogenesis of Alzheimer's in a mouse model. NLRP3 is a so-called inflammasome that triggers production of highly pro-inflammatory cytokines. Furthermore, upon activation, NLRP3 forms large signaling complexes with the adapter protein ASC, which are called "ASC specks" that can be released from cells.

In the current study, it was demonstrated that ASC specks are also released from activated immune cells in the brain, the microglia. Moreover, the findings provide a direct molecular link to classical hallmarks of neurodegeneration. "We found that ASC specks bind to amyloid-β in the extracellular space and promote aggregation of amyloid-β, thus directly linking innate immune activation with the progression of pathology." This view is supported by a series of experiments in mouse models of Alzheimer's disease. In these, the researchers investigated the effects of ASC specks and its component, the ACS protein, on the spreading of amyloid-β deposits in the brain. "Additionally, analysis of human brain material indicates at several levels that inflammation and amyloid-β pathology may interact in a similar fashion in humans. Together our findings suggest that brain inflammation is not just a bystander phenomenon, but a strong contributor to disease progression. Therefore, targeting this immune response will be a novel treatment modality for Alzheimer's."

Microglia-derived ASC specks cross-seed amyloid-β in Alzheimer's disease

The spreading of pathology within and between brain areas is a hallmark of neurodegenerative disorders. In patients with Alzheimer's disease, deposition of amyloid-β is accompanied by activation of the innate immune system and involves inflammasome-dependent formation of ASC specks in microglia. ASC specks released by microglia bind rapidly to amyloid-β and increase the formation of amyloid-β oligomers and aggregates, acting as an inflammation-driven cross-seed for amyloid-β pathology.

Here we show that intrahippocampal injection of ASC specks resulted in spreading of amyloid-β pathology in transgenic double-mutant APPSwePSEN1dE9 mice. By contrast, homogenates from brains of APPSwePSEN1dE9 mice failed to induce seeding and spreading of amyloid-β pathology in ASC-deficient APPSwePSEN1dE9 mice. Moreover, co-application of an anti-ASC antibody blocked the increase in amyloid-β pathology in APPSwePSEN1dE9 mice. These findings support the concept that inflammasome activation is connected to seeding and spreading of amyloid-β pathology in patients with Alzheimer's disease.

The current standard treatments for cancer, chemotherapy and radiotherapy, are quite unpleasant and harmful; no-one would voluntarily undergo them given a better alternative. In fact, treatment makes people physically older, accelerating the processes of aging. There is evidence to suggest that this is due to an added burden of senescent cells. Cells become senescent in response to damage or a toxic environment, and there is plenty of that going around in any earnest attempt to treat cancer with radiation or chemical agents; in fact, many cancer therapies are intended to aggressively induce senescence in tumor cells.

The presence of senescent cells is one of the causes of aging. These cells remove themselves from the usual cycle of replication, and in normal circumstances near all self-destruct or are destroyed by the immune system. Unfortunately, enough linger to contribute to aging. They produce harm through inflammatory signaling, the senescence-associated secretory phenotype (SASP), that corrodes tissue structure and disrupts tissue function - insignificant in small amounts, but very damaging given a sizable number of such cells. There are no doubt other mechanisms by which present cancer therapies touch on the causes of aging, however; given that aging is damage, and cancer treatments are damaging in many ways, we should probably not be surprised to find that aging is accelerated.

Studies among long-term cancer survivors indicate numerous possible clinical complications resulting in considerable morbidity and mortality, related to chemotherapy, radiation therapy, or both. A wealth of observational data on the development of late complications in cancer survivors are available, but information documenting the pathological basis for development of these effects is sparse. To understand the biology of late effects better and provide a foundation for the development of interventions, it is important to characterise late effects at the cellular level. Cancer survivors, in general, appear to develop age-related diseases and phenotypes sooner than members of the general population. This is likely because damage to normal tissues from cancer therapies diminishes physiological reserve, accelerates processes typically associated with ageing, or both.

The roles of telomeres, senescent cells, epigenetic modifications, and microRNA have been described in terms of their contributions to the pathobiology of accelerated ageing. However, published data linking clinical phenotypes seen in cancer survivors with processes of accelerated ageing at the cellular level is lacking. On a microscopic level, ageing is a consequence of gradual, lifelong accumulation of molecular and cellular damage and loss of physiological integrity. Hallmarks of ageing include genomic instability, telomere attrition, epigenetic alterations, mitochondrial dysfunction, loss of proteostasis, chronic low-grade inflammation, and cellular senescence. We have demonstrated with clinical data that cancer survivors develop the health-related manifestations of ageing more quickly than their peers. While ageing prematurely is a better alternative to dying prematurely, a better understanding of what drives this process presents an opportunity for improvement.

As many cancer treatments appear to induce an accelerated ageing-like state, interventions that target fundamental ageing processes may have a role in cancer survivors. Since many cancer therapies induce cellular senescence, among the most promising agents are senolytics, drugs that selectively eliminate senescent cells and SASP inhibitors, which blunt local and systemic effects of the SASP. These agents alleviate frailty, restore progenitor function, reduce insulin resistance, rescue cardiac and vascular dysfunction, decrease adverse effects of radiotherapy and reduce osteoporosis in a variety of animal models of ageing and disease. Senolytics are effective when administered intermittently, potentially reducing toxicity, and resistance to these drugs is unlikely to develop as, unlike cancer cells or microbes, senescent cells do not divide.

Link: https://doi.org/10.1136/esmoopen-2017-000250

It seems that more members of the high profile entrepreneur segment are starting to consider mass manufacture of tissue engineered organs as an area to put time and effort into. The publicity article here offers one example. While the research community has yet to produce a robust means of creating the microvasculature needed to sustain larger tissue sections, that absence is really the only serious roadblock standing between the state of the science today and a manufactured, patient-matched kidney or liver a few years from now. It is high time to consider moving the technology from laboratory to manufactory.

Even lacking the ability to lace tissue with tiny blood vessels, researchers can still create small organoids that exhibit the correct structure and function of their tissue type. In large numbers, organoids could be used instead of a full organ transplant, the aim being to patch a damaged organ with scores of tiny organoids that will integrate with the tissue and augment its failing function. That is a practical vision, just as soon as the ability to mass-manufacture organoids comes to pass. Creating the proof of concept in the laboratory is one thing; creating ten thousand of them to order, and within tight quality constraints, is quite another. A company that succeeds in that goal over the next decade or so will be ready to start on full-sized organs when the blood vessel problem is finally solved.

Basic researchers have produced skin, veins, trachea and urethras -the relatively easy structural tissues and organs those in the field call "sheets and tubes" - but the processes are painstaking and expensive. A decade ago researchers pioneered the development of 3D printers capable of printing customized organ scaffolds made of keratin, collagen, or biodegradable polymers, then ones that could print skin cells directly onto a patient; and then ones that could print cells and the vessel passages that keep them alive directly onto scaffolds that could then be implanted in the body. Growing these tissues or organs can take anywhere from days to weeks depending on their size and complexity.

But getting these groundbreaking innovations off the lab bench and into commercial production has proved a daunting task. The engineering challenges are enormous, and most basic scientists have no experience in creating mass assembly systems, much less ones whose production can earn Food and Drug Administration approval for use in living people. Dozens of private companies have been at work trying to develop products for clinical use, but progress has been painfully slow. "We were making an esophagus, but the manufacturing processes were really the views of a scientist thinking about how manufacturing should be done. The industry is still basically making things largely by hand, one by one, with people handling the equipment that feeds the tissue making decisions in real time... There's very little process control."

Dean Kamen likens the problem to that of a grandmother who can make the world's greatest chicken soup. "OK, Grandma. How are you going to run a canning operation?" he asks. "She wants to go to scale, what does she do? She hires 10,000 other grandmas! They have a bigger kitchen They all stir by hand in bowls. And then the FDA comes in there and says 'How do you know your production is consistent?'!" If she were making soup, Grandma could outsource production to Campbell's Soup, but tissue engineering researchers can't. "They could win the Nobel prize for figuring out how to grow more cool stuff in a petri dish than anyone I know, but they're not going to figure out how to make 400,000 of the things. But interestingly, he can't go to Campbell's because there is no Campbell's!"

A chance meeting with another famous entrepreneur, Martine Rothblatt, set Kamen on a path that would lead him to try to create, from scratch, the manufacturing equipment, procedures and the know-how to move regenerative medicine from a science experiment to mass production. Then, out of the blue, one of Kamen's colleagues saw a request for proposal from the Department of Defense to establish a state-of-the-art institute tasked with creating an advanced innovation ecosystem for the manufacture of human tissues and organs to help wounded soldiers and civilian patients alike. "We looked at this and we saw that the equipment they were going to need to help soldiers were pretty much the same things we would need to build for Martine. So we figured, let's scale this thing up and build all the tools and processes for all the tissues and organs."

One year later, a three-story, 65,000-foot former mill building next to Kamen's headquarters houses the Advanced Regenerative Manufacturing Institute, where over 100 engineers, researchers and programmers are already at work building machines and devices and testing the processes that will allow its dozens of member firms to perfect and mass produce their respective products, from skin to, one day, hearts. Kamen has persuaded venture capital firms to help fund the startups that have joined the coalition and recruited a veteran FDA official to consult with the agency on regulatory approval. "I think in the next five years we are going to have some awesome results and some nice functional tissues to really start helping people on a bigger scale."

Link: https://www.politico.com/magazine/story/2017/12/18/human-organ-manufacturing-transplant-artificial-3d-printing-216104

Today I'll point out a recent collection of papers on calorie restriction from the Journals of Gerontology, including a report on the CALERIE human study in which algorithmic approaches to measuring biological age - constructing a measure from simple health metrics, such as the measures found in blood tests - indicate a slowing of aging in participants. Calorie restriction has been shown to slow aging in near all species and lineages tested to date, much more so in short-lived species than in long-lived species. Thus calorie restriction and methods of mimicking some of the cellular response to calorie restriction make up the present majority of initiatives among those scientists of the aging research community who have shown themselves willing to embrace the goal of treating aging as a medical condition. This encompasses investigations of mTOR, involving rapamycin and related compounds, slow steps towards any one of half a dozen approaches to autophagy enhancement, the long drawn-out dead end of sirtuin research programs, and many more lines of work.

Aubrey de Grey has called this a false dawn - a blossoming of research that accompanied a great change in the culture of the scientific community, as it transformed from a closed-mouth group whose members denied and discouraged all interest in treating aging, to one in which many researchers now talk openly and excitedly about extending healthy life spans. Yet they have largely settled upon a program of research and development, focused on calorie restriction, that cannot possibly produce sizable effects on human life span, and is in addition demonstrably expensive, slow, and challenging. It dovetails well with the urge to map metabolism in detail, however, which is perhaps why this field has expanded despite the poor prospects for benefits to health and longevity at the end of the day.

By any sensible cost-benefit analysis, the practice of actual calorie restriction is, like exercise, a great gift from our evolutionary history: a reliable and free way to improve long-term health to a greater degree than any presently available medical technology can achieve. It is a sound idea to adopt this proven approach as a health strategy; the evidence is compelling. A few additional years for free, and a lower risk of age-related disease? Sign me up. Yet spending billions and decades of researcher time to reproduce that in a pill? Not so great, when the alternative uses of that time and funding, such as pursuing the rejuvenation therapies of the SENS programs, could be expected to add decades of additional healthy years to our lives. The expected quality of the outcome matters greatly when choosing strategy, and currently most of the research community is choosing poorly.

In Delaying Aging, Caloric Restriction Becomes Powerful Research Tool as Human Studies Get Underway

The beneficial longevity effect of a simple reduction in calorie intake was first established in rodent studies more than 80 years ago. In the last few decades as genetic techniques have advanced, scientists have made considerable progress in identifying cellular and systemic processes that likely contribute to the increase in disease vulnerability that is associated with aging. Traditionally, these insights have come from studies of short-lived laboratory animals, but the recent confirmation of the relevance of the CR paradigm to primates has placed renewed emphasis on studies that delve into the mechanisms of delayed aging by CR. "Remarkably, caloric restriction has been shown to be effective in delaying aging in multiple species and the results in humans look equally promising. Indeed for many studies, CR is used as the gold-standard for enhanced longevity against which new drugs and anti-aging strategies are measured."

Caloric Restriction Research: New Perspectives on the Biology of Aging

The principle of geroscience is that aging itself is a worthy target for intervention: if aging can be offset then age-related vulnerability to diseases and disorders such as cancer, heart disease, frailty, and neurodegeneration, would be postponed and attenuated. If we could understand how CR exerts its effects to prolong health and delay mortality we will surely be able to identify key regulatory nodes involved in countering the causative factors in aging that lead to morbidity and mortality.

Within the last 10 years, the long suspected but previously unconfirmed demonstration that primate aging is indeed malleable came from studies of CR in rhesus monkeys. Over the course of that ~30-year study longitudinal biometric, physical activity, and metabolic data, were captured and used to evaluate the monkey model as a means to investigate frailty. The group showed clear differences between control-fed and CR monkeys. Further, the CALERIE study is the first human clinical trial of CR. Conducted across three sites in the United States, this pioneering work showed not only that CR could be tolerated in humans but it also produced beneficial effects on numerous clinical disease risk indices.

The search for agents that can exert the beneficial effects of CR without the requirement for a reduction in calorie intake has undergone considerable expansion over the last decade. Among these aptly named "CR mimetics" are resveratrol and metformin both of which have been shown to produce beneficial effects in rodents. Recent studies point to potential new applications for these CR mimetics as a means to counter skeletal muscle aging. Furthermore, they demonstrates the power for mechanistic discovery in the application of CR mimetics to uncover the biology of discrete factors within tissues that contribute to the aging phenotype.

Change in the Rate of Biological Aging in Response to Caloric Restriction: CALERIE Biobank Analysis

Biological aging refers to the gradual and progressive decline in the integrity of the body's systems occurring with advancing chronological age. Rather than any specific disease process, this decline in system integrity is thought to reflect biological changes having their origins in aging itself. Whereas chronological age increases at the same rate for everyone, biological age can increase faster for some and slower for others. To the extent that geroprotective therapies modify basic biological processes of aging, their effects should be reflected in a slowed rate of decline in system integrity - slowed biological aging. Recently, several methods have been proposed to quantify biological aging using algorithms that combine information from multiple biomarkers.

Caloric restriction is among the oldest and most effective geroprotective interventions in worms, flies, and mice. Growing evidence suggests caloric restriction also benefits life span and healthspan in primates and humans. A unique resource to study effects of caloric restriction in humans is the 2-year randomized controlled trial of caloric restriction in young, non-obese healthy humans, Comprehensive Assessment of the Long-term Effects of Reducing Intake of Energy (CALERIE).

We analyzed CALERIE Biobank data to test whether recently proposed methods to quantify biological aging would prove sensitive to geroprotective effects of caloric restriction over the relatively short, 2-year span of the human trial. Tests using two different methods to quantify biological aging (Klemera-Doubal method Biological Age and homeostatic dysregulation) produced a consistent result: participants in the caloric-restriction arm of the trial experienced slowed biological aging as compared to participants in the ad libitum arm. Sensitivity analysis showed that slowed biological aging in the caloric restriction arm of the trial was not accounted for by weight loss during the intervention phase.

The main contribution of this study is to provide initial evidence that methods to quantify biological aging are sensitive enough to detect effects of geroprotective therapy delivered to middle-aged adults in a small randomized trial. This evidence argues for using methods to quantify biological aging as outcomes in trials of geroprotective therapies.

Here, researchers demonstrate restoration of lost memory function in old rats though increased levels of FKBP1b in the hippocampus. This is a very intriguing paper, firstly for the size of the effect, and secondly because it touches on the question of the degree to which dysfunction in the aging brain is damage versus inappropriate cellular reactions to damage. Inappropriate reactions can be overridden, at least for a time. Ever-increasing damage always wins in the end, however, which is why damage repair after the SENS model should be more efficient and cost-effective as an approach. Further, repairing damage doesn't require researchers to learn how to safely manipulate a very complex disease state, or even to learn exactly how the damage produces that disease state; it is a reversion to a known good state. Given this, it is either a tragedy or a hidden benefit that sometimes overriding an inappropriate reaction looks good enough to justify the expenditure of serious effort on development of a therapy. Which of those two options is the case is really only possible to determine in hindsight.

Hippocampal overexpression of FK506-binding protein 12.6/1b (FKBP1b), a negative regulator of ryanodine receptor Ca2+ release, reverses aging-induced memory impairment and neuronal Ca2+ dysregulation. Here, we test the hypothesis that FKBP1b also can protect downstream transcriptional networks from aging-induced dysregulation. We gave hippocampal microinjections of FKBP1b-expressing viral vector to male rats at either 13-months-of-age (long-term) or 19-months-of-age (short-term) and tested memory performance in the Morris water maze at 21-months-of-age. Aged rats treated short- or long-term with FKBP1b substantially outperformed age-matched vector controls and performed similarly to each other and young controls.

Transcriptional profiling in the same animals identified 2342 genes whose hippocampal expression was up-/down-regulated in aged controls vs. young controls (the aging effect). Of these aging-dependent genes, 876 (37%) also showed altered expression in aged FKBP1b-treated rats compared to aged controls, with FKBP1b restoring expression of essentially all such genes (872/876, 99.5%) in the direction opposite the aging effect and closer to levels in young controls. This inverse relationship between the aging and FKBP1b effects suggests that the aging effects arise from FKBP1b deficiency.

Functional category analysis revealed that genes downregulated with aging and restored by FKBP1b associated predominantly with diverse brain structure categories, including cytoskeleton, membrane channels, and extracellular region. Conversely, genes upregulated with aging but not restored by FKBP1b associated primarily with glial-neuroinflammatory, ribosomal and lysosomal categories. Immunohistochemistry confirmed aging-induced rarefaction, and FKBP1b-mediated restoration, of neuronal microtubular structure. Thus, a previously-unrecognized genomic network modulating diverse brain structural processes is dysregulated by aging and restored by FKBP1b overexpression.

Link: https://doi.org/10.1523/JNEUROSCI.2234-17.2017

The popular science article noted here covers a recent advance in the understanding of brain waves and their interaction with memory. The damage done to the brain over the course of aging produces functional decline of a variety of forms. One of the many systems in which this decline becomes apparent is in the generation of brain waves. These are coherent oscillating patterns of activity in neurons, important to the higher level functions of the brain. Unfortunately, definitively linking specific physical, cell and tissue damage to brain wave changes is one of the many areas of aging research in which the chain of cause and effect is yet to be filled out.

On that topic, note that the researchers involved in the research here venture to suggest a compensatory therapy rather than a therapy that addresses root causes. This is all too often the case in the research community, and it is something that must change if we are to see meaningful progress towards an end to aging. Comprehensively filling in the links between this finding and the many forms of physical damage found in the aging brain remains a matter for future research, but the fastest way forward to those answers, I believe, is to fix the known forms of damage that cause aging and then see what happens. Compensatory approaches will never be all that effective, as they fail to address the underlying damage that will continue to cause degeneration and eventual death.

During deep sleep, older people have less coordination between two brain waves that are important to saving new memories. The finding appears to answer a long-standing question about how aging can affect memory even in people who do not have Alzheimer's or some other brain disease. "This is the first paper that actually found a cellular mechanism that might be affected during aging and therefore be responsible for a lack of memory consolidation during sleep." To confirm the finding, though, researchers will have to show that it's possible to cause memory problems in a young brain by disrupting these rhythms.

The study was the result of an effort to understand how the sleeping brain turns short-term memories into memories that can last a lifetime. A team of scientists had 20 young adults learn 120 pairs of words, then put electrodes on their head and had them sleep. The electrodes let researchers monitor the electrical waves produced by the brain during deep sleep. They focused on the interaction between slow waves, which occur every second or so, and faster waves called sleep spindles, which occur more than 12 times a second.

The next morning the volunteers took a test to see how many word pairs they could still remember. And it turned out their performance was determined by how well their slow waves and spindles had synchronized during deep sleep. "When those two brain waves were perfectly coinciding, that's when you seem to get this fantastic transfer of memory within the brain from short term vulnerable storage sites to these more permanent, safe, long-term storage sites." Next, the team repeated the experiment with 32 people in their 60s and 70s. Their brain waves were less synchronized during deep sleep. They also remembered fewer word pairs the next morning. "If you're 50 milliseconds too early, 50 milliseconds too late, then the storing mechanism actually doesn't work."

The team also found a likely reason for the lack of coordination associated with aging: atrophy of an area of the brain involved in producing deep sleep, the medial frontal cortex. People with more atrophy had less rhythm in the brain. That's discouraging because atrophy in this area of the brain is a normal consequence of aging, and can be much worse in people with Alzheimer's. But the study also suggests that it's possible to improve an impaired memory by re-synchronizing brain rhythms during sleep. One way to do this would be by applying electrical or magnetic pulses through the scalp.

Link: https://www.npr.org/sections/health-shots/2017/12/18/571120472/older-adults-forgetfulness-tied-to-faulty-brain-rhythms-in-sleep

This year's Fight Aging! challenge fund matches the next year of donations made by supporters of SENS rejuvenation research who sign up as monthly donors to the SENS Research Foundation. Josh Triplett, Christophe and Dominique Cornuejols, and Fight Aging! have put up $36,000 to encourage you to create a brighter future for medicine. The fund expires at the end of 2017, and with just two weeks left in this fundraiser, the final third of the challenge fund is yet to be claimed.

So please join us in helping to support the scientific research needed to build a comprehensive suite of therapies to reverse the causes of aging and bring an end to all age-related disease. The SENS Research Foundation is one of the most influential organizations in this field, having achieved tremendous progress using the donations of past years. Few other causes have the potential to produce so great a benefit at such a low cost. When we say that we want to change the world for the better, we mean it: the existence of rejuvenation therapies will touch everyone, bringing the capacity to greatly improve all lives.

This year has certainly been one of ups and downs in fundraising; a lot of new funding has poured into the for-profit ecosystem with the arrival of investors such as Jim Mellon's team and the launch of ventures such as the Methuselah Fund. We're now all looking for more credible companies to emerge, run by teams focused on SENS-relevant approaches to aging, ways to repair the cell and tissue damage that produces degeneration and age-related disease. At the same time, charitable fundraising has been tough in 2017; if we want to do better, the community must grow. We must reach new audiences and persuade them of the merits of rejuvenation research, that the construction of rejuvenation therapies is both relevant and plausible as a goal.

Yet we were still fortunate enough to see the Pineapple Fund choose the SENS Research Foundation as one of the recipients of $1 million in bitcoins just a few days ago. This was made possible by the thousands of supporters who, over the years, lead the way by making modest donations and talked about the prospects for rejuvenation research. The anonymous principal of the Pineapple Fund could look at the SENS Research Foundation, and all that has been written about it, and because of our actions see a small organization of sizable influence and importance. The larger our community of supporters, the more credible that SENS research becomes in the eyes of potential donors, and the more likely it is that large donations are made to support future research. We make a real difference - so join in and make a donation this year!

It helps to know a little bit about the views of the author S. Jay Olshansky when reading this piece. He is one of the scientists behind the Longevity Dividend initiative, the goals of which can be summarized as greatly increasing government funding for current mainstream programs at the National Institute on Aging, with the aim of adding a few years to life expectancy over the next few decades. For those of us who seek far larger outcomes, and a way to turn back aging rather than merely slowing it down, he wishes us luck, but doesn't seem convinced that the goal of additional decades through rejuvenation research after the SENS model is practical.

Olshansky has long been vitriolically opposed to the "anti-aging" marketplace of the past few decades, packed as it is sellers of fraudulent pills and potions, and believes it a baleful influence that damages the prospects for serious science. You might look at the Silver Fleece awards that he conducted for some years, for example. I think that went a long way to determining his early position of opposition to SENS rejuvenation research and related advocacy for actuarial escape velocity, the unbounded increase in life span that would follow any meaningful first implementation of rejuvenation therapies. That is an opposition that has mellowed somewhat, though Olshansky clearly still strongly dislikes talk of radical life extension.

From my point of view, this unwillingness to seriously consider sizable outcomes and potentials is a part of the problematic legacy of the last generation of researchers in this field. It is why they suppressed interest in efforts to treat aging as a medical condition. It is why they failed to make significant progress despite all the evidence in hand pointing to the causes of aging. It is why people like Aubrey de Grey and others involved in SENS had to come in from outside the field to shake things up.

The story of Faust has become a metaphor for a promise or tradeoff that at first seems appealing, but with time is revealed to be a bad bargain. The story of human aging and the modern rise in longevity has remarkable correlates to the story of Faust, but with some interesting twists. Here's the connection. The first longevity revolution that began in the middle of the nineteenth century occurred primarily because of gains made against infant and child mortality resulting from advances in basic public health. This was followed by reductions in death rates from cardiovascular disease late in the twentieth century. A quantum leap in life expectancy of 30 years ensued at lightning speed. Nothing in history has ever come close to the magnitude of this benefit to humanity. While there is no disputing the value of life and health extension from the first longevity revolution, rarely does something so desirable come without a Faustian-like price.

Along with 30 years of additional life and the opportunity to see almost all our children live long enough to have families of their own, humanity also witnessed a subsequent dramatic escalation in the prevalence of age-related chronic, fatal and disabling diseases and their attendant costs and heartache. That is, we now live long enough to experience the aging of our bodies. In retrospect, it was worth every part of the bargain. But Mephistopheles isn't done with us. Like a street magician that lets you win the first game, and then sucks you into a bigger con with larger stakes, or a drug dealer that gets you hooked with free samples, the next much costlier offer is before us now. We've had our taste of longevity, but now we want more - much more at any cost, and Mephistopheles knows this.

With life itself as the most precious commodity there is, it's easy to see the next con. The first is the rise of what has become known as the antiaging industry - a multibillion dollar enterprise designed to convince us that the secret to the fountain of youth is already within our grasp. Pay dearly for their elixirs now and wait for the promise of a longer life to appear decades later. What do you think the chances are that your investment will pay off? The catch is that the alleged benefits don't appear, if at all, until after the longevity salesmen has left the scene and pocketed your cash. What's different today from the cons of the past is the rise of the scientific study of aging and genuine opportunity offered for healthy life extension. The modern practitioners of anti-aging medicine try and sell the public what appear to be genuine scientific interventions based on real science, before they're proven to be safe and efficacious: "whenever science makes a discovery, the devil grabs it while the angels are debating the best way to use it."

The second response to an insatiable desire for more life is also predictable, but the danger could be an even worse Faustian bargain than that posed by the antiaging industry. The method used to manufacture the first longevity revolution is known as the "infectious disease model" - that is, as soon as a disease appears, attack it with everything in the medical arsenal. Beat the disease down, and once you succeed, push the patient out the door until they face their next challenge; then beat that one down. The formula is simple - repeat until failure. This model was perfect for infectious diseases and effective at first for chronic degenerative diseases, and no doubt there is still progress to be made, but evidence has emerged that this approach is likely to run out of steam. The application of an infectious disease model to chronic fatal and disabling diseases associated with aging is Mephistopheles latest "bargain." The irony behind this new bargain (otherwise known as the current medical model of disease) is that the medical community advocating for disease eradication doesn't even recognize the health consequences of success.

The bargain today is crystal clear - we're being offered incrementally smaller amounts of survival time at a very high cost, and the prospect that most of the additional months and years of life will be riddled with frailty and disability. Keep in mind that the human body has no designer; it was not constructed for long-term use; and our Achilles heels are already visible - neurological conditions such as Alzheimer's disease and related conditions are associated with non-replicating neurons; and muscles and joints have a difficult time navigating the ravages of biological time. The Faustian bargain before us now is, in exchange for small doses of additional life, humanity will experience a suite of fatal and disabling conditions expressed at later ages that rob us of what we hold most precious - our mental and physical functioning.

What's the solution? Don't sign the contract! A clue about what we should do instead was presented to us decades ago. In the mid-1950s, it was suggested that attacking aging itself rather than the diseases associated with it offered the greatest hope in warding off the infirmities of old age. In 2006, my colleagues and I extended this line of reasoning by coining the phrase "the Longevity Dividend" to describe the economic and health benefits that would accrue to individuals and societies if we extend healthy life by slowing the biological processes of aging. This idea was distinctive because we proposed to extend healthy life by shifting our emphasis from disease management to delayed aging. Recent advances in biogerontology suggested that it is plausible to delay aging in people. For example, "senolytics" may offer a unique opportunity to forestall the ravages of aging through the systematic elimination of cells that are still alive, but which no longer function normally.

The Longevity Dividend is an approach to public health based on a broader strategy of fostering health for all generations by developing a new horizontal model to health promotion and disease prevention. Unlike the current vertical approach to disease that targets individual disorders as they arise, the Longevity Dividend model seeks to prevent or delay the root causes of disease and disability by attacking the one main risk factor for them all-biological aging. Evidence in models ranging from invertebrates to mammals suggests that all living things have biochemical mechanisms influencing how quickly they age, and these mechanisms are adjustable.

Slowing down the processes of aging - even by a moderate amount - will yield dramatic improvements in health for current and future generations. Advances in the scientific knowledge of aging may thus create new opportunities that allow us, and generations to follow, to live healthier and longer lives than our predecessors. By embracing a new model for health promotion and disease prevention in the twenty-first century, we can give the gift of extended health and economic wellbeing to current and all future generations. What is the cost of this new more effective model of primary prevention that will save the world trillions in health care costs? A fraction of the basic research cost required to create sixth generation fighter jets; or the salary from just one quarterback in the National Football League.

Link: https://doi.org/10.3389/fmed.2017.00215

All fields of medicine are characterized by a history of wrong ideas, many of them very strange from a modern viewpoint. These ideas were slowly winnowed out as technology advanced to the point of being able to prove them wrong, and as the culture of science advanced to the point of being taken seriously. Considerations of aging are no exception, and like most of the very complex issues in biology, this is arguably one in which the wrong and the strange persisted to a later date than was the case for other areas of medical science.

Many early theories of aging revolved around loss of some form of resource: that people were born with a given amount, that it was needed for life, and the process of living depleted it. No such resource exists, of course. Rate of living theories of aging might be seen as the more modern final last gasp of that sort of thinking regarding fixed limits and the passage of time. In reality, life span is fluid, determined by the accumulation of cell and tissue damage that arises as a side-effect of the normal operation of cellular metabolism, by the rising mortality rate caused by the presence of that damage and its consequences. It is the damage that is important, not the time spent alive. Repair the damage and people will live for longer in good health; the first rejuvenation therapies, such as those that destroy senescent cells, should prove that point in the years ahead.

In the second half of the 19th century, doctors believed that old age occurred when the body ran out of "vital energy" - which was no mere metaphor. The stuff was thought to be tangible, literally present in the body and its fluids. Everyone had a finite reservoir of vital energy that gradually became depleted over a lifetime. When you began to run low on vitality, you were old; death followed when the tank was empty.

For the era's doctors, the concept conveniently solved the mystery of why illness seemed far more curable in the young than the old. Physicians supposed that the loss of vitality created a "predisposing debility," as one historian has put it, making the older body vulnerable to a host of secondary maladies. The theory also fit with American religious thought as influenced by the Second Great Awakening, which peaked in the 1830s. The amount of vitality you were endowed with at birth was simply your lot. Whether you used it well or squandered it, however, was your personal responsibility.

In continental Europe in the 1850s and 1860s, vitality theory began to wane as French and German pathologists realized that the lesions, fibrous tissue and calcium deposits they discovered in older people's cadavers could provide an explanation for some of the complaints of old age. But in the United States and Britain, many of those aware of these continental findings simply doubled down on their existing beliefs: Any wasting observed in cadavers was simply due to the loss of vital energy.

Perhaps the best evidence for that point of view was the moment in a patient's life when vitality began to appreciably decline, which English-speaking physicians named the "climacteric period," or "climacteric disease." In women, the climacteric period was believed to begin between ages 45 and 55 and was associated with menopause; in men, it took place between 50 and 75 and was indicated by such signs as wrinkles, white hair, and complaints of feebleness.

Eventually, insights from the medical field of pathology discredited vital-energy theory, but only after it molded the development of a long-lasting set of social, cultural and economic institutions. The first dedicated old-age homes, the rise of public and private pensions, the normalization of retirement both as something bad your boss could do to you and also a new stage of life - these all marinated in vital-energy theory for decades before emerging fully baked into the 20th century, complete with implications for what it meant to be an "older person."

Link: https://www.washingtonpost.com/national/health-science/why-do-people-get-old-history-offers-up-some-very-weird-theories/2017/12/08/418367c4-ca3d-11e7-b0cf-7689a9f2d84e_story.html

This year's Project for Awesome runs from December 15th to 17th. It is a short and energetic festival of fundraising and video creation in which people give and vote on which causes to distribute the funds to. The event has been growing from its modest start for the past decade. The world could use more such initiatives, and I encourage you to join the festivities and vote for videos that take your fancy at Project for Awesome before the end of the week.

The very first Project for Awesome was organized in 2007, and has been held each December since. This year, Project for Awesome is December 15th (beginning at 12:00pm EST) to December 17th (ending at 11:59am EST). During Project for Awesome, thousands of people post videos about and advocating for charities that decrease the overall level of world suck. As a community, we promote these videos and raise money for the charities. In 2016, the community raised over $2,000,000, including several generous matching donations. The donations were split between two organizations chosen by John and Hank along with twenty charities chosen by the online video community.

This year supporters of the Life Extension Advocacy Foundation and SENS Research Foundation have assembled a fair few video submissions to put forward the case for charitable funding of rejuvenation research programs. Vote for them! This continues a fine tradition for our community, as the best of the organizations involved in advocacy and research to have emerged over the past twenty years were built atop the collaborative philanthropy of ordinary folk. Great progress has been achieved because we came together to give individually modest amounts, and then persuade others to do the same and more. We have led the way. The reason that we can celebrate sizable donations to the cause of defeating age-related disease, such as the one announced earlier today, is that our activity has made this a plausible and noted cause.

The defeat of aging makes sense. The overwhelming majority of the pain, illness, and death in the world is caused by aging: more than 100,000 lives lost every day, while tens of millions more suffer with little hope of help. Beyond the human toll, the economic cost of this constant, massive wave of debility and loss is staggering. Our societies tie themselves in knots attempting to pay the vast sums it would require to merely cope with the consequences of aging - not do anything about it, just cope. Yet for less than the cost of a sports stadium, or the latest stealth bomber, or twelve months of the US National Institute on Aging budget, a complete set of biotechnologies to control aging by repairing its causes could be realized in just a handful of years. This is the promise of the SENS rejuvenation research programs, a very cost-effective approach to the problem of aging. Take the known causes of aging, the cell and tissue damage that causes aging and age-related disease, and repair them.

We would be foolish not to work towards this goal.

Cellular senescence is one of the causes of aging; senescent cells accumulate in tissues, and their inflammatory and other disruptive signaling causes considerable harm. With the newfound and rapidly spreading interest in senescent cells in the research community over the past few years, a lot of efforts are now underway to better understand how cellular senescence fits into the existing knowledge of the biochemistry of age-related conditions. Since senescent cells are a cause of chronic inflammation, and since inflammation and oxidative stress go hand in hand, near any condition in which inflammation or oxidative stress feature prominently is a good candidate for reexamination.

Recently, evidence has emerged for senescent cells to be involved in the growth and weakening of heart muscle that follows the age-related increases in blood pressure known as hypertension. Hypertension occurs because stiffening of blood vessels and dysfunction in the muscle of blood vessel walls breaks the intricate feedback system that controls blood pressure. The consequences include damage to delicate tissues, such as those of the brain and kidney, as small vessel rupture at an accelerated rate, and the aforementioned restructuring of heart muscle. The heart becomes larger and weaker. But why? The paper here looks at oxidative stress and senescent cells on heart stem cells that occurs in rats engineered to develop hypertension.

In human hearts there is 0.5 to 1% of myocyte turnover annually, envisaging the role of cardiac stem cells (CSCs) in the maintenance of cardiac tissue homeostasis. CSCs differentiate and replace the lost myocytes; and in the event of myocardial injury, stem cells contribute towards tissue repair. The involvement of stem cells in cardiac failure associated with age and disease has been speculated. However, the temporal variation in the density and efficiency of cardiac stem cells and the effect of disease on the stem cell characteristics has not been systematically analyzed.

Cardiac hypertrophy is recognized as an independent risk factor for cardiac failure. Efficient management of hypertensive heart disease requires identification of factors that can possibly mediate the transition from hypertrophy to heart failure. Decline in the proportion of healthy cardiac stem cells (CSCs) can affect tissue regeneration. In pathological conditions, apart from natural aging, an adverse microenvironment can lead to decrease in efficiency of CSCs. This study was designed with the objective of examining the age associated variation in stem cell attributes of Spontaneously hypertensive rats (SHR) in comparison with normotensive Wistar rats. Spontaneously hypertensive rat was used as the experimental model since the cardiac remodeling resembles the clinical course of hypertensive heart disease.

DNA damage and the proportion of senescent CSCs increased with age both in SHR and Wistar rats. Age associated increase was observed in the oxidative stress of stem cells, possibly mediated by the enhanced oxidative stress in the microenvironment. The changes were more pronounced in SHR, and as early as six months of age, there was significant decrease in efficiency of CSCs of SHR compared to Wistar. The density of healthy CSCs determined as a fraction of the differentiated cells was remarkably low in 18-month-old SHR. Age associated decrease in functionally efficient CSCs was therefore accelerated in SHR.

The expression of senescence-associated markers p21 and p16ink4a and the proportion of SA-β-gal positive cells increased with age. The proportion of senescent cells was significantly higher in SHR compared to age matched Wistar rat. Senescence and death of CSCs with increasing age in wild type mice has been implicated in impairment of growth and turnover of cells in the heart. Senescent stem cells affect their microenvironment by decreasing regenerative potential of the entire stem cell pool, while also affecting neighboring myocytes and vasculature. This study for the first time reports the increased expression of p16ink4a and p21 in CSCs with age and its preponderance in SHR. The difference between SHR and Wistar was apparent as early as 6 months of age, which is the compensatory phase of hypertrophy.

In conclusion, age associated decrease in efficiency of stem cells can be responsible for the degenerative cardiac changes in physiological aging. Aging of CSCs can affect migration and proliferation and promote apoptosis. Accelerated aging in stem cells isolated from hearts of SHR is possibly mediated by an adverse microenvironment. Decrease in the healthy stem cell pool can affect efficient tissue repair and precipitate the transition from compensated hypertrophy to cardiac failure. Enhanced oxidative stress in the microenvironment can be a predominant factor contributing to stem cell aging. The salient findings of accelerated decline in cardiac stem cell efficiency in SHR provide insight for further studies to examine whether reduction of cardiac oxidative stress can restore stem cell function and prevent progressive cardiac remodeling.

Link: https://doi.org/10.1371/journal.pone.0189129

The Pineapple Fund is one of the more sensible responses to sudden wealth that I've seen in my time, a charitable giving initiative set up by someone who finds themselves a multi-millionaire as a result of the enormous rise in the valuation of blockchain initiatives over the past couple of years. We might hope that this will inspire other newly wealthy long-term holders of cryptocurrencies to take similar steps to support the change they want to see in the world.

Today's good news is that the anonymous principal of the Pineapple Fund has chosen to donate $1 million in bitcoins to the SENS Research Foundation, one of the larger donations to SENS rejuvenation research made over the years. Thank you to all involved! This will make a large difference over the next few years, allowing the SENS Research Foundation scientists and their allies to unblock more of the lines of research that lead to a comprehensive toolkit of therapies to control the causes of aging. As that work spins out into the broader research community, we will see a blossoming of treatments that can reverse age-related disease and greatly reduce the suffering of old age.

The breaking news today is that the SENS Research Foundation has managed to secure the sum of $1 million in bitcoins from the Pineapple Fund. The Pineapple Fund is a charitable initiative run by a very generous person who wishes to remain anonymous and has a large number of bitcoins to donate to charities. The suggestion was made on Reddit to the founder of the Pineapple Fund to donate some bitcoins to SENS and they agreed. Thanks to the work of a number of people in the community, Dr. Aubrey de Grey was alerted and he promptly arrived to talk to the amazingly generous person behind the Pineapple Fund.

"Sometime around the early days of bitcoin, I saw the promise of decentralized money and decided to mine/buy/trade some magical internet tokens. The expectation shattering returns of bitcoin over many years has lead to an amount far more than I can spend. What do you do when you have more money than you can ever possibly spend? Donating most of it to charity is what I'm doing."

So who is the mysterious caped crusader behind this awesome initiative? We do not know who you are but we know why you do what you do and we think it is fantastic! There is only so much money a person can spend and giving the rest away to help charities in need is one of the greatest things a person can do. From everyone working in the field of rejuvenation biotechnology and the community who support a future free from age-related diseases, thank you!

Link: https://www.leafscience.org/the-pineapple-fund-commits-1-million-to-the-sens-research-foundation/

The population of stem cells that supports muscle tissue is one of the better studied classes of such cell. Stem cells enable tissue maintenance and regeneration by delivering a supply of new daughter somatic cells that can multiple to make up losses, and through signaling that alters cell behavior. This activity declines with advancing age, however, with stem cells spending ever more of their time in a quiescent state. This is thought to be a response to rising levels of cell damage and tissue dysfunction, behavior that evolved because it serves to reduce the risk of cancer over a period in which our ancestors were under selection pressure for greater longevity. Cancer is a numbers game: more damage, more cell replication, and more cells all raise the odds of a cancerous mutation taking place.

Up close, the dynamics of stem cell behavior within the trend of age-related decline are anything but simple and uniform. The more data that researchers obtain, the more complexity they uncover. Biology is rarely as simple as the present understanding, and never as simple as would be convenient for the development of new therapies. Nonetheless, reliable manipulation of muscle stem cells is an important goal because it should enable some degree of reversal of age-related loss of muscle mass and strength, the condition known as sarcopenia.

There are many different layers of muscle biology at which benefits might be obtained. These range from the brute force approach of myostatin blockade, to put a thumb on the higher level controlling mechanisms that govern when muscle growth takes place at all, to adjusting the internal behavior of stem cells to make them more readily active, to repairing the underlying cell and tissue damage that causes stem cells to retreat from youthful levels of activity. Some of these methodologies are closer to realization than others; as a general rule, therapies that bypass the need for more detailed knowledge of these stem cell populations can make it to the clinic more rapidly.

Researchers Track Muscle Stem Cell Dynamics in Response to Injury and Aging

"Our study is one of the first to look at muscle stem cells in their native tissue with resolution at the level of a single clone. This allowed us to probe the dynamic heterogeneity of the cells, a measure of their flexibility to respond to exercise, injury, and the normal wear and tear that occurs with aging. Using this approach, we found surprising differences in the degree to which stem cells can maintain this heterogeneity, depending on what they are asked to do."

Adult muscle stem cells are essential for repairing and regenerating muscle throughout life. These cells are located between muscle fibers and exist as a heterogeneous population that need to "self-renew" to maintain the stem cell population, as well as differentiate into myogenic cells that proliferate, differentiate, and fuse to create new muscle fibers. "Here, we focused on studying how the pool of muscle stem cells responds to age or after an injury to the muscle. Our goal is to understand how stem cells uniquely cope with or yield to these different pressures. Then, we can use this information to create new approaches designed to specifically prevent muscle stem cell loss and/or dysfunction linked to sarcopenia or in association with muscle diseases that are characterized by chronic tissue damage, such as dystrophies."

The research team followed the self-renewal capacity and range of progeny produced by individual stem cells. "The results were quite different from what we expected - aged muscle stem cells maintained a diverse assortment of cells in the overall pool, despite being less able to proliferate and multiply sufficiently. The outcome was flipped when we caused an injury and watched how the pool responded to tissue damage. In the case of injury, the stem cell pool becomes less diverse, but maintains its proliferative capacity. Our findings lead to several interesting questions about the potential causes of these observed differences."

Muscle Stem Cells Exhibit Distinct Clonal Dynamics in Response to Tissue Repair and Homeostatic Aging

Emerging evidence supports a significant functional heterogeneity in adult stem cell compartments. Single-cell studies in several tissues have revealed a range of behavioral capacities with regard to proliferation, self-renewal, and differentiation potential. This heterogeneity has been proposed as a beneficial feature of stem cells, which must rapidly adjust to the changing demands of their host tissue. By maintaining a spectrum of functional abilities, stem cells are better prepared to respond to various tissue repair scenarios while contributing to homeostatic turnover.

Single-cell lineage tracing offers a powerful means of studying functional heterogeneity in stem cells. Prior lineage tracing studies in vivo have demonstrated a broad array of clonal histories in different tissues. Modeling efforts leveraging these clonal datasets have begun to describe the dynamics of stem cell hierarchies. Intriguingly, several groups have described a loss of clonal complexity, or the diversity of stem cells in a pool or niche with distinct clonal origin, with accumulated stem cell activity. However, much of this work has taken place during youthful tissue homeostasis, and thus, little is known about how different environmental settings may alter the rate of this decline over time, including aging or wound healing. Moreover, the impact that reductions in clonal complexity may have on functional heterogeneity and stem cell behavior is still unclear.

To answer these questions, it is critical to study both aspects of individual stem cell behavior as part of the greater whole, particularly within a readily manipulated host tissue. To this end, skeletal muscle is well suited to examine changes in stem cell heterogeneity in response to disruptive or pathological settings. Skeletal muscle contains a bona fide stem cell population, termed muscle stem cells (MuSCs) or satellite cells, distributed throughout the tissue in their niche, where they remain poised to activate and contribute to cellular turnover.

To determine the impact of homeostatic aging and tissue repair on MuSC clonal complexity, we longitudinally assessed individual MuSC fate over time using in vivo multicolor lineage tracing. Surprisingly, we demonstrated that clonal complexity is largely preserved with homeostatic aging despite reductions in proliferative heterogeneity. Conversely, biostatistical modeling revealed that MuSCs undergo symmetric expansion and stochastic cell fate acquisition specifically during tissue repair, predicting neutral competition between clones resulting in clonal drift, or an increasingly small number of dominant clones. Accordingly, we observed that sustained regenerative pressure resulted in a progressive reduction in clonal complexity. Overall, this work establishes the importance of context in defining the principles underlying stem cell dynamics in skeletal muscle.

The normally secretive California Life Company, or Calico, recently shared some of their investigations into the rejuvenation that takes place in the earliest stages of the reproductive process - parents are old and children are young, so a form of rejuvenation must happen at some point, or reproductive cells must be exceptionally well protected from aging. The Calico team showed that in nematodes and frogs, egg cells, or oocytes, undergo a burst of cellular housekeeping when they are used, clearing out damaged proteins. It is thought that something similar happens in mammalian early embryonic development, a process that also seems to be triggered in part by induced pluripotency. Is this all useful and relevant to efforts to produce rejuvenation therapies? Here is a lengthy commentary from the SENS Research Foundation, whose founder has been one of a number of researchers very critical of Calico Labs in the past:

Some readers got the impression that this study had uncovered a special molecular mechanism that allows these nematodes' oocytes uniquely to stay "young," even as the body as a whole grew old. This impression may have been reinforced by a quote from one researcher, contrasting the aging of the human body with the (seeming) "immortality" of the germline (the "line" of sperm and egg genes that actually passes from generation to generation): "You take humans - they age two, three or four decades, and then they have a baby that's brand new."

Taken together, some readers came away with the suggestion that the fact that babies are born young implies the ability of oocytes to "sweep themselves clean" of their adult parents' lifetime burden of deformed proteins, and excitedly hoped that the tricks that oocytes use to execute this feat could somehow be engineered into aging cells elsewhere in the body to keep our muscle and brain cells young. Unfortunately, no such tricks emerged from this study, nor are they likely to. This study adds substantial insight to a body of work on nematode (and later frog) oocyte biology sparked by a discovery made by French scientists in 2010 and prior work in yeast and in mouse embryos. However, there is nothing here that can be exploited for developing anti-aging therapies.

The real finding of the paper is better captured by its own title than the newspaper headlines: "A lysosomal switch triggers proteostasis renewal in the immortal C. elegans germ lineage." The key word in there is not "immortal," but "renewal" - renewal of "proteostasis," the somewhat equivocal concept of the young cell's dynamic maintenance of stably low levels of damaged proteins. As it turns out, the "renewal" in question is a reactivation of the normal "proteostatic" activity of the lysosome - the cell's recycling center, where old and damaged proteins are broken down into raw materials that can then be reused to build new proteins.

While oocytes are held in storage, they adopt a metabolically dormant state to conserve energy and reduce the production of metabolic wastes. This much is just as true in mammals as it is in the roundworms and frogs studied in this new report. What the new study uncovered is a particular energy-conservation strategy these animals' oocytes use. No special rejuvenative power is involved in this process: other cells clean up these same wastes routinely, as a matter of day-to-day housekeeping, instead of letting them build up until it's absolutely necessary to get rid of them.

Despite the lengths to which the body goes to maintain only viable, "young" eggs, oocytes do still manage to degenerate with age, which is part of the reason why older parents are less fertile. The silver lining in all of this bad news: because the nature of the degenerative aging process in the reproductive system is not different from the aging of the rest of the body at the cellular and molecular level, the "damage-repair" heuristic of rejuvenation biotechnology can be applied to rejuvenate the aging reproductive system just as it can to the rejuvenation of the rest of our bodies.

We're not going to solve the degenerative aging process by borrowing any special tricks from the oocyte. The oocyte doesn't really have any tricks for us to profitably exploit - and more importantly, no cell in the body is naturally able to remove or repair many of the kinds of damage that accumulate in aging bodies and ultimately lead to age-related disease, debility, and death. The oocyte has no way to clear beta-amyloid from aging brains, or TTR amyloid from aging hearts - nor to cleave AGE crosslinks from aging arteries, as they are subject to none of this damage. It has no internal means to replace cells that are lost to aging damage, and is no more able to degrade the truly stubborn intracellular aggregates that accumulate in aging cells than any other cell type. For that, we need a new class of medicines that can do what we can't do on our own: remove, repair, replace, or render harmless the cellular and molecular damage of aging in our tissues. It is when we develop rejuvenation biotechnologies and deploy them comprehensively that we will finally be able to effectively "turn back time" for aging bodies as a whole.

Link: http://www.sens.org/research/research-blog/question-month-16-any-rejuvenation-relevance-roundworm-reproduction

The study noted here can be added to the list of those that find modest activity to associate with reduced risk of cardiovascular disease risk in old people. This sort of finding is a comparatively recent development in epidemiology because it relies upon the use of accelerometers, of the sort found in every mobile device these days. Before the advent of low-cost accelerometers, studies of exercise and health relied on self-reporting, which is simply not accurate enough to identify effects resulting from low levels of everyday physical activity such as gardening, cleaning, and so forth. The current consensus on this sort of data is that activity causes health benefits and reduced mortality, not that people who are healthier tend to undertake more activity. This is based on a smaller amount of human data in which effects can be observed over years based on earlier levels of exercise, and on animal studies structured in order to prove that benefits derive from exercise.

Physical activity (PA) is known to improve health and decrease the risk of developing cardiovascular disease (CVD) in a variety of populations. However, less is known regarding the influence of habitual or daily PA in preventing cardiovascular events among older adults. In particular, data are lacking regarding the influence of daily PA on cardiovascular risk among older adults with mobility limitations that restrict the ability to engage in PA.

Although associations between the quantity of PA and cardiovascular risk factors have been reported in older adults, few have made these connections using objective measurements of PA. To date, most studies have relied on self-reported measures of PA, which commonly misclassify the volume and/or intensity of PA. Although PA has been shown to have an inverse relationship with cardiovascular risk factors and morbidity, it is unknown whether participation in activity reduces cardiovascular incidence in populations of older adults displaying habitually low levels of PA. Prospective studies to date have largely focused on increasing exercise participation, although formal exercise interventions have been insufficient in reducing the incidence of cardiac events in this population. However, few studies have utilized objective measurements using accelerometry to evaluate cardiovascular risk in older adults.

Our previous study found that every 25 to 30 minutes per day spent being sedentary - defined by less than 100 accelerometry counts per minute - was associated with a 1% higher predicted risk of myocardial infarction (MI) or coronary-related death. Conversely, daily time spent in activities registering 100 to 499 counts per minute was associated with lower predicted hard coronary heart disease risk. Every 30 to 35 minutes of inactivity in this range was also associated with a 1-mg/dL lower circulating high-density lipoprotein cholesterol concentration. Somewhat surprisingly, however, the mean intensity of daily activities was not associated with predicted cardiovascular risk in this population.

The cross-sectional nature of the prior study prevented the ability to draw causal inferences and provided only a projection of cardiovascular risk. Therefore, the overarching objective of the present study is to expand on these prior findings using longitudinal assessment of accelerometry-based PA patterns and the observation of cardiovascular events among this population. The primary finding of this study is that objective measurement of PA via accelerometry was significantly associated with incidence of cardiovascular events among older adults with limited mobility. The 1,590 study participants had an 11% lower incidence of experiencing a subsequent cardiovascular event per 500 steps taken per day based on activity data at baseline. At baseline, every 30 minutes spent performing activities ≥500 counts per minute were also associated with a lower incidence of cardiovascular events. Throughout follow-up (6, 12, and 24 months), both the number of steps per day and duration of activity ≥500 counts per minute were significantly associated with lower cardiovascular event rates.

Link: https://doi.org/10.1161/JAHA.117.007215

The political establishment is a plague upon the land; this is generally true of any era. We are fortunate to live in an age in which the level of impact is less brutal and more bureacratic than it has been, and in a region in which the level of wealth is high enough to allow most people to live comfortably despite the constant wars and vast waste of the powers that be. There is, importantly, sufficient space in our society left unpillaged and uncontrolled for technological development to take place at a fair pace. Technology determines near everything about our lives, the degree to which they are worth living, the shape of our societies, and the pace at which we age to death. Faster progress is a great and wondrous thing. Yet, sooner or later, new technologies become promising enough to come to the attention of the political establishment, at which point the challenges of development turn into the challenges of fending off various genteel and less genteel forms of banditry and sabotage.

I noticed the article below in the political press today; it is surprisingly informed in its details, if not some of its premises, given the source. Political journalism is just about the worst of the press industry, and "worst" in this context has become a very low bar of late; the stentorian propaganda of the past has given way to a sort of tawdry crab bucket mass hysteria. As to the article here - should we start to see more of this sort of thing, repeated more often, that might mark the beginning of an interventionist establishment in the matter of longevity science. This probably isn't something to be welcomed: the first instinct of that establishment is to put a halt to any form of change, the second is to tax every new thing regardless of the damage done, and the third is to restrict and control access, limiting it to those with connections.

Where the attention of the establishment results in funding wrestled from the pool generated by involuntary taxation and devoted to a specific cause, such funds are invariably largely diverted into useless activities and waste, or used to prop up unrelated activities carried out by the politically connected. Look at just how little the US National Institute on Aging has accomplished over the last twenty years: so much funding, so many studies, so many programs, and yet where are the results in terms of years of human life span gained? Remaining life expectancy at 60 has moved very slowly upward in a trend unrelated to public research expenditure. The future of additional years of healthy life will be enabled by philanthropy, charities, and startup companies using a tiny fraction of the NIA budget, based on science that was sufficiently explored to get started thirty years ago.

Meanwhile, the first instinct of the propagandists of the political press is to ask how any improvement to the suffering of the elderly might affect the balance of votes or entitlement payments or political parties or current regulations. One gains the distinct impression that people, that suffering, that death really don't matter all that much in their eyes, save for how they are seen at a distance from the city on the hill. It is ugly, I think.

We could do worse than to shun all politicians and their creatures, and work on doing the good that we want to see in the world ourselves. The political establishment exploits and thrives by co-opting our worst instincts, however, and as the present state of the world demonstrates, this strategy is highly effective. As a choice in life, I'd advise reading more Thoreau and Spooner and less of the press as it stands today - advice that was no doubt just as relevant a few centuries past as today. Engaging with the political establishment is a poisoned chalice, one that drags down the productive and ensnares them in a system that does little but generate waste and mockery. The real work is done elsewhere.

Why a drug for aging would challenge Washington

What if you could live to 85, 90 or even 100 with your mental faculties intact, able to live independently without debilitating conditions until the last year of your life? What if just one medical treatment could stave off a handful of terrifying ailments like heart disease, cancer, and Alzheimer's? The idea of a pill for aging sounds like science fiction or fantasy. But the hunt is increasingly real. The leading approach even has a name: senolytic drugs. The science is still far from proven, but the prospect of a drug for healthier aging has already attracted significant investment from well-known drug companies, and the first human studies of anti-aging drugs are getting underway. If the results pan out, the first drugs could be available in as little as a decade.

As the research moves forward, however, it is raising a series of new questions that both medicine and regulators will need to confront. And the most complex questions arise around exactly the issue that makes the field so exciting: The notion of treating the aging process itself. There's never been a drug for aging in part because "aging" isn't considered a disease by the FDA. Should it be? What signs and symptoms of aging is it OK to medicalize? And if a drug were approved for aging - something that every human experiences - who would bear the costs for a pill that potentially could be prescribed for every person alive? And those aren't the only questions. It turns out that evaluating the science is also complex, partly because it's hard to measure whether a drug is fundamentally changing the course of human aging. It's also ethically fraught: Aging is a normal human process, so testing a drug for "aging" means that otherwise healthy people would be subjected to its inevitable side effects, for unproven benefit. How long a trial would even be needed? Regulators aren't close to answering this kind of question.

So far scientists are tiptoeing around many of these complicated issues by testing these drugs only in very sick people, studying to see if they help treat deadly diseases with few other treatment options. The idea is to get a potential anti-aging drug approved first under more traditional protocols without having to tackle the thornier, longer-term questions raised by the idea of treating "aging." However, doctors are unlikely to wait for answers to the larger questions around these drugs before they begin to prescribe them to patients. As soon as a senolytic or other anti-aging drug is approved for any purpose, physicians are allowed to start prescribing them to their patients for any condition they want, and likely will.

Anti-aging science has long been viewed with skepticism, a "soft" science more often the province of quacks selling dubious potions than serious medical researchers. But senolytic drugs are changing that. The idea behind them is to attack senescent or "zombie" cells - cells that have stopped dividing, but aren't dead. Senescent cells release toxic and inflammatory compounds that impair the function of healthy cells, and scientists believe they help drive the decline of important body tissue, like organs. Scientists have found that the number of senescent cells increases with aging in mice, monkeys and humans; they're associated with chronic conditions like diabetes, heart disease, cancer, arthritis and overall frailty. In small mammals, scientists have found that killing senescent cells delays and prevents many age-related conditions and diseases. In animal testing, senolytic agents have also successfully treated conditions including heart dysfunction, lung diseases, diabetes, osteoporosis, and damage induced by radiation. Clearing senescent cells from adult mice has even been shown to increase median lifespan.

Interpreting results of human anti-aging studies won't be easy. To prove that a drug prevents aging, companies will ultimately have to find changes in people that aren't known to be affected by disease. For example, skin gets lined and wrinkled and loses elasticity over the years - but that doesn't cause illness. Muscle mass also decreases with age. If a company could show that the drug alters these changes, "that's a pretty good argument that you are affecting aging." But the potential for approving anti-aging drugs on the basis of these signposts is already triggering the alarm bells of bioethicists. They fear companies' pressure to approve these medicines quickly could lead to patients being exposed to medicines that offer only superficial benefits - and possibly hidden harm. This concern over "indication creep" - the tendency for drugs to be prescribed for problems they weren't approved to treat - is another trigger for ethicists. Many of the companies testing the first senolytic drugs aren't trying to get them approved for aging but instead are targeting diseases where they believe senescent cells play a role.

Because of the enthusiasm around the drugs, researchers are already concerned about anecdotal stories of people wanting to use the medicines to treat aging before they're ready for prime time. Paul Robbins of the Scripps Institute said some senolytics are natural products or older chemotherapy drugs. He's heard of clinics already being set up overseas to provide drugs like these as anti-aging treatments, even without evidence they work, or data on the right dosage. The hype is dangerous, warns James Kirkland, whose employer, the Mayo Clinic, is investing in senolytics. "Anything can go wrong along the way. If you could caution your readers, tell them absolutely not to take these drugs until trials are done, because this is a new way of doing things. We don't know if they are going to work and we don't know what the side effects are."

"If you demonstrate that these drugs work, probably everybody is going to want to take the drugs. So then the question becomes a question of cost," said Steven Austad, scientific director of the American Federation for Aging Research. A high-priced drug taken by everyone could place a burden on an already strained health care system, which presumably would have to pay for everyone to take the drug for many decades. And the longer people live, the longer they will draw from government benefit programs. "Politically, this is a hot topic," said Laura Niedernhofer of the Scripps Research Institute. "Someone who does not dig in deeply thinks immediately, 'Oh my God, lifespan is going to extend and Social Security is already in bad shape, and so how are we going to handle this'?" Niedernhofer is an optimist, however, arguing that the costs of anti-aging therapies will more than pay for themselves, their costs offset by the fact that healthier people will require less medical care in the final years of their lives.

Another concern, said University of Minnesota bioethicist Leigh Turner, is pushing resources toward an unproven idea, instead of toward tried-and-true public health programs that have already been proven to extend lives and improve health, like providing clean drinking water or better waste management. But "nothing in our world is equitably distributed - not money, not food, not water," counters S. Jay Olshansky, who studies aging at the University of Illinois at Chicago School of Public Health. These inequities aren't an excuse to stop pursuing an idea that could improve health for everyone. And the potential high cost shouldn't stop the research, he says: Richer countries have pursued a lot of expensive health interventions that were at first not affordable, or are still not affordable to parts of the developing world.

The evolution of multi-cellular life is in essence the story of a tooth and nail struggle with cancer, one that continues even now. Complex structure, regeneration, and growth are all required in higher forms of life, but that combination means that any sort of sustained breakdown in control over cell proliferation tends to be fatal because it disrupts necessary structures. Multiple layered systems, within cells and outside them, have evolved to try to block damaged cells from uncontrolled proliferation, ranging from tumor suppressor genes to the surveillance of the immune system and its destruction of potentially cancerous cells. Cellular senescence is one of these strategies, and like all of them, it is only somewhat successful. With only a few rare exceptions, evolution has curbed cancer risk to the minimum degree needed for a species to survive, no more than that.

Cellular senescence is, of course, one of the causes of aging. Cells become senescence in response to damage, a toxic environment, or at the end of their replicative life span, and near all destroy themselves or are destroyed by the immune system. Enough linger to cause problems, however, producing the senescence-associated secretory phenotype (SASP) that disrupts tissue structure and function. Cellular senescence is an anti-cancer strategy because senescence locks down a cell to prevent replication - so it should function to remove the most at-risk cells before they can run off the rails. Indeed, this works in the early stages of life. But with enough senescent cells lurking in a tissue, the SASP changes the environment to make it much more amenable to cancer: inflammatory, pro-growth, with increased levels of cell damage. Ultimately, cellular senescence becomes an enabler of cancer.

Cellular senescence describes an irreversible growth arrest characterized by distinct morphology, gene expression pattern, and secretory phenotype. The final or intermediate stages of senescence can be reached by different genetic mechanisms and in answer to different external and internal stresses. It has been maintained in the literature but never proven by clearcut experiments that the induction of senescence serves the evolutionary purpose of protecting the individual from development and growth of cancers. This hypothesis was recently scrutinized by new experiments and found to be partly true, but part of the gene activities now known to happen in senescence are also needed for cancer growth, leading to the view that senescence is a double-edged sword in cancer development.

In current cancer therapy, cellular senescence is, on the one hand, induced deliberately in tumor cells, as thereby the therapeutic outcome is improved, but might, on the other hand, also be induced unintentionally in non-tumor cells, causing inflammation, secondary tumors, and cancer relapse. Importantly, aging leads to accumulation of senescent cells in tissues and organs of aged individuals. Senescent cells can occur transiently, e.g., during embryogenesis or during wound healing, with beneficial effects on tissue homeostasis and regeneration or accumulate chronically in tissues, which detrimentally affects the microenvironment by dedifferentiation or transdifferentiation of senescent cells and their neighboring stromal cells, loss of tissue specific functionality, and induction of the senescence-associated secretory phenotype, an increased secretory profile consisting of pro-inflammatory and tissue remodeling factors.

These factors shape their surroundings toward a pro-carcinogenic microenvironment, which fuels the development of aging-associated cancers together with the accumulation of mutations over time. Among well-documented stress situations and signals which induce senescence, oncogene-induced senescence and stress-induced premature senescence are prominent. New findings about the role of senescence in tumor biology suggest that cancer therapy should leverage genetic and pharmacological methods to prevent senescence or to selectively kill senescent cells in tumors.

Link: https://doi.org/10.3389/fonc.2017.00278

Cellular senescence is one of the root causes of aging. A small fraction of the large number of cells that become senescent every day fail to self-destruct, and instead linger in tissues to secrete a mix of inflammatory and other harmful signals. This behavior is known as the senescence-associated secretory phenotype, or SASP. The sizable numbers of senescent cells in old tissues have been implicated as a contributing cause of numerous age-related conditions, from lung disease to cardiovascular issues to forms of arthritis. More causal links will be discovered: this is a newly energetic field of research.

As an example of the sort of thinking presently taking place, researchers here discuss a potential role for cellular senescence in macular degeneration, a progressive blindness caused by destruction of retinal tissue. While it seems fairly likely that senescent cells are involved, the question is always whether or not they are involved to a sufficient degree to be an important cause. That seems plausible based on what is known, but it isn't an open and shut case. There is considerable uncertainty, based on the existing evidence. Fortunately, now that senolytic therapies to clear senescent cells are a going concern, there is a fairly rapid way forward to learning more: remove senescent cells in aged animal models of macular degeneration, and see what happens. Someone will get around to that in the next few years, I'd imagine.

Age-related macular degeneration (AMD) is the main reason of blindness in developed countries. Aging is the main AMD risk factor, but it is a complex disease in which both genetic and environmental factors play a role. The exact mechanism of its pathogenesis is unknown. Oxidative stress, protein aggregation, and inflammation play a central role in AMD development. Early dry AMD is hardly detectable and usually asymptomatic. Its advanced form, called geographic atrophy (GA), is associated with a massive loss of photoreceptors that evokes central visual loss. A clinical hallmark of wet AMD is the presence of neovascular vessels sprouting from the choriocapillaris into the retina.

It has been proposed that cellular senescence of RPE cells plays a role in the etiology of AMD. It seems that many studies on the role of cell senescence in organismal aging and age-related pathologies support this idea. The exposure of cells to recurrent or chronic nonlethal stress might contribute to an increase in the accumulation of stress-induced senescent cells, thereby accelerating tissue aging. A growing body of evidence proves that persistent DNA damage, especially double-strand breaks (DSBs) and DNA damage response (DDR), are closely associated with cell senescence. Evidence also links DNA damage with inflammation and disease, particularly age-dependent diseases. This is sort of a vicious cycle as DNA damage-dependent senescence can lead to secretion of molecules, which can reinforce senescence and can induce DNA damage and DNA damage-dependent bystander senescence.

Retinal pigment epithelial (RPE) cells in the central retina are quiescent, and when damaged, they can be replaced by their proliferating counterparts at the RPE periphery. Oxidative stress can induce senescence in RPE cells and result in inability of peripheral RPE cells to rescue their central RPE counterparts, which can lead to a massive loss of RPE cells observed in clinically detected AMD. If most of macular peripheral RPE cells are affected by senescence, this mechanism can fail leading to AMD. Senescent RPE will be the source of pathology and have a detrimental impact on surrounding tissue through the senescence-associated secretory phenotype (SASP).

We believe that senescence associates with autophagy and DDR. All these three effects, senescence, autophagy, and DDR, can be provoked by oxidative stress, which is a major factor in AMD pathogenesis. Moreover, aging is the main risk factor of pathogenesis of AMD and can be related to oxidative stress. Inflammation associates with oxidative stress, aging (inflammaging), and AMD. Therefore, it is logical and justified to hypothesize that senescence can play a role in AMD and this process can be influenced or regulated by autophagy and DDR. Consequently, GATA4, as an identified factor to be involved in cell senescence, autophagy, DDR, and inflammation, seems to be a natural candidate to play a major role in the proposed mechanism of AMD pathogenesis. However, this is only a hypothesis, which should be verified, but we tried to show some arguments that this subject is worth further study and development.

Link: https://doi.org/10.1155/2017/5293258

Leucadia Therapeutics is a startup company focused on Alzheimer's disease, noteworthy for being one of the few ventures to depart from the orthodoxy of immunotherapy to clear amyloid and tau protein aggregates. The Leucadia staff are working on the establishment of a faster and cheaper path to an effective therapy for Alzheimer's that nonetheless still addresses the deeper causes of the condition.

Leaving the mainstream is perhaps more of a challenge in the Alzheimer's research community than elsewhere; the US National Institute on Aging has for years been primarily an Alzheimer's concern, and the biggest of Big Pharma entities have made equally large investments in the field over that same period of time. As a result there is a great deal of institutional inertia to continue to push forward with large and costly amyloid clearance strategies that are only incremental improvements on those that have failed by the dozen in the past. Publicly advocating any other path can have a negative impact on career prospects when embedded in such a large and structured system. However, going on for two decades in to these efforts, and with no practical therapy yet to show for the billions spent, the Alzheimer's heretics are starting to become more organized and influential.

It is undeniably the case that protein aggregates of amyloid and tau are important in Alzheimer's, and if they were removed safely and efficiently, patients would benefit. But these forms of metabolic waste are not the whole story; how is it that their presence only grows in the aging brain? Is some combination of declining immune function and persistent microbial infection a significant source of protein aggregates, for example? The evidence for that hypothesis is quite compelling. And in the case of Leucadia's work, are protein aggregates observed in the aged brain there due to a failure of drainage systems? The cerebrospinal fluid is thought to carry these aggregates away for disposal elsewhere in the body, but the pathways used fail with age. Thus the slow buildup of amyloid and tau with age might be thought of as a progressive failure of clearance of these waste products, a structural and fluid flow problem, rather than a cellular problem of greater production.

This is an attractive hypothesis, not least because testing it should be a comparatively low-cost, rapid effort - very far removed from the vast expense of current amyloid clearance approaches. Leucadia is the company formed to carry this initiative forward, now that the research and evidence gathered to date has reached the point of making that leap. The Methuselah Fund and a number of other angels and organizations have invested in Leucadia Therapeutics to date, Fight Aging! among them. Since the latest round of funding is now complete, I recently had the chance to talk to founder Doug Ethell and ask some questions about the company and the approach to Alzheimer's disease.

How did Leucadia come about? What led you down this interesting path of research and development?

I'd been undertaking Alzheimer's disease research as a medical school professor for well over a decade and I gave a talk at the Rejuvenation Biotechnology Conference in 2015. David Gobel, director of the Methuselah Foundation, was in the crowd and we got to talking at a poster session later that day. Dave said the foundation would like to fund some of my Alzheimer's research, if I wanted to start a company with that money. I founded Leucadias Therapeutics a few months later and the Methuselah Foundation made an equity investment.

If you could provide an overview for the audience here of the Leucadia approach to Alzheimer's disease and the underlying rationale?

Our approach to Alzheimer's disease has been to take a step back from molecular interactions and see where we are in the forest. The 'Peculiar disease of the cerebral cortex,' that Alois Alzheimer described over a hundred years ago is notable because a significant part of the pathology forms between cells in what is called interstitial spaces. In the brain, those spaces are filled with cerebrospinal fluid, or CSF, that clears away metabolites and debris that won't go blood vessel walls. We are interested in how CSF clears away regions of the brain where Alzheimer's disease starts first, with the idea that those routes are breaking down.

Think of it a small creek in the forest. Oak trees overhand the creek and occasionally a leaf falls in and gets carried away. In late summer, before the leaves change, the creek starts to dry up and leaves are carried away slower and slower, until a threshold is reached where they form a mat and then none of them are carried away. The plaques in Alzheimer's disease are mats of amyloid-beta. As it turns out, Alzheimer's disease pathology appears first in older parts of the cerebral cortex, called allocortex, where CSF is handled very differently than in the neocortex. The allocortex is intimately connected to the olfactory system and CSF that clears interstitial spaces in the allocortex drain from the brain to the nasal cavity thorough a porous bone called the cribriform plate.

With age apertures in the cribriform plate become occluded, and that can be accelerated by life events such as head injuries and broken noses. The net effect of those occlusions is an age-dependent slowing of CSF outflow, resulting is less efficient CSF-mediated clearance of the allocortex. Those leaves (the amyloid) start to accumulate and gum up the works, leading to in the accumulation of factors that cause Alzheimer's disease pathology. At Leucadia Therapeutics, we're developing a way to restore the clearance of CSF from those areas, with a product we call Arethusta. The name is derived from Greek mythology; the water nymph Arethusa was being pursued by the river god, Alpheus. Artemis let her her escape by helping her turn into a hidden underground creek. Arethusta creates a hidden stream so people can escape Alzheimer's disease.

You just raised your first round; what will be achieved with the funding now in hand?

This raise provides a tremendous boost as it allows us to hire more people, expand on our intellectual property, resolve engineering and manufacturing issues, and refine our regulatory strategy. Our goal is to start clinical trials in 2019 so there is plenty to do. The raise adds quite a bit of momentum.

In recent years I recall some independent research from other groups to support drainage issues as a significant cause of protein aggregation in the brain. Which of these results do you think add the most weight to your work?

That work involves CSF uptake from surface of the neocortex by structures that have been called glymphatics. Very interesting stuff, but a bit different than that allocortex and cribriform plate system we focus on. I published a hypothesis paper about the CSF clearance and Alzheimer's disease connection in a 2014 paper in the Journal of Alzheimer's Disease, after 2 years of editorial review. I first reasoned this mechanism in 2010. In comparison, the first glymphatic paper appeared in 2013.

A lot of alternative theorizing on the causes and progression Alzheimer's is taking place these days, people challenging the primacy of the amyloid hypothesis. Have any of these caught your eye as compelling?

Amyloid deposits (plaques) are a definitive feature of Azheimer's disease pathology, so it is certainly involved. The question is, are those deposits cause or effect? The amyloid hypothesis states that amyloid accumulations cause Alzheimer's disease, but my perspective is that plaques are simply effects, manifestations if you will, of an underlying condition that allows them to form. Ten billion has been spent on many failed clinical trials that centered on the amyloid hypothesis, and some are still ongoing, but none of them addressed the underlying cause of amyloid accumulation. Even if they were successful in clearing some plaques, they'll come right back. Leucadia's approach is to treat the underlying cause and let the brain take care of amyloid clearance by itself.

I feel that the long absence of tangible process towards therapies for Alzheimer's disease has led people to fixate on tiny gains rather than the goal of a cure. But what does realistic success look like in the fight against Alzheimer's over the next decade or so?

I spent over a decade looking at amyloid effects on neuronal death and neuroimmune interactions. Over that period, it got to be more and more depressing to watch an unbroken string of failed clinical trials up-close, played out in slow motion. The ball was pushed down the field a few yards at a time. It didn't go anywhere ... not for 25 years. There was a concerted effort by funding agencies to keep everyone viewing Alzheimer's disease research the same way. Neitzsche had it right when he wrote that the prevailing interpretation is a question of power and not truth.

What the Alzheimer's field desperately needed, and still needs, is dissenting voices that say, "There's something we're missing here. Something big." I'm one of those voices and let me tell you, when you rock the boat by challenging dogma, well-connected people whose livelihoods are built on that dogma take great offense, even if they've been proven wrong time and again. As for progress over the next decade, advances won't come in dribs and drabs but in bursts of activity. At Leucadia, we're developing a very significant advance that takes the field in an entirely different direction.

If this all works out well, and the Leucadia therapy does produce the desired outcome in patients, where next?

We are absolutely focused on slowing the relentless progression of Alzheimer's disease pathology. That's a pretty tall order, and once we get there, then we'll see about setting some new goals.

Researchers here present evidence for the appropriately named death receptors to be biomarkers for cardiovascular disease risk, an indirect measure of the damage accumulating in the vascular system over the course of aging, and its effects on cellular biochemistry. The research community is very interested in establishing reliable, easily measured biomarkers that relate to age-related disease, mortality, and known mechanisms of aging. The more that exist, the more likely it is that these biomarkers can be combined in some algorithmic way to generate a more precise overall biomarker of biological age - something that can be used to rapidly assess the performance of the first rejuvenation therapies, as they arrive, and to steer their development.

Death receptors are activated, for example, in the case of infections when white blood cells that have combatted a virus are to be removed. It was previously known that death receptors in the blood can be measured, but not whether an elevated level was linked to increased cell death in type 2 diabetes and arteriosclerosis. The aim of the study was therefore to investigate whether "death receptors" could be used as a marker that could be linked to ongoing tissue damage and if this could be used to predict the risk of developing diseases. The results show that increased cell death can be linked to increased levels in the blood of three different members of the same "death receptor family" (TNFR-1, TRAILR-2 and Fas). Increased cell death is seen in type 2 diabetes as well as arteriosclerosis.

High blood sugar and blood fats (low levels of HDL, "the good cholesterol") subject the body's blood vessels and insulin-producing beta cells to stress. Long-term stress damages the cells and can cause the death receptors on the surface of the cell to trigger a cell suicide program within the cell. "When the beta cells are damaged, the production of insulin decreases, which increases the risk of diabetes. The damage activates repair processes in the blood vessels. If these are not properly resolved, this usually leads to the development of plaque in the blood vessels (arteriosclerosis). The formation of cracks in this plaque is the primary cause of myocardial infarction and stroke."

The study also looked at the connections between different risk factors - age, BMI, blood fats, blood sugar and blood pressure - and the death receptors TNFR-1, TRAILR-2 and Fas in blood samples from 4,742 people who are part of the population study Malmö Diet Cancer. Samples from the 1990s were compared with the risk of suffering from diabetes, heart attack, and stroke in the coming 20 years. The results show clear links between the level of death receptors in the blood and the different risk factors. High levels of death receptors were common in diabetics which indicates increased cell stress and risk of damage to different organs. Among non-diabetics, high levels of death receptors were linked with an increased risk of developing diabetes and cardiovascular diseases. This indicates that the level of death receptors in the blood reflects the damage that the risk factors cause in different organs.

Link: https://www.lunduniversity.lu.se/article/death-receptors-new-markers-for-type-2-diabetes-and-cardiovascular-disease

Leucadia Therapeutics is one of the young companies shepherded by the Methuselah Fund, in this case working on an Alzheimer's treatment predicated on a theory of the disease that views impaired drainage of cerebrospinal fluid as an important cause. Alzheimer's disease is a condition characterized by a build up of protein aggregates, and one of the ways in which the brain normally removes these aggregates is through drainage of cerebrospinal fluid out into the body. The passages for that drainage, like most other bodily systems, fail over time. An increasing amount of supporting evidence for this to contribute to age-related disease has emerged in recent years.

In the example here, researchers arrive at the consideration of failing cerebrospinal fluid drainage from a quite different position, the study of hydrocephalus, or excess accumulation of cerebrospinal fluid in the brain. This is not uncommon in older individuals, and there is a noted overlap with Alzheimer's disease - it is not hard to join the dots between these two areas of research. Evidence for one tends to support the other, and the various research groups exploring the physiology of drainage in the brain may well wind up converging on the same destination.

Syndromes of progressive neurological disturbances in the setting of normal cerebrospinal fluid (CSF) pressure have been termed as "normal pressure hydrocephalus" (NPH). Patients without known precipitating factors are diagnosed with idiopathic NPH (iNPH), the mechanism of which remains largely unknown. However, the steep increase in the incidence of iNPH in individuals who are 60 years of age or older suggests an association with aging. Some recent studies have emphasized on the primary role of abnormal water/blood drainage or viscoelasticity changes in the brain parenchyma as the likely mechanisms underlying age-related development of the disease.

Nevertheless, since the initial reports, the immediate improvement in symptoms following removal of CSF through a lumbar tap has not only been useful for clinical purposes, but has also suggested abnormal perfusion as the direct cause of clinical manifestations. Despite the body of evidence demonstrating changes in blood flow following the "tap test" (TT), there are no established diagnostic criteria based on blood flow imaging. It is critical that iNPH be diagnosed sufficiently early to enable CSF diversion using a shunt where appropriate to prevent irreversible damage. Thus, there is a need for novel, non-invasive techniques to assess this condition in the elderly population.

Recently, mapping the low-frequency phase in a blood oxygenation level-dependent (BOLD) signal time-series has been proposed as a clinically useful biomarker in cerebrovascular diseases. In the present study, we acquired resting-state BOLD magnetic resonance imaging (MRI) scans before and after a spinal TT, and compared the BOLD lag maps to evaluate the effect of treatment on brain perfusion in subjects with iNPH.

We observed an abnormal phase in the periventricular region where the deep veins converge. Under healthy conditions, the phase or relative drainage time in this region consistently exhibited a late venous phase. This abnormally long drainage or "wash-out" time in iNPH was normalized by TT, while the global mean of the phase remained stable. Collectively, these results permit an interpretation that a part of the deep venous system is drained by collaterals in iNPH instead of the normal route via the internal cerebral veins. The broad change after TT may reflect the normalization of this state, involving a change in the drainage pattern. Altered venous drainage has been observed in chronic NPH and the periventricular area may be one of the commonly affected sites of this venous inefficiency.

The fact that both normal aging and abnormalities in iNPH (which is corrected by TT) involve deep venous insufficiency may have etiological implications, as this suggests altered venous drainage in the absence of pathological ventricular dilation. Accordingly, for example, a causal relationship between hydrocephalus and periventricular edema may be questioned. It can also imply an initiating role of venous congestion in brain compliance reduction which develops during both pathological and aging processes. Although the concept of venous inefficiency as the cause of hydrocephalus is not new, it has not been linked to aging. Although the role of CSF in the mechanism cannot be inferred from the present data, it is interesting that affected areas encompass regions related to CSF turnover.

Link: https://doi.org/10.3389/fnagi.2017.00387

Historically, the public at large has shown themselves to be quite disinterested in living longer. Over the years I've been aware of the longevity science movement, it has always been a challenge to expand the community towards greater acceptance, support, and funding. As an example of attitudes we observe, you might look at the Pew survey of attitudes to life extension from a few years back, in which the people surveyed generally agreed that they wanted to live a few years longer than their peers - in the same sort of way as a house should be just a little bit larger than those of the neighbors, to make the point, but not so much so as to be gauche. Humanity is ever petty in the details when conducting any of its grand madnesses; we can see that in even a cursory glance across a lengthy history of what is, by modern standards, a series of sweeping, cruel insanities. Yet we will be judged just as harshly by those yet to come.

Are we asking the right questions? It has long been thought in our community, though gathering supporting evidence for this hypothesis is ever a difficult proposition, that people are on the whole unenthused by the prospect of longevity because they instinctively feel that a longer life would mean becoming ever more decrepit and sick. They think that superlongevity would mean a collapse into an exaggerated caricature of a wizened elder, unable to do anything other than suffer ever more bitterly. This hypothesis for the public rejection of longevity science for so many years was outlined more than a decade ago, and brought up again at the time of the aforementioned Pew study.

Yet "older for longer" is not the outcome that rejuvenation therapies will achieve. It was never the plan, and no researcher has ever claimed to be working towards that end. Functional, working rejuvenation biotechnologies based on periodic repair of the cell and tissue damage that causes aging will instead postpone aging in the young, and restore health and youthful ability to the old. They will turn back age-related disease. The future is not being older for longer, but rather being younger for longer. This has proven to be a very difficult message to deliver; it has been repeated over and again, and never seems to stick.

Yet in the past few years, a few small surveys have shown that if you ask the right questions in the right context, then ordinary, everyday people will say that they want greater longevity. The right question is whether or not one would want to live longer if health is guaranteed for those additional years. Focus on the health, and people inch towards wanting more time. We have yet to collectively figure out how this should translate into our advocacy for rejuvenation research - it isn't quite as straightforward as one would hope. After all, the message we have delivered for years is exactly that we want to extend health as well as overall life span, and that in fact the only practical way to achieve longevity is to provide greater and longer-lasting health.

People say they want to live longer - if in good health

Longevity is a such a pervasive goal in public health policy and even popular media, but individually most people only want to live long lives if they will be healthy, according to a new study. "People in three cultures from around the world are reluctant to specify their desired longevity. To me this is interesting because longevity is such a valued public health objective, but at the individual level, longer lives are a goal 'only if' I remain healthy."

The results of these interviews reinforce previous findings from this research group that revealed many older adults - in various cultures - think of life as not a smooth continuum of time but segmented into different states. The researchers refer to four "ages" or stages of life, including the third age, which is an active retirement where people leave traditional work and family roles, followed by the fourth age. "People seem to view one part of the future as wanted and another as not wanted, typically the 'fourth age' which is basically the period when one might experience a disability or a potential health decline."

For this study, the researchers interviewed 30 people in each country, and they recruited the sample with sex and age quotas to reflect a range of experience with retirement. About one-third of respondents did not express aspirations for a longer life. "Some felt their lives had already reached a stage of completion, and others as a form of fate acceptance." A larger number of respondents did mention they wanted to extend their lives. Yet less than half of that group noted a specific amount of time they desired to live. The strongest opinion among that group was the desire to live longer only if they maintained their current or what they deemed to be acceptable levels of health.

Is longevity a value for older adults?

The human desire to prolong life and postpone death has a long history. In modern times, population longevity, as measured by the statistical estimate of life expectancy, is taken as a measure of nations' progress and development. The promotion of longer lives, principally through reduced mortality at younger ages, is a prominent goal of public health policy and research. Academic units concerned with gerontology have been adding the term longevity to their titles - a center for longevity, a longevity institute. Presumably, this skirts the negative connotation of aging and aligns the organization with a desirable end. Longevity can be an organizational mission in a way that aging cannot.

At the same time, longevity is not without shadows because modern medical care can maintain lives that are felt to be too long. At the population level, rising numbers of long-lived persons can pose societal challenges. Sheer longevity is also qualified by the age from which it is projected, for the hope of a long, full life is one thing at age 10 or age 20, but another in the seventh, eighth, and further decades of life. This latter stretch is the concern of our paper.

Longevity counts time from some point forward but it is also an individual perception about time left before the ultimate deadline of death. Deadlines are motivators and none more so than death. The question about future time left and one's goals can be reshuffled to ask another question: whether time left is itself a goal. Do older people value longevity for themselves? That is the focus of our analysis, based on conversational interviews with older adults in three cultures. The study of "desired longevity" (vs. expected longevity) has been quite limited, which is particularly puzzling given such theoretical interest in the end of life and gerontology's tacit assumption that most people want to live a long life. On the one hand, the modern promise of increasing health and vitality predicts an embrace of longevity. On the other hand, worries about late-life frailty and illness may make people hesitate to welcome extended lives.

Survey techniques have been used to ask adults about desired longevity, this in order to examine the distribution of replies (always contingent on respondents' ages) as well as associated factors that may explain the replies. One feature of these findings is a curious amount of non-response (refused to answer, don't know) to questions about desired longevity. Distributions of numerical answers about desired longevity also display another pattern: the "age heaping" of replies at five-year intervals, such as 80, 85, 90, etc. Taken together, approximate-age replies along with nontrivial amounts of response refusal suggest that older adults' longevity goals may not be sufficiently measurable by survey techniques.

In this study, we asked people in an open-ended way about their desire for longer life: Would you like to have more time? What age would you like to become? This was something more specific than asking about a preference for survival without reference to any length of time; about one's plans for the future; or whether people see the future as open or limited, as in studies of future time perspective. Our attempt was to discover whether there were preferred temporal spans with which older adults framed their futures and plans.

The two-question series about extra years and desired age ("How old would you like to become?") was designed to generate talk about extended life. Free to answer the questions in their own way, participants could say any number of things about longer life during the interviews. Amid these responses, our analysis capitalized on a pattern that was strongly apparent. When it came to desired longevity, most people did in fact want to live longer, but few supplied a numerical answer that was not also conditional on the maintenance of continued good health. The majority preference was for longer life but "only if."

The health stipulation was cited by three-quarters of the 57 cases who desired longer lives. This stance was a prominent pattern, and in the replies to our questions there were certain similarities: the conditional expressions (if, as long as, it depends), the anecdotes about others in poor health, and the reference to medical discourse about quality of life. The bundling of longevity desires with a health stipulation was common to all three research sites. Such similarities suggest to us that longevity expectations, while personal expressions, are also generated from social discourse of a kind that exists in the three cultures and that yields shared styles of talk about extended life. We posed questions to individuals and each replied in his or her own way, yet there was a consistent, cultural convention favoring health-qualified longevity.

In the research here, injections of blood plasma from young rats are shown to improve autophagy and liver function in old rats. This is interesting given the so far mixed evidence for young to old plasma transfer to be beneficial. There is, however, a history of research to show that increased levels of the cellular maintenance processes of autophagy can improve liver function in old rodents. Autophagy normally declines with age, and this appears to contribute to a variety of issues, such as loss of stem cell activity. You might recall that increasing the number of receptors on lysosomes in old rats can improve liver function; lysosomes are the portion of the autophagic infrastructure that break down damaged proteins and structures, and they function more effectively when equipped with more receptors.

The young to old plasma transfusion strategy is an outgrowth of parabiosis research in which the circulatory systems of a young and old individual are linked. This worsens measures of aging in the younger individual and improves them in the older individual. Current opinion in the research community is divided between the hypothesis that factors in young blood improve cell and tissue function, or that factors in old blood harm cell and tissue function. There is evidence for both sides, and the balance has swung back and forth over the past few years.

The study here adds something new, meaning the evidence for beneficial effects of plasma transfer to be primarily mediated by increased autophagy, at least in the liver. This has been demonstrated for calorie restriction and a number of related methods of modestly slowing the aging process in laboratory species - autophagy is clearly important in the hierarchy of biological systems that determine the relationship between environmental circumstances and natural variations in the pace of aging. Given that those approaches fail to extend life in humans and other long-lived species to anywhere near the same degree as occurs in short-lived species, one might speculate that the same unfortunate relationship will apply here. Parabiosis might turn out to be just another way of manipulating some of the beneficial cellular reactions to calorie restriction, achieving the same poor results on life span in humans, but possibly still a useful degree of other benefits to health.

Recent studies showing the therapeutic effect of young blood on aging-associated deterioration of organs point to young blood as the solution for clinical problems related to old age. Given that defective autophagy has been implicated in aging and aging-associated organ injuries, this study was designed to determine the effect of young blood on aging-induced alterations in hepatic function and underlying mechanisms, with a focus on autophagy.

Aged rats (22 months) were treated with pooled plasma (1 ml, intravenously) collected from young (3 months) or aged rats three times per week for 4 weeks, and 3-methyladenine or wortmannin was used to inhibit young blood-induced autophagy. Aging was associated with elevated levels of alanine transaminase and aspartate aminotransferase, lipofuscin accumulation, steatosis, fibrosis, and defective liver regeneration after partial hepatectomy, which were significantly attenuated by young plasma injections.

Young plasma could also restore aging-impaired autophagy activity, while inhibition of the young plasma-restored autophagic activity abrogated the beneficial effect of young plasma against hepatic injury with aging. In vitro, young serum could protect old hepatocytes from senescence, and the antisenescence effect of young serum was abrogated by 3-methyladenine, wortmannin, or small interfering RNA to autophagy-related protein 7. Collectively, our data indicate that young plasma could ameliorate age-dependent alterations in hepatic function partially via the restoration of autophagy.

Link: https://doi.org/10.1111/acel.12708

Is random mutational damage to nuclear DNA a sizable cause of aging? The consensus in the scientific community on that question is that it is an important cause, with the theory being that this results in sufficient change in protein production and cellular behavior to produce degraded function. That consensus is challenged, however, and at present there is a distinct lack of supporting evidence for either position, even given a few intriguing studies from recent years. It is well known that mutation level correlates with age, and methods of slowing aging also slow the increase of mutational damage. So every aspect of aging does in fact tend to correlate with mutation load, but that doesn't necessarily tell us anything about cause and effect - and that is the case here.

Aging in humans brings increased incidence of nearly all diseases, including neurodegenerative diseases. It has long been hypothesized that aging and neurodegeneration are associated with somatic mutation in neurons; however, methodological hurdles have prevented testing this hypothesis directly. Markers of DNA damage increase in the brain with age, and genetic progeroid diseases caused by defects in DNA damage repair (DDR) are associated with neurodegeneration and premature aging. While analysis of human bulk brain DNA, comprised of multiple proliferative and non-proliferative cell types, revealed an accumulation of mutations during aging in the human brain, it is not known whether permanent somatic mutations accumulate with age in mature neurons of the human brain. Here, we quantitatively examined whether aging or disorders of defective DDR results in more somatic mutations in single postmitotic human neurons.

Somatic mutations that occur in postmitotic neurons are unique to each cell, and thus can only be comprehensively assayed by comparing the genomes of single cells. Therefore, we analyzed human neurons by single-cell whole-genome sequencing (WGS). Since alterations of the prefrontal cortex (PFC) have been linked to age-related cognitive decline and neurodegenerative disease, we analyzed 93 neurons from PFC of 15 neurologically normal individuals from ages 4 months to 82 years. We further examined 26 neurons from the hippocampal dentate gyrus (DG) of 6 of these individuals because the DG is a focal point for other age-related degenerative conditions such as Alzheimer's disease. Finally, to test whether defective DDR in early-onset neurodegenerative diseases is associated with increased somatic mutations, we analyzed 42 PFC neurons from 9 individuals diagnosed with the progeroid diseases Cockayne syndrome (CS) and Xeroderma pigmentosum (XP).

Our analysis revealed that somatic single-nucleotide variant (sSNVs) accumulated slowly but inexorably with age in the normal human brain, a phenomenon we term genosenium, and more rapidly still in progeroid neurodegeneration. Within one year of birth, postmitotic neurons already have ~300-900 sSNVs. Three signatures were associated with mutational processes in human neurons: a postmitotic, clock-like signature of aging, a possibly developmental signature that varied across brain regions, and a disease- and age-specific signature of oxidation and defective DNA damage repair. The increase of oxidative mutations in aging and in disease presents a potential target for therapeutic intervention. Further, elucidating the mechanistic basis of the clock-like accumulation of mutations across brain regions and other tissues would increase our knowledge of age-related disease and cognitive decline. CS and XP cause neurodegeneration associated with higher rates of sSNVs, and it will be important to define how other, more common causes of neurodegeneration may influence genosenium as well.

Link: https://doi.org/10.1101/221960

Aubrey de Grey of the SENS Research Foundation took a few hours from his packed schedule yesterday to answer questions from the community at /r/futurology. It is a pity that we can't get a full day of his time at some point - clearly there are way too many interested folk with questions and not enough hours to answer more than half of them. It is a sign of progress, I hope, that ever more people recognize that the SENS approach to the development of rejuvenation therapies is promising, and understand enough of the science to ask intelligent questions about the details.

SENS is simple enough to explain at the high level: identify the cell and tissue damage that (a) appears in old tissues but not in young tissues, and (b) is caused by the normal operation of metabolism, not by some other form of damage. The resulting short list includes the causes of aging. It may include some other things as well, that in the end turn out not to need fixing, but why take the chance? In modern biotechnology and life science research, it is faster and cheaper to develop a repair therapy and see what happens than it is to painstakingly figure out how everything fits together.

When de Grey first evaluated the field of aging research, back before the turn of the century, he found that the causes of aging by the above definition were largely known, with a good deal of evidence in support of each one. Yet next to no-one was working on fixing them. Since then, he has campaigned tirelessly to build organisations, assemble allies, raise funding, and persuade researchers, and all of that to ensure that the scientific and biotechnology communities do in fact move ahead with a repair-based approach to building functional rejuvenation therapies. It has been surprisingly hard work, given a research community that was hostile towards the idea of treating aging as a medical condition versus merely observing it, and a public at large who seem disinterested in living longer in good health. Nonetheless, here we are today, on the verge of the first rejuvenation therapies making it into the clinic, and with a growing number of research, investment, and business interests showing great interest in treating aging.

Aubrey de Grey, AMA, December 7th at /r/futurology

I've noticed in the last year you seem a lot more optimistic about the timeline.

I wouldn't say a LOT, but yeah, it's been a good year. Basically just the cumulative progress, both on the science and on the public attitude and funding stream. I'm still cautious, because for sure we are still really struggling for funds, but I'm hopeful.

If you were to find all the funding you'd ever need, how long until you make major breakthroughs in all 7 areas and essentially completely remove aging?

50% chance: 20 years.

What do you think were the biggest wins of the last couple of years in SENS-relevant advocacy, research, and development? What has moved the needle?

There have been lots. On the research I would highlight our paper in Science two years ago showing how to synthesize glucosepane and our paper in Nucleic Acids Research one year ago showing simultaneous allotopic expression of two of the 13 mitochondrial genes. Both those projects have greatly accelerated in the meantime as a result of those key enabling breakthroughs; watch this space. On advocacy I think the main win has been the arrival of private capital; I would especially highlight Jim Mellon and his Juvenescence initiative, because he is not only a successful and energetic and visionary investor, he is also a highly vocal giver of investment advice.

Can give your thoughts on Mark Zuckerberg's plan to "cure all diseases" within his child's lifetime? I suspect there's a lot you could talk about regarding that.

Mark is (as far as I can tell) not well-informed about this area. Unlike Page and Brin, who were quite assiduous more than a decade ago in educating themselves on matters technovisionary including medical (I first met them both in that era), Zuckerberg seems to be reluctant to reach out to those who actually know stuff. Anyone who can get me an hour of his time, you could save a lot of lives.

Is there anything new you are able to say about the breaking of cross-links in the extracellular matrix?

Absolutely. Short story, we now have a bunch of glucosepane-breaking enzymes, and we are within a few months of spinning the work out into a startup.

The SENS strategy to migrate mitochondrial DNA (mtDNA) into the nucleus seems to be preventive engineering approach rather than a maintenance approach. In light of new techniques like killing senescent cells, why wouldn't killing off cells that have given in to mutant mitochondria make more sense?

Great question - see my early papers on the subject. Basically the issue is that the majority of mutant mtDNA in an aged body is in muscle fibres, which do not get completely taken over, only segments a millimeter or so long, so we would do much more harm than good if we zapped the whole fibre.

RepleniSENS describes the thymus rejuvenation project. How does this approach compare to directly injecting stem cells into the recipient's thymus?

Actually we have discontinued that work, mostly because we were basically overtaken. A raft of approaches seem to be working: our approach of building a new one, or growth factors to regrow the old one, or even tricks to repopulate the T cell pool by proliferation in the periphery (i.e. without a thymus).

Some researchers attempt to eliminate mutated mitochondrial genomes from the cell. Would you reckon these approaches have a chance of success?

The work you referenced is terrific, but it is intrinsically limited to mitochondriopathies that are caused by inherited, single mutations, whereas in aging we have different ones in different cells. There are some ideas out there for tipping (reversing) the selective advantage enjoyed by mutant mtDNA without being sequence-specific, but they are not all that promising yet.

Once we have an efficient senolytic drug and we can get rid of a significant number of senescent cells in the body, do we also have to clear the senescence associated secretory phenotype (SASP) that has been secreted over the years or is it something that the metabolism can naturally get rid of?

The latter. The SASP molecules have a short half-life.

Aside from funding, what do you consider to be a burden or delay for your type of research?

Nothing. Seriously, nothing at all. We have the plan and we have the people. It's all about enabling those people, giving them the resources to get on with the job.

How come the epigenetic changes and changes to our microbiome that accumulate with age are not a part of the categories of damage? When do you predict that rejuvenation approach as a solution to the problem of aging will become accepted by clear majority of scientists?

The microbiome is basically a highly dynamic population of cells, hence it is virtually certain to become right on its own when we fix everything else (even assuming that there is anything suboptimal about it in old age in the first place). For epigenetic changes, this is also the case if you mean coordinated ones that happen across all cells of a given type. If you mean drift, i.e. epimutations, my explanation for that is protagonistic pleiotropy (see my 2007 paper with that title). Rejuvenation is already accepted as a solution by most scientists, and it is being reinvented by other people. See for example the 2013 "Hallmarks of aging" paper.

How confident are you still in your previous prediction that humans will be able to control aging by 2029?

I think we've slipped a few years, entirely because of lack of funding. The tipping point will be when results in mice convince a critical mass of my curmudgeonly, reputation-protecting expert colleagues that rejuvenation will eventually work, such that they start to feel able to say so publicly. I think that's on the order of five years away.

Given current funding, how far away from robust mouse rejuvenation do you think you are?

My estimate is 5-7 years, but that's not quite "given current funding". My overoptimism in saying "10 years" 13 years ago consisted entirely of overoptimism about funding - the science itself has not thrown up any nasty surprises whatsoever - but nonetheless I am quite optimistic as of now about funding, simply because the progress we have made has led to a whole new world of startups (including spinouts from the SENS Research Foundation) and investors, so it's not only philanthropy any more. Plus, the increase in overall credibility of the approach is also helping to nurture the philanthropic side. We are still struggling, that's for sure, but I'm feeling a lot surer that the funding drought's days are numbered than I felt even two or three years ago.

It was some time ago that you guys published your paper on inserting the enzyme into white blood cells to help them break down 7-ketocholesterol, I know a company was spun out not to long after that. Are they making good progress?

Actually, of all our (so far five) spinouts, that's the one that has rather lost its way. We are working to reboot that work and get it moving more promisingly. A lot of the problem was that it was bankrolled by one wealthy person, so that (rather like Calico) it had no incentive to let the world (or even me) know what it was doing.

When would you guess that we will have the first, direct evidence of human rejuvenation through removal of senescent cells (also considering self-experimenting individuals, which could get there first)?

To start at the end: if it works, the first evidence will indeed quite probably be from self-experimentation. Of course it will be n=1 so it will be very provisional evidence, but you knew that. So, when? - that mostly depend on the extent to which humans reproduce what has been seen in rodents, where the benefits of removing senescent cells were a lot broader than I (or anyone, I think) would have anticipated. We just don't know.

You have recently accepted a position as Vice-President of New Technology Discovery at BioTime Subsidiary AgeX Therapeutics. Can you give an overview of why you accepted this position and how it affects your current work at SENS?

I'm still defining my role there, but it is a big deal. I am there 30% so my primary affiliation remains SENS Research Foundation. But the emergence of the private-sector component of the rejuvenation biotech effort is a hugely important recent advance, and for me to have an official foot in both camps makes a strong statement. Also, it is a huge thing for me to be finally working closely with Mike West, who has been a hero of mine for 20 years. The two roles will certainly dovetail a lot: at AgeX my basic task is to come up with new therapeutic ideas, and naturally that will feed off what we are doing and have done at SRF.

Given that cells can reverse their age through induced pluripotency, do you see this as a viable strategy for reversing aging in humans, or is it too difficult and dangerous to do in vivo?

As of now it's definitely dangerous in terms of its carcinogenicity. However, we may be able to reduce that soon. I am particularly excited by the recent work of the awesome researcher Vera Gorbunova on the difficulty of dedifferentiating cells from naked mole rats; I suspect that that work may uncover ways to be more selective and controlled with in vivo dedifferentiation.

Has your position on the relative importance of the stem cell side of aging changed over the years? I know that in earlier years I was somewhat convinced that stem cell decline was fairly secondary to other parts of SENS.

It very much remains to be seen. In some tissues, like the substantia nigra where cell loss causes Parkinson's disease, I'm pretty sure we will indeed need stem cell therapy. In other places, the failure of stem cells to maintain their numbers and/or their proliferative vigour seems to be quite largely determined by the systemic environment, i.e. by what is and is not present in the circulation, and there I agree that recovery is quite likely to be largely spontaneous once we fix other stuff.

It seems likely that artificial intelligence will be a necessary tool in order to reach longevity escape velocity. I was wondering how much of a role does artificial intelligence play in your research? Is this something you devote many resources to?

We don't, but that is because other major players in this field (and good friends of mine), such as Alex Zhavoronkov and Kristen Fortney, are doing it so well already (with Insilico Medicine and BioAge respectively). They are both awesome and massively committed crusaders for this mission. Check out the BioData West conference that will occur in San Francisco a couple of days before our Undoing Aging conference in Berlin; I will be chairing a session on this.

With the recent departure of Calico's Head of R&D for GSK, do you think that there is a chance that Calico might now redirect its efforts in a more productive direction?

No. A good approximation to how Calico operates is as two entities: one that is essentially Genentech 2.0, setting itself up to make massive money from big deals with other traditional pharma, and one that is to pursue its actual remit, namely to defeat aging. Barron was squarely on the former side. The latter side is led by David Botstein, who is as pure a basic scientist as they come and has no time whatsoever for "dreamers" who think we might actually know enough already to be able to develop therapies. His philosophy is unfortunately permanent: no amount of progress will make him become translational and cease to be 100% discovery-focused. I don't remotely blame him - he is who he is. I only slightly blame Levinson: there was nothing wrong with hiring a chief science officer to do discovery, the only thing he got wrong was not also to hire a chief technology officer (me, obviously) alongside him. The people who have all the blame are Larry and Sergey, for allowing their billions to be wasted like this and not having the guts to step in and impose a change of direction.

Given that it's such an emotionally charged field how do you personally, and SENS in general, remain objective and keep hope from interfering with your work?

That's not so hard as you might think. Ultimately, we are driven by the desire to increase the chance of success, or equivalently to reduce the likely time until success - but from what to what is secondary. If we hasten the defeat of aging by a year, who cares whether it's from 2050 to 2049 or from 2030 to 2029? - it's still 40 million lives.

You have been wrong in the past with your expectation of peoples willingness to get onto this idea. Thus I can easily see a path where this technology is proven enough to be clearly happening but most people just don't care and the funding is still very hard to come by. Have you given much thought to this potential scenario?

You're right that I was overoptimistic in the past about the willingness of other high net worth individuals to follow in the wake of Peter Thiel, who started funding us in 2006. However, when it comes to support from scientists, I have never made such a mistake - I always knew it would take robust mouse rejuvenation. I have the advantage in that regard that the community in question is just the most credentialed, authoritative biogerontologists - no one else. Thus, they are (a) really few in number (truly, we are talking about something like a dozen people), (b) scientists (hence I know how they think, unlike billionaires) and (c) people I know well, personally. So I have very strong confidence regarding what determines what they say publicly.

Many wealthy celebrities and smart individuals can easily afford to invest into SENS. How come they are not?

Everyone has rationalisations. The key thing to remember is that humanity has been hoping against hope for a cure for aging since the dawn of civilisation, and it has been suckered time and time again into believing we had one, so there is a rather strong incentive not to get hopes up. And if something is impossible, its desirability is irrelevant: there is still no basis for funding it. So it falls to the small minority of wealthy people who are also truly independent-minded to support this work. Yes, people like Elon Musk may well feel rather ashamed a decade or two from now that they didn't do more earlier. But we're working on it.

How do you feel about the impact of groups like LEAF advocating and reporting on rejuvenation biotech? Has the advocacy and reporting of these groups made your life any easier?

Massively! A huge thing that I say all the time is that advocacy is one thing that absolutely relies upon diversity of messenger. Different people listen to different forms of words, different styles of messaging, etc. The more the better.

Researchers here provide evidence for increased autophagy, achieved via targeting mTOR to mimic some of the response to calorie restriction, to improve stem cell function in old mice. As a result some of the loss of bone mass and strength that occurs with age was reversed. Autophagy is the collection of maintenance processes responsible for clearing out broken proteins and structures in the cell, but like most of our biochemistry it declines in effectiveness with age. Increased levels of autophagy have been shown to be necessary for the gains in health and longevity provided by calorie restriction in short-lived species, and mTOR is one of the regulatory genes through which the calorie restriction response works. It is not surprising to find that inhibiting mTOR improves autophagy, and thus also improves the function of many systems in the body that benefit from having less garbage and breakage in their cells.

The overall slowing of aging produced by calorie restriction touches on all aspects and measures of aging, and that includes a reduction in the usual rate of decline in stem cell activity in old age. So the study here illustrates that calorie restriction, stem cell activity, autophagy, and mTOR all link together nicely. Unfortunately, we should not expect the same size of effect in humans as is observed in mice: calorie restriction is very good for health, but it certainly doesn't extend human life span by 40%, as is the case in mouse studies. This is generally the case for all longer-lived species, as the size of the life span increase produced by calorie restriction and its mechanisms under the hood scales down as life span scales up.

Mesenchymal stem cells (MSCs) are pluripotent cells that play crucial roles in tissue maintenance, repair, and regeneration. However, data suggest that beneficial functions of MSCs may become compromised with age; this is closely associated with age-related loss of repair and regenerative capacity of different tissues. Bone marrow-derived mesenchymal stem cells (BMMSCs) decline in number with aging and show degenerative properties including reduced osteogenic differentiation capacity, increased adipogenic differentiation capacity and reduced proliferative ability; these are partially caused by bone aging.

Autophagy is a process in which cellular components such as proteins and damaged mitochondria are engulfed by autophagosomes and delivered to lysosomes to be degraded and recycled in order to maintain cellular homeostasis. Autophagy has been widely studied as a mechanism for anti-aging effects and in alleviating age-related diseases. Recent studies have indicated that autophagy is required for maintaining the stemness and differentiation capacity of stem cells. It has been reported that autophagy is a crucial mechanism in the maintenance of the young state of satellite cells, and failure of autophagy causes declines in the number and function of satellite cells. Autophagy can protect BMMSCs from oxidative stress, which indicates that autophagy plays a protective role in cell aging. Conversely, autophagy also has been proven to be a requirement for maintenance of replicative senescence of MSCs. Therefore, whether and how autophagy regulates MSC aging remains unclear.

Bone marrow-derived mesenchymal stem cells have been regarded as the main source of osteoblasts for skeletal repair. It has been reported that degenerative changes of BMMSCs in humans and rodents during aging are associated with bone aging. Bone marrow-derived mesenchymal stem cells tend to partially lose their self-renewal capacity and differentiate into adipocytes instead of osteocytes with aging, which causes bone loss and fat accumulation. Our findings showed that aged BMMSCs had decreased osteogenesis, elevated adipogenesis and decreased proliferation compared with young BMMSCs; these results are in line with the previous findings.

We speculate that decreased autophagy in aged BMMSCs might be one of the causes of degenerative changes of aged BMMSCs, and bone loss by decreased autophagy could be a potential new mechanism of bone aging. The results of the manipulation of autophagy in both young BMMSCs and aged BMMSCs confirmed our speculations. As an autophagy inhibitor, 3-MA was used on young BMMSCs; the results showed that inhibition of autophagy not only reduced osteogenesis and promoted adipogenesis but also inhibited proliferation of young BMMSCs, which indicated that decreased autophagy could turn young cells into an aged state with degenerative properties. Meanwhile, the autophagy inducer rapamycin could partially convert aged BMMSCs to a young state by increasing osteogenesis, reducing adipogenesis and promoting proliferation. In summary, we conclude that activation of autophagy can restore degenerative properties of aged BMMSCs via regulating oxidative stress and p53 expression.

Link: https://doi.org/10.1111/acel.12709

Covalent Bioscience is the company formed to carry forward work on catalytic antibodies capable of clearing aggregated proteins found in old tissues, such as transthyretin amyloid. This type of amyloid, a misfolded protein that disrupts normal tissue function when present in large enough amounts, is associated with cardiovascular mortality and osteoarthritis, and is thought to be a prevalent cause of death in supercentenarians. The advantage of catalytic antibodies over normal antibodies is that they bind to the target site on a protein, then destroy that site, then move on. One antibody can attack thousands of targets, making low doses potentially highly effective.

Covalent Bioscience is one of a handful of startups and young companies working on science funded in part by the SENS Research Foundation, the foundation for rejuvenation therapies based on repairing and reversing the fundamental cell and tissue damage that causes aging, such as the presence of amyloid. There are a now a number of serious investors and venture firms interested specifically in SENS strategies to treat aging, including figures such as Jim Mellon, Peter Thiel, Michael Greve, James Peyer, and so forth - far more than was the case just a few years ago. This is the time for SENS startup companies to flourish, and gain the funding needed to bring the first batch of rejuvenation therapies to the clinic.

We are a development stage company with intellectual property rights to novel therapeutic antibodies and chemically activated vaccines in all major markets. These rights have been developed from discoveries indicating the power of the immune system to use covalent bonding as the basis for synthesizing antibodies that neutralize and remove target antigens with efficacy and safety superior to conventional antibodies.

The two classes of therapeutic monoclonal antibodies (MAbs) being developed by Covalent, Inc are: (a) irreversible MAbs (iMAbs), which bind and neutralize the target antigen with virtually infinite affinity, (b) catalytic MAbs (cMAbs), which hydrolyze and destroy the target antigen in an enzyme-like manner. Covalent, Inc has proof-of-principle for superior efficacy and diminished side effects of the cMAbs/iMAbs compared to conventional MAbs that bind the target antigen reversibly. Covalent's cMAbs/iMAbs are isolated from the innate immune repertoire that has developed by Darwinian evolution, and immunization with Covalent's electrophilic antigen analogs induces the synthesis of the cMAbs/iMabs adaptively.

Covalent is in a position to generate cMAbs/iMAbs to diverse antigen targets for development as immunotherapies. In addition, Covalent is developing the electrophilic antigen analogs as therapeutic and prophylactic vaccine for unmet medical needs. Covalent has in hand: (a) candidate immunotherapeutic cMAbs to amyloid proteins for treating central nervous system and systemic amyloidosis, and (b) a candidate electrophilic vaccine for treating and preventing HIV infection.

Link: http://www.covalentbioscience.com/

As a companion piece to an earlier post on the relationship between the mechanistic target of rapamycin (mTOR) gene and cellular senescence in aging, you might take a look at the research here that investigates the relationship between mTOR and the characteristic decline in stem cell activity that occurs with advancing age. In addition to the large body of research focused on insulin and growth hormone metabolism, work on mTOR is among the most active areas of study resulting from investigations of calorie restriction. The practice of calorie restriction has been shown to slow aging in near all species and lineages studied to date, so insofar as the response to calorie restriction is partially mediated through mTOR, we should expect mTOR to have some connection to most of the causes of aging.

Unfortunately, calorie restriction has only a small effect on life span in our species. The research community doesn't yet know exactly how small, but it would be very surprising for it to be greater than five years or so. It would be hard for an effect much larger than that to remain hidden over the length of human history. The health effects are worth it in all other respects; calorie restriction greatly reduces the risk of age-related disease in our species, just as in others. Why are the effects on longevity so much less in humans than in mice? The response to calorie restriction most likely evolved because it grants a greater chance of survival through seasonal famine. The famine is the same length regardless of species, and thus short-lived species evolve under selection pressure to develop a proportionally greater extension of life span, while longer-lived species do not. The result is mice that live 40% longer if they eat less, and humans that do not.

Stem cells of many varied types are responsible for maintaining our tissues in good condition. Their activity declines with age, however, due to some combination of (a) intrinsic damage of the sort listed in the SENS view of aging, and (b) reactions to rising levels of damage elsewhere. It is thought that stem cells become less active with age because this acts to reduce the risk of cancer; the more cells that replicate, the greater the risk that one of those cells acquires mutations that lead to a tumor. That risk rises as the damage of aging grows, as the environment becomes more inflamed and dysfunctional, and the immune system, responsible for destroying potentially cancerous cells, falters. Our life span, longer than that of other primates, came to its present position by balancing the slow decline due to failing tissue maintenance against the fast end due to cancerous growth.

In calorie restricted individuals, the decline in stem cell activity tends to be a little bit slower. So if this effect is in part mediated by mTOR, what exactly is going on under the hood? It is a complex business, trying to reverse engineer the operation of metabolism. Even when it is possible to identify lynchpin genes, such as mTOR, it usually turns out that they are influential in dozens of important low-level cellular operations that can in turn slightly speed or slow the aging process in any number of ways. That just means it is challenging work, however. I think my greater objection to putting such a large focus on this way forward towards potential therapies to treat aging is that, based on what is known of calorie restriction, we shouldn't expect the results in mice to in any way translate to similarly sized results in humans. The effects should be analogous to one another, but in humans the size of those effects will be small.

Inhibiting TOR boosts regenerative potential of adult tissues

In most of our tissues, adult stem cells hang out in a quiet state - ready to be activated in case of infection or injury. In response to such injury, however, stem cells have to be able to rapidly divide, to generate daughter cells that differentiate into cells that repair the tissue. Previous research showed that TOR needs to be maintained at a low level in order to preserve stem cells in a quiet state and prevent their differentiation. But in this study, researchers discovered that TOR signaling becomes activated in many stem cell types when they are engaged in a regenerative response.

This activation is important for rapid tissue repair, but at the same time it also increases the probability that stem cells will differentiate, thus losing their stem cell status. This loss - in this case in the fly intestine, mouse muscle and mouse trachea - is particularly prevalent when the tissue is under heavy or chronic pressure to regenerate, which occurs in response to infections or other trauma to the tissue. During aging, repeated or chronic activation of TOR signaling contributes to the gradual loss of stem cells. Accordingly, by performing genetic or pharmacological interventions to limit TOR activity chronically, the researchers were able to prevent or reverse stem cell loss in tracheae and muscle of aging mice.

Mice were put on differing regimens of the mTOR inhibitor rapamycin starting at different stages of life. Rapamycin was able to rescue stem cells even when given to mice starting at 15 months of age - the human equivalent of 50 years of age. "In every case we saw a decline in the number of stem cells, and rapamycin would bring it back." Whether this recovery of tissue stem cell numbers is due to a replenishment of the stem cell pool from more differentiated cells, or due to an increase in "asymmetric" stem cell divisions that allow one stem cell to generate two new ones, remains to be answered.

mTORC1 Activation during Repeated Regeneration Impairs Somatic Stem Cell Maintenance

The balance between self-renewal and differentiation ensures long-term maintenance of stem cell (SC) pools in regenerating epithelial tissues. This balance is challenged during periods of high regenerative pressure and is often compromised in aged animals. Here, we show that target of rapamycin (TOR) signaling is a key regulator of SC loss during repeated regenerative episodes. In response to regenerative stimuli, SCs in the intestinal epithelium of the fly and in the tracheal epithelium of mice exhibit transient activation of TOR signaling.

Although this activation is required for SCs to rapidly proliferate in response to damage, repeated rounds of damage lead to SC loss. Consistently, age-related SC loss in the mouse trachea and in muscle can be prevented by pharmacologic or genetic inhibition, respectively, of mammalian target of rapamycin complex 1 (mTORC1) signaling. These findings highlight an evolutionarily conserved role of TOR signaling in SC function and identify repeated rounds of mTORC1 activation as a driver of age-related SC decline.

Now that the research community has finally woken up to the significance of cellular senescence in aging, a point long advocated for by the SENS Research Foundation and Methuselah Foundation, scientists are busily patching it in to their existing understanding and models of aging. This is just as true for studies of mechanistic target of rapamycin (mTOR) as elsewhere. This is one of the more popular areas of research to emerge from the study of calorie restriction, an intervention that slows aging in near all species tested to date. There is a sizable contingent of researchers interested in finding ways to mimic some fraction of the benefits of calorie restriction through therapies that target mTOR.

Since calorie restriction slows aging, albeit to a much larger degree in short-lived animals than in humans, it is generally agreed that it also slows the accumulation of senescent cells, one of the causes of aging. Thus to the degree that mTOR is involved in the calorie restriction response, we should also expect mTOR to be relevant in some ways to the harms done by cellular senescence: either reducing the number of cells that become senescent, or reducing the harm done by cells once they are senescent. Since we know that calorie restriction doesn't greatly extend life in humans (though it is very good for long term health), we should not expect these effects to be large. Certainly, senolytic therapies that clear out senescent cells should have a much greater positive impact on health and longevity.

The mechanistic target of rapamycin (mTOR) is an evolutionary conserved serine-threonine kinase that senses and integrates a diverse set of environmental and intracellular signals, such as growth factors and nutrients to direct cellular and organismal responses. The name TOR (target of rapamycin) is derived from its inhibitor rapamycin. We now know that the role of mTOR goes far beyond proliferation and coordinates a cell-tailored metabolic program to control cell growth and many biological processes including aging, cellular senescence, and lifespan.

Rapamycin is currently the only known pharmacological substance to prolong lifespan in all studied model organisms and the only one in mammals. Rapamycin was shown to extend the lifespan of genetically heterogeneous mice at three independent test locations by about 10-18% depending on sex. Interestingly, treatment was only started late when the mice were 600 days of age equivalent to roughly 60 years of age in a human person. This proposes that inhibition of mTOR in the elderly might be enough to prolong life. The findings were confirmed and extended in mice, in which rapamycin treatment started earlier. However, they failed to substantially observe larger effects on longevity.

It is now accepted that mTOR inhibition increases lifespan; yet, the mechanism through which this occurs is still uncertain. mTORC1 inhibition may not delay aging itself, but may delay age-related diseases. However, many researchers directly link the longevity effects of mTOR inhibitors to a decrease in aging. Conserved hallmarks of aging have recently been proposed and include telomere attrition, epigenetic alterations, genomic instability, loss of proteostasis, deregulated nutrient sensing, mitochondrial dysfunction, cellular senescence, stem cell exhaustion, and altered intercellular communication. The mTOR network is known to regulate some of these aging hallmarks. Ultimately, the prominence of mTORC1 signaling in aging likely reflects its exceptional capacity to regulate such a wide variety of key cellular functions.

Cellular senescence has been suggested to function as a tumor suppressor mechanism and promotor of tissue remodeling after wounding. However, senescent cells may also directly contribute to aging. Senescent cells show marked changes in morphology including an enlarged size, irregular cell shape, prominent and sometimes multiple nuclei, accumulation of mitochondrial and lysosomal mass, increased granularity and highly prominent stress fibers that are accompanied by shifts in metabolism and a failure of autophagy. Interestingly, many of these phenotypes are regulated by mTORC1 in various cell types. The secretion of proinflammatory mediators by senescent cells contributes to aging and has been termed senescence-associated secretory phenotype (SASP). Recent data identified a main role of mTORC1 to promote the SASP. Rapamycin blunts the proinflammatory phenotype of senescent cells by specifically suppressing translation of IL1A.

Despite maintaining a nondividing state, senescent cells display a high metabolic rate. Metabolic changes characteristic of replicative senescence often show a shift to glycolytic metabolism away from oxidative phosphorylation (which is also observed in proliferative cells), despite a marked increase in mitochondrial mass and markers of mitochondrial activity. This might stem from a rise in lysosomal pH as a consequence of proton pump failure, which leads to an inability to get rid of damaged organelles such as mitochondria caused by a failure of autophagy. Dysfunctional mitochondria not cleared by autophagy in senescent cells produce reactive oxygen species, which cause cellular damage including DNA damage. mTORC1 has been postulated as main driver of these metabolic changes. Hence, rapamycin treatment prevents metabolic stress and delays cellular senescence.

Link: https://doi.org/10.1159/000484629

Mitochondria, the power plants of the cell, suffer a general malaise in older individuals. Their dynamics change and their production of energy store molecules declines. This is distinct and separate from the damage to mitochondrial DNA outlined in the SENS vision for rejuvenation therapies, in that it occurs across all cells rather than in a small but significant number of cells. It is probably a secondary or later consequence of other forms of cell and tissue damage, an inappropriate reaction that makes things worse. This decline in mitochondrial function is implicated in neurodegenerative diseases; the brain requires a great deal of energy to function, and some portion of the changes and symptoms of cognitive decline are due to insufficient energy store production.

Researchers here make some inroads to putting numbers to that portion, at least in mice, but the challenge inherent in the use of animal models of Alzheimer's disease is that they are very artificial. Mice don't normally suffer from Alzheimer's, and their neural biochemistry must be altered significantly in order to produce any of the protein aggregates seen in Alzheimer's disease. The current models only recapture a slice of the full human condition, focusing on amyloid aggregation rather than the full biochemistry of the Alzheimer's. Thus there is always the question for any specific finding as to whether it will also apply to humans, or whether it is a quirk of the model, no matter how plausible the assumptions.

Alzheimer's disease is the most common form of dementia and neurodegeneration worldwide. A major hallmark of the disease is the accumulation of toxic plaques in the brain, formed by the abnormal aggregation of a protein called beta-amyloid inside neurons. Most treatments focus on reducing the formation of amyloid plaques, but these approaches have been inconclusive. As a result, scientists are now searching for alternative treatment strategies, one of which is to consider Alzheimer's as a metabolic disease.

Researchers looked at mitochondria, which are the energy-producing powerhouses of cells, and thus central in metabolism. Using worms and mice as models, they discovered that boosting mitochondria defenses against a particular form of protein stress, enables them to not only protect themselves, but to also reduce the formation of amyloid plaques. During normal aging and age-associated diseases such as Alzheimer's, cells face increasing damage and struggle to protect and replace dysfunctional mitochondria. Since mitochondria provide energy to brain cells, leaving them unprotected in Alzheimer's disease favors brain damage, giving rise to symptoms like memory loss over the years.

The scientists identified two mechanisms that control the quality of mitochondria: First, the "mitochondrial unfolded protein response" (UPRmt), which protects mitochondria from stress stimuli. Second, mitophagy, a process that recycles defective mitochondria. Both these mechanisms are the key to delaying or preventing excessive mitochondrial damage during disease. "These defense and recycle pathways of the mitochondria are essential in organisms, from the worm C. elegans all the way to humans. So we decided to pharmacologically activate them." The team started by testing well-established compounds that can turn on the UPRmt and mitophagy defense systems in a worm model (C. elegans) of Alzheimer's disease. The health, performance and lifespan of worms exposed to the drugs increased remarkably compared with untreated worms. Plaque formation was also significantly reduced in the treated animals.

Most significantly, the scientists observed similar improvements when they turned on the same mitochondrial defense pathways in cultured human neuronal cells, using the same drugs. The encouraging results led the researchers to test in a mouse model of Alzheimer's disease. Just like C. elegans, the mice saw a significant improvement of mitochondrial function and a reduction in the number of amyloid plaques. But most importantly, the scientists observed a striking normalization of the cognitive function in the mice.

Link: https://actu.epfl.ch/news/healthy-mitochondria-could-stop-alzheimer-s/

Blood pressure tends to increase with age, ultimately producing clinical hypertension in a sizable fraction of the population. This is driven by the progressive stiffening of blood vessels, which breaks the finely tuned feedback system that reacts to and controls blood pressure. Stiffening of blood vessels is in turn caused by factors such as calcification and inflammation resulting from cellular senescence, as well as cross-linking in the extracellular matrix that degrades tissue elasticity, and dysfunction of the muscle tissue that controls contraction and dilation of blood vessels. Control of blood pressure is considered highly important in modern medicine, and raised blood pressure is one of the most important factors determining risk of cardiovascular disease and mortality.

Given the justifiable focus on high blood pressure and its consequences, it is interesting to note that there is evidence for blood pressure in the population at large to peak and then drop in later life. As the paper here notes, the simple hypotheses for this phenomenon, such as that people with high blood pressure tend to die at a greater rate before reaching older ages, don't in fact explain enough of the phenomenon. My first guess at a mechanism was weight loss in later life due to frailty and pre-clinical levels of age-related disease, but that also doesn't seem to be enough to explain all of the effect.

A second guess might involve the effects of age-related muscle loss, sarcopenia, on the strength of the heart. This is something that doesn't appear to be all that well studied in older individuals without heart disease, and isn't commented on in the paper here. Unfortunately it isn't a straightforward relationship, given all of the ongoing changes in the cardiovascular system; older patients with either healthy hearts or hearts weakened by heart failure can exhibit higher blood pressure, lower blood pressure, or anything in between depending on their specific circumstances.

Blood Pressure Begins to Decline 14 Years Before Death, Study Says

Researchers looked at the electronic medical records of 46,634 British citizens who had died at age 60 or older. The large sample size included people who were healthy as well as those who had conditions such as heart disease or dementia. They found blood pressure declines were steepest in patients with dementia, heart failure, late-in-life weight loss, and those who had high blood pressure to begin with. But long-term declines also occurred without the presence of any of these diagnoses.

Doctors have long known that in the average person, blood pressure rises from childhood to middle age. But normal blood pressure in the elderly has been less certain. Some studies have indicated that blood pressure might drop in older patients and treatment for hypertension has been hypothesized as explaining late-life lower blood pressures. But this study found blood pressure declines were also present in those without hypertension diagnoses or anti-hypertension medication prescriptions. Further, the evidence was clear that the declines were not due simply to the early deaths of people with high blood pressure.

Blood Pressure Trajectories in the 20 Years Before Death

Both systolic blood pressure (SBP) and diastolic blood pressure (DBP) follow progressive upward trajectories from childhood to middle age, but blood pressure (BP) trends at older ages are unclear. Several studies reported flattening of the upward trend or a decrease in BP at advanced ages, although a few have reported continued BP increases. Blood pressure decreases in older age have been associated with poorer health, onset of dementia, and excess mortality. Hypothesized explanations for BP decreases in later life include (1) advancing age; (2) increasing end-of-life disease, especially heart failure, suggesting a link to the years before death rather than to age; (3) more intensive use of antihypertensive medications; or (4) that excess mortality of hypertensive individuals leaves healthy survivors with lower BP. Data to test these hypotheses are currently limited.

Observing individuals with multiple repeated BP measures over time could help clarify the causes underlying trends. If increasing end-of-life disease explains BP changes, then similar downward BP trajectories should not be observed in age- and sex-matched controls who die much later. In this study, we used the Clinical Practice Research Datalink (CPRD) to estimate clinically measured SBP and DBP trajectories for 20 years prior to death, for individuals dying at 60 years and older. Second, we compared the linear SBP trends for years 10 to 3 years before death in patients who died and age- and sex-matched controls who survived at least 9 years. These approaches aimed to separate age from end-of-life associations, and avoid healthy survivor biases.

Twenty years before death, estimated mean SBPs increased with increasing age at death (60-69 years, 139.5 mm Hg; ≥90 years, 150.0 mm Hg). All age-at-death groups initially experienced increasing SBP, reaching peak values and then declining with proximity to death. Peak SBPs occurred 14 years before death in those dying aged 60 to 69 years (mean peak SBP, 146.3 mm Hg) to 18 years before death for those dying aged at least 90 years (mean peak SBP, 150.8 mm Hg). Overall, 64.0% of individuals experienced SBP decrease of more than 10 mm Hg following the peak.

Antihypertensive medication was prescribed to 85.1% of patients for at least 1 year during the analysis period: mean SBP changed by -20.8 mm Hg from peak to year of death in those treated vs -11.2 mm Hg in those not treated. Peak SBP occurred at a mean of 15 years before death in the treated vs 14 years in those not treated. Adjustment for antihypertensive treatment made little difference to the main model results. Smoking status, alcohol consumption, and levels of physical activity measured in the 20 years prior to death had little association with SBP decreases. Weight loss (the difference between the maximum weight during the first 10 years of follow-up and weight in the final year) findings showed that patients losing at least 20 kg experienced a bigger absolute SBP decrease (mean, -24.87 mm Hg) compared with those who did not lose weight.

More work is needed to elucidate the specific mechanisms involved in late-life BP dynamics. Such studies may also be useful in addressing ways of optimizing the clinical care of older patients who experience decreasing BP. Also, downward BP trajectories before death have the potential to introduce reverse causation or "reverse epidemiology" effects in risk analyses, yielding misleading associations between BP and outcomes in older patients.

The gene ANGPTL2 is starting to look like an interesting basis for therapy, something to bump closer to the top of the lengthy list of targets to consider for first generation human gene therapies. In animal studies, lowering the level of protein produced by this gene has been shown to reduce chronic inflammation in older individuals and slow progression towards heart failure. These effects might be mediated through the presence of senescent cells in the cardiovascular system, in that it is these cells that are the primary producers of ANGPTL2. One of the most easily measured consequences of the growing numbers of senescent cells in older tissues is a higher level of inflammation.

Here researchers show that loss of ANGPTL2 can slow the age-related decline in muscle mass that takes place in later life, a condition known as sarcopenia. They also consider cellular senescence to be a plausible mediating mechanism for the detrimental effects of ANGPTL2 when it is present, and certainly there is plenty of evidence to link sarcopenia with chronic inflammation. Raised levels of inflammation and other activities of senescent cells derail the normal processes of tissue maintenance. If this is the case, and ANGPTL2 does cause harm due to increased levels of cellular senescence or increased activity of senescent cells, then senolytic therapies that destroy senescent cells should capture all of the benefits of reduced levels of ANGPTL2, rendering gene therapy approaches redundant in this case. That is a proposition that could be tested in mice now, given the present state of the field.

Sarcopenia is defined as age-related loss of skeletal muscle mass and strength, a condition that worsens subjects' quality of life. Clarification of molecular mechanisms underlying sarcopenia development is important to devise effective approaches to treat this condition. Several lines of evidence support the idea that in skeletal muscle chronic inflammation and reactive oxygen species (ROS) accumulation due to redox imbalance contribute to sarcopenia development, and chronic inflammation in aging skeletal muscle is positively correlated with sarcopenia development in humans and mice.

The pro-inflammatory cytokines interleukin-6 (IL-6) and interleukin-1β (IL-1β) both decrease skeletal muscle mass by causing inflammation and subsequently facilitating muscle proteolysis, ROS accumulation, and growth hormone resistance. Moreover, excess ROS accumulation causes oxidative damage to skeletal muscles, resulting in myofibers loss. Both inflammation and ROS accumulation inactivate "satellite cells", the precursors of skeletal muscle cells, thereby accelerating sarcopenia development.

Previous studies reveal that expression and secretion of angiopoietin-like 2 (ANGPTL2) significantly increase in cells stressed by pathophysiological stimuli, such as hypoxia and senescence-associated secretory phenotype (SASP) factor. Moreover, excess ANGPTL2 signaling is pro-inflammatory in pathological states and contributes to development of aging-associated diseases.

Although ANGPTL2 hyperactivation is associated with age-related diseases, ANGPTL2 function in sarcopenia development remains unknown. Here, we investigated the roles of ANGPTL2 in sarcopenia development using aging mice. We report that ANGPTL2 expression increases in skeletal myocytes of aging mice and that running exercise decreases that expression, suggesting that excess ANGPTL2 signaling in aged skeletal muscular myofibers accelerates sarcopenia development. Moreover, ANGPTL2 deficient mice showed attenuated loss of skeletal muscle by reduced muscular inflammation and ROS accumulation and increased satellite cell activity. To the best of our knowledge, this is the first report showing that ANGPTL2 signaling may accelerate sarcopenia pathologies.

Link: https://doi.org/10.1074/jbc.M117.814996

Researchers can create functional organ tissue in small quantities, building few-millimeter-sized structures known as organoids. Yet because there is still no reliable approach to the creation of the capillary networks required to support thick tissue sections, this cannot yet scale up to the production of full-size replacement organs. That may not be a roadblock for organs such as the liver and kidney, which are responsible for what are essentially chemical manufacture and filtration tasks; in this case the large-scale structure of the organ isn't as important as the small-scale structure, and much of the organ might be thought of as countless tiny factories operating independently in response to circumstances. The arrangement of those factories can vary.

Thus it should be possible to rescue a failing liver or kidney by transplanting scores or hundreds of functional organoids grown from the patient's own cells. The organoids will integrate with the existing tissue, and blood vessel networks will growth into and through them - that much has been demonstrated in animal studies for single organoids in a number of different organs. The only challenge standing in the way of this vision for the near future is the cost and time required to create organoids, a process that has yet to be scaled up for mass manufacture.

Researchers report creating a biologically accurate mass-production platform that overcomes major barriers to bioengineering human liver tissues suitable for therapeutic transplant into people. The new process allows researchers to bioengineer single batches of up to 20,000 genetically matched, three-dimensional and highly functional liver micro-buds. When combined, the batch has a sufficient quantity of liver cells and size feasibility for transplant into a person with liver failure, or for drug testing. The liver tissues were also generated entirely from human induced pluripotent stem cells (iPSCs), making the process free of animal feeder byproducts used to make cells for research purposes - a barrier to the cells being used therapeutically.

"Because we can now overcome these obstacles to generate highly functional, three-dimensional liver buds, our production process comes very close to complying with clinical-grade standards. The ability to do this will eventually allow us to help many people with final-stage liver disease." The researchers stress continued research and refinement of their process is required before initial clinical trials could begin, and estimate this might occur in the next two to five years.

Over the past five years the reseearch published several studies that made continuous progress into defining the precise genetic and molecular blueprints needed to mimic natural human development. This allows the researchers to develop and bioengineer functional, three-dimensional human mini livers in the laboratory. To help overcome the biological challenge of animal-product feeder cells in the current study, the team used their fine-tuned formula of genetic and molecular components to generate the liver tissues in custom-designed, U-shaped bottom micro-well cell plates. The plates use a combination of chemistry techniques to form a finely structured film inside the micro-wells, designed to nurture the developing liver buds.

But prior to this step, the researchers started mass production by initially using the donor-derived iPSCs to grow three critical types of liver progenitor cells needed to generate healthy livers. These include hepatic endoderm cells and both endothelial and septum mesenchyme cells. Study data show this generates robust and highly functional progenitor cells that are placed into the custom-designed, film-coated micro-wells. The progenitor cells then engage in high levels of molecular cross-communication to form into self-organizing, three-dimensional liver buds.

Link: https://www.cincinnatichildrens.org/news/release/2017/bioengineered-livers

The Life Extension Advocacy Foundation folk have put together a compact summary of some of the progress towards SENS rejuvenation therapies that has taken place in recent years. These treatments, some existing in prototype forms, and some yet to be constructed, are based on repair of the forms of cell and tissue damage known to cause aging. It is a good article to show to a friend who has expressed interest in greater human longevity, or to mine for talking points to use when you next bring up the topic with those unfamiliar with the current state of the science. You might also compare it with my bullet point list of the high points in SENS advocacy, research, and fundraising over the past fifteen years.

Efforts to explain the history and progress to date of SENS rejuvenation research are useful and necessary. The SENS Research Foundation does a good job in summarizing the causes of aging and the research programs that will tackle each cause. The staff also do a good job in listing and explaining the work they carry out year by year, funded by philanthropic donations, in their annual reports. They don't however, tend to publish much that links all of the stories together, to show the scope of progress over the lifetime of the SENS programs, and the positive changes that SENS researchers and advocates have created in the culture of aging research. Fortunately, we can do that, and I think that we must do that: this is some of the most convincing evidence to show that it is all worth it, that the wheel is turning, and that we are much further ahead than we were a decade ago.

Science moves very slowly. It usually takes years for the results of fundraisers and advocacy to bear fruit, and so in this age of instant gratification, it is necessary to show those who are new to SENS that this isn't just another flash in the pan - that present efforts are part of a long upward curve towards the technologies of human longevity, and that past efforts have resulted in success. The dots have to be joined to show that the radical change in the attitudes of the research community with respect to treating aging as a medical condition didn't just happen on its own, that young companies advancing potential rejuvenation biotechnologies didn't just materialize out of nothing. A great deal of work went into these changes, both inside and outside the laboratory, and a sizable fraction of that work was carried out by the SENS Research Foundation and allies such as the Methuselah Foundation.

SENS Research: Progress in the Fight Against Age-related Diseases

Today, there are many drugs and therapies that we take for granted. However, we should not forget that what is common and easily accessible today didn't just magically appear out of thin air; rather, at some point, it used to be an unclear subject of study on which "more research was needed", and even earlier, it was just a conjecture in some researcher's head. Hopefully, one day not too far into the future, rejuvenation biotechnologies will be normal and widespread as aspirin is today, but right now, we're in the R&D phase, so we should be patient and remind ourselves that the fact we can't rejuvenate people today doesn't mean nothing is being done or that nothing has been achieved to that end. On the contrary, we are witnessing exciting progress in basic research - the fundamental building blocks without which rejuvenation, or any new technology at all, would stay a conjecture.

A mitochondrion is a component of the cell in charge of converting food nutrients into ATP, a chemical that powers cellular function. Each mitochondrion is equipped with its own DNA. Mitochondria with damaged DNA may become unable to produce ATP or even produce large amounts of waste that cells cannot get rid of. To add insult to injury, mutant mitochondria have a tendency to outlive normal ones and take over the cells they reside in, turning them into waste production facilities that increase oxidative stress - one of the driving factors of aging.

Cell nuclei are far less exposed to oxidative stress than mitochondria, which makes nuclear DNA less susceptible to mutations. For this reason, the cell nucleus would be a much better place for mitochondrial genes, and in fact, evolution has driven around 1000 of them there. Through a technique called allotopic expression, we could migrate the remaining genes to the nucleus and solve the problem of mitochondrial mutations. The SENS Research Foundation (SRF) team managed to achieve stable allotopic expression of two mitochondrial genes in cell culture. As Aubrey de Grey explains, of the 13 genes SRF is focusing on, it's now managed to migrate almost four. This had never been done before and is a huge step towards addressing this aspect of aging in humans. In the past few months, the SRF team has presented its results around the world and worked on some problems encountered in the project.

Lysosomes are digestive organelles within cells that dispose of intracellular garbage - harmful byproducts that would otherwise harm cells. Enzymes within lysosomes can dispose of most of the waste that normally accumulates within cells, but some types of waste, collectively known as lipofuscin, turn out to be impossible to break down. As a result, this waste accumulates within the lysosomes, eventually making it harder for them to degrade even other types of waste.

As normal lysosomal enzymes cannot break down lipofuscin, a possible therapy could equip lysosomes with better enzymes that can do the job. The approach suggested by SRF originates with ERT - enzyme replacement therapy - for lysosomal storage diseases. This involves identifying enzymes capable of breaking down different types of intracellular junk, identifying genes that encode for these enzymes, and finally delivering the enzyme in different ways, depending on the tissues and cell types involved.

SRF funded a preliminary research project on lipofuscin clearance therapeutics and another project relating to atherosclerosis and the clearance of 7-ketocholesterol (found in lipofuscin), which eventually spun into human.bio, an early-stage private startup. Another SRF-based approach is currently being pursued by Ichor Therapeutics, where the staff are working on an ERT treatment for age-related macular degeneration. The treatment consists of providing an enzyme capable of breaking down a type of intracellular waste known as A2E. The company earlier this year announced a series A offering to start Phase I clinical trials of its product.

As cells divide, their telomeres - the end-parts of chromosomes protecting them from damage - shorten. Once a critical length has been reached, cells stop dividing altogether and enter a state known as senescence. Senescent cells are known to secrete a cocktail of chemicals called SASP (Senescence Associated Secretory Phenotype), which promotes inflammation and is associated with several age-related conditions. Normally, senescent cells destroy themselves, but some of them manage to escape destruction. The result is that late in life, senescent cells have accumulated to unhealthy amounts and significantly contribute to the development of age-related diseases.

The proposed SENS solution is straightforward: if senescent cells become too numerous, then they need to be purged. Since they are useful in small amounts, the optimal solution would be periodically removing excess senescent cells. This could potentially be achieved by either senolytic drugs or gene therapies that selectively target senescent cells. SRF has funded a number of studies on the subject of cellular senescence, and it's recently begun working on a project in collaboration with the Buck Institute for Research on Aging, which is focusing on the immune system and its role in clearing senescent cells. Another extramural project, again with the Buck Institute, is focused on SASP inhibition. Further, in conjunction with Methuselah Foundation, SRF provided seed funding for Oisin Biotechnologies, a company working on a gene therapy approach to destroying senescent cells.

The extracellular matrix is a collection of proteins that act as scaffolding for the cells in our body. The component parts of this scaffolding eventually end up being improperly linked to each other through a process called glycation. The resulting cross-links impair the function and movement of the linked proteins, ultimately stiffening the extracellular matrix, which makes organs and blood vessels more rigid. Eventually, this leads to high blood pressure, loss of skin elasticity, and organ damage, among other problems.

In order to eliminate unwanted cross-links, the SENS approach proposes to develop molecules that sever the linkages and return tissues to their original flexibility. In order to do this, cross-link molecules need to be available to researchers attempting to combat them with drugs, and especially in the case of glucosepane, this has been a problem for years. The lack of tools to work with glucosepane has been greatly hampering the progress of cross-link breaking research, but thankfully, this problem is now solved thanks to a collaboration between the Spiegel Lab at Yale University and the SENS Research Foundation, which supported the study financially. It is now possible to fully synthesize glucosepane, allowing for researchers to create it on demand and at a cost-effective price. The Spiegel Lab's scientists are now developing anti-glucosepane monoclonal antibodies to cleave unwanted cross-links.

Researchers have identified adrenomedullin as a contributing factor in age-related memory loss in mice, and in the open access paper here note that levels of adrenomedullin increase with age in humans as well. This research is a fair distance from a rigorous proof of the relevance of adrenomedullin to human memory loss, but it is nonetheless quite interesting. The observed correlations suggest that the important connection is between adrenomedullin and the aggregated tau protein that gives rise to tauopathies, and consequently that tau is influential in the lesser degree of mental decline with age that occurs in people without full-blown neurodegenerative conditions. Aggregation of altered tau protein is a fairly fundamental form of age-related damage, something that occurs as a side-effect of the normal operation of metabolism, so it might be expected to contribute to declining function in proportion to its presence.

Memory loss is a common characteristic of normal aging, and is greatly accelerated in some neurodegenerative diseases. The causes of memory loss during normal aging are not completely understood. Atrophy of some brain areas has been shown in normal aging and changes in intrinsic neural electrical excitability associated with oxidative stress have been hypothesized as potential causes. Subtle perturbations in stabilization of neuronal cytoskeleton, reminiscent of those occurring during Alzheimer's disease (AD) neurodegeneration, may also be an important underlying cause of age-associated neuronal dysfunction and cognitive decline. In this line, modifications of tau expression and status akin to those of tauopathies are also typical of normal aging and their distribution pattern correlates with memory capabilities.

In the search for predictive blood biomarkers of AD cognitive decline, some studies have found that mid-regional proadrenomedullin is elevated in the plasma of AD patients and that the concentration of this peptide could have predictive value in the progression from predementia to clinical AD, although a recent study found no correlation. The proadrenomedullin gene, adm, generates two biologically active peptides: proadrenomedullin N-terminal 20 peptide (PAMP) and adrenomedullin (AM).

Expression of these peptides is widespread and several functions have been ascribed to them, including vasodilatation, bronchodilatation, angiogenesis, hormone secretion regulation, growth modulation and antimicrobial activities, among others. In the central nervous system (CNS), AM is expressed throughout the whole brain and spinal cord where it acts as a neuromodulator. It has been shown that plasma levels of AM increase with normal aging.

Knockout studies have shown that total abrogation of adm results in embryo lethality. To circumvent this problem, we generated a conditional knockout model where adm was eliminated just from neurons. Consequently, we have shown that aged mice that lack neuronal AM have better contextual and recognition memory than their wild type littermates. In parallel, the brain cortex and hippocampus of these mice have a lower accumulation of phosphorylated tau, suggesting that tau may be the link between lack of AM and memory preservation, although we cannot rule out other alternative molecular pathways. In addition, we also showed that older human individuals present higher levels of AM and lower levels of acetylated tubulin in their brains than younger controls.

Our data suggest that reducing AM/PAMP levels may constitute a novel path to preventing or delaying memory loss. A few years ago, a particular single nucleotide polymorphism (SNP) close to the adm gene was found to be responsible for a natural reduction in the circulating levels of AM and to correlate with cancer susceptibility. Therefore, it would be interesting to test whether carriers of this SNP are more protected from developing memory impairment. Also, several physiological inhibitors of AM have been proposed for clinical development, and some of these inhibitors may be used for the pharmacological prevention of age-related memory loss.

Link: https://doi.org/10.3389/fnmol.2017.00384

As a companion piece to a recent sizable study on weight and risk of age-related disease, here is another set of data to suggest that the existing consensus on the harms done by excess visceral fat tissue are, if anything, an underestimate. There is a large body of research that covers the many mechanisms by which the visceral fat packed around internal organs causes damage, such as through inflammation and immune dysfunction, the presence of raised numbers of senescent cells, the metabolic disarray that leads to diabetes, and so forth. Collectively it is a lengthy cautionary tale for those living far enough along the upward curve of technological progress to have reliable access to cheap calories, but not far enough to have reliable technological means to prevent the consequences of consuming those calories.

The harmful effects of being overweight have been underestimated, according to a new study. Previous studies have suggested that the optimum body mass index (BMI), at which the risk of death is minimised, appears to be above the range normally recommended by doctors, leading to claims it is good for health to be mildly overweight. However, scientists suspect these studies do not reflect the true effect of BMI on health, because early stages of illness, health-damaging behaviours, such as cigarette smoking, and other factors can lead to both lower BMI and increased risk of death. This makes it difficult to estimate how BMI actually influences risk of death (the causal effect), as opposed to the observed association between BMI and risk of death. This aim of this study was to assess the causal link between BMI and risk of death.

Using HUNT, a Norwegian population-based health cohort study based in a rural county with 130,000 residents, researchers were able to see how mortality in the parents related to both their own BMI (the conventional approach) and to the BMI of their adult children. Because BMI of parents and their offspring is related, due to genetic factors, offspring BMI is an indicator of the BMI of the parents. The BMI of adult children is not influenced by illness among the parents, therefore using offspring BMI avoids the problems inherent in simply relating the BMI of the parents to their risk of death.

The health records of around 30,000 mother and child pairs and 30,000 father and child pairs were assessed to examine the extent to which BMI may influence mortality risk in a situation that is not biased by "reverse causation" - illness leading to low BMI rather than BMI influencing illness. The team found that when offspring BMI was used instead of the parent's own BMI, the apparent harmful effects of low BMI were reduced and the harmful effects of high BMI were greater than those found in the conventional analyses. Importantly, the results suggest that previous studies have underestimated the harmful effects of being overweight. The current advice from doctors to maintain a BMI of between 18.5 and 25 is supported by this study, and the widely reported suggestion that being overweight may be healthy is shown to be incorrect.

Link: https://www.eurekalert.org/pub_releases/2017-12/uob-heo120117.php

Aubrey de Grey of the SENS Research Foundation will be answering your questions in the /r/futurology subreddit later this week, on Thursday December 7th 2017 at 2PM PST / 10PM GMT. There is a stickied post up now to collect questions in advance for the Ask Me Anything (AMA) post that will go up on Thursday, largely as a service for those who might not be able to be online at the time. For this audience, de Grey needs little introduction - he has spent the last fifteen years energetically pushing the research community into paying greater attention to the most plausible, high-value lines of development likely to result in rejuvenation therapies. It is hard to overstate just how influential de Grey and his allies have been in changing the culture of the research community over this time, and in raising the odds of functional rejuvenation therapies coming to pass soon enough to matter to you and I.

So, if you have things you'd like to know regarding the progress of the past couple of years, and the ventures being lined up for the next couple of years, then this is your chance. As matters are moving into the realm of startup companies and other for-profit development in a number of areas relevant to SENS rejuvenation research, the current state of progress can become harder to follow. Biotech startups tend to be much less noisy about their work in comparison to research groups, at least for the first few years, something that is typically forced upon them by regulatory concerns.

On the topic of the work of the de Grey and the SENS Research Foundation, I thought I'd point out a couple of items published online recently. The first detail-free article results from one of de Grey's numerous conference appearances, this one being the latest Virtual Futures event, and demonstrates that the logical consequences of functional rejuvenation technologies continue to make an attractive lure for the publicity industry. If the research and medical communities can move at a sufficient pace in improving the outcome of rejuvenation therapies over time, then even if the first rejuvenation therapies are comparatively poor, the end result is people who live in good health for a very, very long time. The second item is an extended version of the article by de Grey published at the MIT Technology Review recently, and is worth reading even if you're quite familiar with the SENS vision for rejuvenation through repair of cell and tissue damage.

Why This Aging Expert Thinks First 1,000-Year-Old Person is Already Alive

Through his foundation, de Grey is working to solve seven types of aging damage that he believes are the key to a breakthrough. These are tissue atrophy, cancerous cells, mitochondrial mutations, death-resistant cells, extracellular matrix stiffening, extracellular aggregates, and intracellular aggregates. It may sound like a complex salad of jargon, but de Grey claims that because science has an understanding of how to fix all these damages, aging can end for good. "It unequivocally causes far more suffering than anything else that we have to experience, and contrary to the impression that most of humanity has forced itself into, it's indeed a problem which is amenable through technological intervention."

In the future, de Grey imagines humans will develop rejuvenation clinics to regularly combat these seven issues and send people on their way. These clinics may stay in the realm of the super-rich for a short time, but de Grey believes that a movement will very quickly form to bring these technologies to the general public. "It will become impossible to get elected unless you have a manifesto commitment to have a real war on ageing. Not only in getting the therapy developed as quickly as possible, but also putting in place the infrastructure."

Undoing Aging with Molecular and Cellular Damage Repair

The goal of bringing aging under comprehensive medical control is probably humanity's oldest dream - and it is certainly humanity's foremost problem today. However, our progress toward it is lamentably slight. The history of our attempts to control aging can be summarized as a sequence of mis-steps: of misguided approaches that never had a chance of succeeding. They can each be summarized in a single word: disease, design, and deprivation. And the worst of it is that they have not even been sequential: the earlier ones have survived the arrival of the later ones.

The "aging as disease" false dawn, otherwise known as geriatric medicine, rests on the assumption that the diseases of old age are inherently amenable to the same kind of medical assault as the most prevalent diseases of youth, that is, infections. They are not. The "aging as design" false dawn emerged a century or so ago with the proposal that aging serves an evolutionary purpose. It gave rise in the early twentieth century to an approach that relies upon the idea that the genes determining the variation between species are rather few in number, and thus that it is realistic to seek to tweak those of a given species (such as Homo sapiens) so as to extend its healthy lifespan. Does the "aging as design" basis for the pursuit of medical postponement of age-related ill health actually make sense? Is it even remotely compatible with what we know about aging? Again, the painfully obvious answer is no. And yet, just as with geriatric medicine, faith in the existence of some elusive "magic bullet" has persisted in the minds of a depressing number of biologists.

By the third false dawn of "deprivation" I refer, as I hope you have guessed, to calorie restriction (CR), an intervention that was shown as early as the 1930s to extend the lives of mice and rats by as much as fifty percent. To this day, biomedical gerontology research is hugely dominated by the quest for better ways to emulate the effect of calorie restriction by genetic - or, more recently, pharmacological - means. Why is this a third false dawn? Because its true biomedical potential is, and has long been, obviously almost nil. The performance of CR itself varies inversely with the non-CR longevity of the species: longer-lived species derive much less benefit as a proportion of their lifespan, and in fact not much more benefit in absolute time. This should have been expected, since the selective pressure giving rise to the pathways that mediate the response to CR arises from the frequency of famines, which is independent of the lifespan of the organisms experiencing those famines.

But this century, step by painfully small step, things are changing. I first introduced the rejuvenation biotechnology approach to combating aging called SENS, the "Strategies for Engineered Negligible Senescence", about fifteen years ago. Since first proposed in 2002, marked progress has been made in every relevant area of research. SENS is a hugely radical departure from prior themes of biomedical gerontology, involving the bona fide reversal of aging rather than its mere retardation. By virtue of a painstaking process of mutual education between the fields of biogerontology and regenerative medicine, it has now risen to the status of an acknowledged viable option for the eventual medical control of aging. I believe that its credibility will continue to rise as the underlying technology of regenerative medicine progresses.

The coming era of gene therapies will be considerably more distributed and bottom-up than the advent of stem cell therapies. This will be a dynamic industry in which many small groups compete to set up distribution of mail order kits and clinics to provide widespread access to therapies. Regulators will attempt to suppress all of this, and will largely fail, as money talks and many regions will choose to host the businesses that offer gene therapies. This will come to pass because gene therapy technologies are many times cheaper, more easily managed, and capable of centralization and mass production than stem cell technologies. You might look at how medical tourism for stem cells progressed over the past twenty years, and expect the gene therapy industry to grow many times faster once the spark is lit. It will also be far more accessible to members of the public in its earlier stages: cost of the product drives the character of an industry.

There are several very promising targets for the first gene therapies, the best of which, in my opinion, are follistatin and myostatin, which control muscle growth, and are well studied. There are even a few natural human myostatin mutants, to accompany the many well-muscled myostatin mutants in other mammalian species, both natural and engineered. A number of other genes will be targeted in the first years of the industry, such as those that can dramatically lower blood cholesterol, and which also either have thriving human mutants or are already targeted by drug-based therapies. The only thing holding back an explosion of activity is the fact that current methodologies, even those based on CRISPR, are not yet up to scratch. They don't reliably introduce the therapy into a large enough number of cells in adults, and particularly into stem cells in order to make it truly lasting. When that changes, we'll all be in for an interesting ride.

Two companies say they'll continue offering DNA-altering materials to the public. The companies, The Odin and Ascendance Biomedical, both recently posted videos online of people self-administering DNA molecules their labs had produced. Following wide distribution of the videos, the FDA last week issued a harshly worded statement cautioning consumers against DIY gene-therapy kits and calling their sale illegal. A growing number of cases of DIY gene therapy are putting the health regulator in a difficult situation as individuals argue that no law stops them from self-administering the substances. In fact, there is a long history of scientists carrying out experiments on themselves, including some Nobel Prize winners. Last month, Josiah Zayner, CEO of The Odin, which sells DIY biology kits and supplies through its website, posted a video in which he injected himself with the gene-editing tool CRISPR during a biohacker conference.

The problem facing regulators is that interest in biohacking is spreading, and it's increasingly easy for anyone to obtain DNA over the internet. It's also easy to get hold of the recipes necessary to carry out gene editing using CRISPR, a potent new technique for modifying DNA. In October, Zayner's website began selling $20 copies of a DNA molecule containing the necessary genetic information to deactivate the human gene for a certain protein, myostatin, using CRISPR. Human DNA can be purchased through a number of other companies that cater to research labs. The difference is The Odin markets its DNA to amateur biologists. The materials sold by The Odin also can't be directly used to alter a person's genes. Instead, they contain DNA that would have to be produced in larger amounts, purified, and then delivered to the body using methods well beyond the skills of most consumers.

At least one other company appears to have begun offering finished gene-therapy preparations directly to patients for their own use. In October, an HIV patient was filmed injecting himself with a gene therapy designed to generate antibodies that he believed would help his body destroy cells infected with the virus. The material he used was supplied by Ascendance Biomedical, an until recently unknown startup company that promotes "decentralized" testing of new drugs. The company is also developing a herpes vaccine, as well as a follistatin gene therapy to boost muscle mass and reduce fat. Aaron Traywick, the CEO of Ascendance, says Ascendance plans to make both of those therapies available for self-administration by early next year.

Link: https://www.technologyreview.com/s/609568/biohackers-disregard-fda-warning-on-diy-gene-therapy/

George Church is one of the more noteworthy business-oriented scientists whose work touches on aging and longevity science. He is involved in a number of different companies, and while his primary focus is genetics, his interests include tissue engineering, farming engineered pigs for xenotransplantation, and a range of other items. Just about everyone of note in the scientific community has a different view on aging: the theory, the plausibility of various endeavors, and how best to go about tackling it as a medical challenge. This interview illuminates a little more of Church's viewpoint, which is, as one might expect, quite focused on using gene therapies as the primary tool for delivery of therapeutic effects. In principle, though not yet in reality, a gene therapy can do everything a drug can, more effectively and more accurately. There is a little way to go yet in generating the necessary methodologies and a reliable technology platform, probably built atop CRISPR.

Is there an accepted causal or ultimate theory of aging? There are hypotheses and different schools of thought. It's not so mature that there's total consensus. There are relatively few exciting fields of biology where there's total consensus. In aging, there's a school of thought that it's all about damage and you have to repair that damage. There's another school it's all about regulation and epigenetics, and if you get the cell in the right epigenetic state then it can repair its own damage; a young cell is much more powerful at repair than an old cell.

Then there's hallmarks of aging - about nine components - and maybe you have to get all of them pushed back for rejuvenation. I like this version where they talk about specific biological mechanisms. If you fight or leverage those mechanisms you get your best shot at treating aging. Why we age is less useful than the mechanisms, but having some intuition for why the mechanisms are the way they are can help you manipulate them. And very often you want to manipulate them in an unnatural way, and that requires a deeper understanding. If you're trying to do something totally natural your protocol is clear. If you find that in the western world we're eating a lot of marbled cow that didn't exist in the ancient days, all you have to do is get rid of the marbled cow and you're all set. On the other hand if you're trying to get people to live past 150, there's no precedent for that.

Certainly if you could fix all nine hallmarks at once that would do well to solve aging. Reversal of aging has been demonstrated in simple animals. Some people will dismiss those as too simple - because they have such a short life already, it's not surprising you can make them live longer. But I think it's quite clear that aging is programmed in some sense. It's not like you've been programmed to die at some age, but the laziness of evolution has resulted in your program to not avoid dying. Over evolutionary time, to use analogy, it was not cost effective to invest a lot of your precious food to live longer because you're going to get eaten by a wolf anyway.

To address the hallmarks of aging, the idea is to take the subset of genes that has been demonstrated to work for longevity or aging reversal in smaller organisms and reconfigure them into something that's usable in gene therapy. You change it from longevity that requires introducing it into the germ line, which is not really a good strategy for humans because most of us that want longevity are already past the zygote stage, and we're reconfiguring it as a adeno-associated virus gene therapy.

How far off is age reversal? The simple answer is, I don't know. Probably we'll see the first dog trials in the next year or two. If that works, human trials are another two years away, and eight years before they're done. Once you get a few going and succeeding it's a positive feedback loop. The FDA doesn't need to classify aging as a disease in order to treat it. If you actually have something that causes aging reversal, they'll approve it. You'll frame it in conventional terms, but it can have additional benefits. In other words If you have something that fixes one disease problem and happens to fix a bunch of others, you don't need to put them all on the label. The FDA doesn't stop you for using things off label or curing two things at once.

Link: https://endpoints.elysiumhealth.com/george-church-profile-4f3a8920cf7g-4f3a8920cf7f

This is another in a series of posts in which I think out loud about how to organize and conduct a useful short self-experimentation or single person informal trial of an alleged rejuvenation therapy. The focus is on senolytic drug candidates, because those are the only potential rejuvenation therapies worthy of the name that are currently accessible to ordinary individuals such as you and I. The general points made here are applicable to any other novel therapy that might arise in the years ahead, however - and arise they will - as well as to assessment of personal fitness, should that topic interest you. You might look at the last post in the series for a general outline of how such a study would be planned at the high level.

The usual cautions apply in these matters. There is risk in using senolytic drug candidates: they are chemotherapeutics, and one should well understand their profile of side-effects and hazards - which means, at a minimum, reading through a fair few scientific papers and reports. Further, just about everything to do with taking matters into your own hands with any sort of pharmaceutical is illegal in the US, even those that are not controlled substances, albeit rarely prosecuted when it is a matter of individual use. "Rarely" is not "never," however, and the prevailing cultural zeitgeist is that you are a terrible human being for even trying this, regardless of circumstance. This is a sad state of affairs, especially for those who are dying, priced out of the US market but not the global market for specific pharmaceuticals, and nonetheless forbidden to make the attempt to help themselves.

Here, however, I will say little about senolytics, and instead offer a first take on a practical list of tests that might be used to assess whether or not anything happened as a result of self-experimentation in rejuvenation treatments. This is the essence of the thing: there is no point in trying a treatment and merely hoping for the best. That adds no value, and helps no-one. A world in which hundreds or thousands of people are trying an approach and publishing their own measurements is a different story, however. Should it come to pass, that will go along way towards helping to push more formal trials into progress, by identifying promising directions that might otherwise take some time to be discovered by the slow and formal trial process.

A Short List of Simple Tests

For a first venture, it helps to keep things simple and flexible. The objective is a set of tests that anyone can run without the need to involve a physician, as that always adds significant time and expense. Since we are really only interested in the identification of large and reliable effects as the result of an intervention, we can plausibly expect a collection of cheaper and easier measures known to correlate with age to be useful in this matter. Once that hill has been climbed, then decide whether or not to go further. Don't bite off more than is easy to chew for a first outing. I picked the following:

• A standard blood test, with inflammatory markers.
• Resting heart rate and blood pressure.
• Heart rate variability.
• Pulse wave velocity.
• Biological age assessment via DNA methylation patterns.

The cardiovascular health measures in that list are those that are impacted by changes in the elasticity or functional capacity of blood vessels, such as would be expected to occur to some degree following any rejuvenation therapy that addresses senescent cells, chronic inflammation, or other factors that stiffen blood vessels, such as calcification or cross-linking. Positive change of the average values in most of these metrics are achievable with significant time and effort spent in physical training, so movement in the numbers in a short period of time as the result of a treatment should be an interesting data point.

Bloodwork

There are online services such as WellnessFX where one can order up a blood test and then head off the next day to have it carried out by one of the widely available clinical service companies. Of the set of test packages offered by WellnessFX, the Advanced Heart Health is probably the most useful for present purposes. But shop around; this isn't the only provider.

Resting Heart Rate and Blood Pressure

A simple but reliable tool such as the Omron 10 is all you need to measure heart rate and blood pressure. It is worth noting here a couple of general principles for cardiovascular measures. Firstly, the further away from the center of the body that the measurement is taken, the less reliable it is - the more influenced by any number of circumstances, such as position, mood, stress, time of day, and so forth. Fingertip devices are convenient, but nowhere near as useful as something like the Omron 10 that uses pressure on the upper arm. Secondly, all of the above-mentioned line items also influence every cardiovascular measure, so when you are creating a baseline or measuring changes against that baseline, carry out each measure in the same position, at the same time of day, and make multiple measurements over a week and take the average.

Heart Rate Variability

There are surprisingly few consumer tools for measuring heart rate variability. Some of the regulated medical devices are quite easy to manage, but good luck in navigating the system to obtain one. The easiest way is to buy second hand medical devices via one of the major marketplaces open to resellers, but that requires a fair-sized investment in time and effort - which comes back to the rule about keeping things simple at the outset. After some reading around the subject, I settled on the combination of the Polar H10 device coupled with the SelfLoops HRV Android application. I also gave EliteHRV a try, but despite all the recommendations, I could not convince it to produce sensible numbers for the heart rate variability data, while SelfLoops HRV had no issues.

Pulse Wave Velocity

For pulse wave velocity, the situation for consumer tools is even more sparse. I was reduced to a fingertip device, the iHeart, picked as being less unreliable and easier to use than the line of scales that measure pulse wave velocity. The recommendations suggest that decently reliable data from non-invasive devices is only going to be obtained by measures at the aorta and other core locations, or with more complicated regulated medical devices that use cuffs and sensors at several places on the body. My experience with a fingertip pulse wave velocity measure is that it is possible to obtain consistent measures at any given point in time, but there is a large variation from day to day even when striving to keep as many of the variables as consistent as possible: position, finger used for a fingertip device, time of day, time since last meal and exercise, and so forth.

DNA Methylation

DNA methylation tests can be ordered from either Osiris Green or Epimorphy / Zymo Research. I picked Zymo's product because at the time I first wrote this, the Osiris Green founders were still bailing out their laboratory after Hurricane Irma; they are back in business now, however. I am told that these tests are very consistent over time, with the Zymo test claiming a range of error of two years or so for the age assessment when comparing two tests on the sample sample. Nonetheless, as for the cardiovascular measures, it is wise to try to make everything as similar as possible when taking the test before and after a treatment: time of day, recency of eating or exercise, recent diet, and so forth.

Scheduling

The schedule for a single person self-experimentation trial might look something as follows:

• Day 1-7: Once or twice a day, take measures for blood pressure, pulse wave velocity, and heart rate variability.
• Day 7: Bloodwork and DNA methylation test.
• Day 8 and on: Carry out the treatment.
• Day 30-36: Repeat the blood pressure, pulse wave velocity, and heart rate variability measures.
• Day 36: Repeat the bloodwork and DNA methylation test.

One person's data is an anecdote. We won't really understand the profiles of potential rejuvenation therapies, or indeed any new interventions, until a great many people have tried them and reported on the results of trying them. At the moment, that proceeds through small trials organized by a variety of companies. History suggests that few people will in fact self-experiment in a useful way that that adds to the bigger picture, but nonetheless, formal trials don't have to be the only effort taking place.

Costs of Measurement

For the choices mentioned above, the rough costs are as follows:

• 2 MyDNAge tests: $600
• 2 Advanced Heart Health tests from WellnessFX: $760
• Omron 10 device: $70
• iHeart device and Android application: $210
• Polar H10 and SelfLoops HRV Android application: $110

Which amounts to $1750, along with a fair amount of time spent reading around the subject and becoming familiar with the devices and their quirks. The hardware is of course reusable for any other health assessment you might want to carry out. There is a lot of reading material out there produced by members of the quantified self movement, for example, that focuses on assessing the results of more mundane matters of exercise, weight, and fitness. I encourage you to explore it.

As a result of failed commercial efforts a decade ago, research into sirtuins - particularly SIRT1 - in the context of aging is broader than it might otherwise be, and has a great deal of inertia. A lot of funding poured into this area, and as a result efforts to map all of the biochemistry that touches upon SIRT1 continue today, long after the goal of building a therapy to slow aging based upon manipulating SIRT1 was abandoned. The early evidence for SIRT1 to be important enough in aging to be a basis for therapies was demolished, no useful treatment ever emerged, a bunch of investors nonetheless made a very large profit, and the "anti-aging" marketplace continues to sell useless supplements hyped on the basis of sirtuin-related expectations long since shown to be wrong.

Since the primary goal of the scientific community is to gather knowledge, and the one concrete outcome of the sirtuin hype was a foothold of new knowledge in this tiny slice of metabolism, research into sirtuins continues. Since researchers are better able to raise funding when they can offer at least the prospect of application of their research, even when the real goal is only the accumulation of knowledge, sirtuin researchers tend to explain their work in terms of potential impact on aging. But I think that ship has sailed. One should read SIRT1 research nowadays as a matter of interest, an example of the research community making slow progress in building the grand map of how exactly aging functions in detail. That is, sadly, of little relevance to the construction of effective therapies, which can be achieved by bypassing all of that detail to focus on repairing the known root causes of aging, and worrying about how exactly they generate aging in detail further down the line.

A study by researchers reveals that an anti-aging protein can be targeted to rejuvenate cells in the immune system. The protein in question is called SIRT1. The scientists found that it is involved in how cells in the immune system develop with age. They wanted to find out how this anti-aging protein affects a specific category of immune cells known as cytotoxic T cells. These cells are highly specialized guardians of the immune system and their role is to kill cells infected by a virus, damaged cells, or cancer cells.

"Over the course of a person's life, with repeated exposure to bacteria and viruses, these T cells mature and eventually lose a protein called CD28. And as these cells get older, they become more toxic to their environment." This aging process is accelerated by persistent viral infections, such as HIV and cytomegalovirus. In fact, HIV-infected patients accumulate mature cytotoxic T cells at a much younger age than an uninfected person.

When a young (or naive) T cell is in a resting state, it uses oxygen to "breathe". Once it is activated to defend the body against a bacteria or virus, it shifts into enhanced glycolysis and uses sugar to get an immediate boost in energy. This is useful to jump into action, but it isn't sustainable for long-term performance. As the cells age and lose CD28, they can shift into glycolysis much more quickly if breathing is inhibited. They also lose the anti-aging protein SIRT1. This becomes a problem, as it makes them more toxic to the cells around them.

"We studied human T cells, isolated from blood donors of all ages, to compare mature cytotoxic T cells with naive ones." The researchers found that naive T cells have a high concentration of SIRT1. This stabilizes an entire mechanism that prevents the cells from entering glycolysis to use sugar as an energy source, and limits their toxic effects. As the cells age, they lose SIRT1, which changes their basic metabolism. They can then rapidly shift into glycolysis and start producing more toxic proteins called cytokines, which could lead to inflammatory diseases.

Link: https://gladstone.org/about-us/press-releases/anti-aging-protein-could-be-targeted-rejuvenate-immune-cells

As a general rule, a 10% extension of life in short-lived species is nothing of any great significance. There are an increasing number of methods shown to do this, such as the one noted here. Researchers have more than doubled the life span in flies and worms in a few different ways over the past twenty years, however, and where the effects of any given intervention can be compared with the results in humans, it has been found that short-lived species have a much greater plasticity of life span. The large gains of calorie restriction and growth hormone receptor loss of function observed in lower species don't occur in our own species. This should be broadly true for just about everything that involves manipulating the operation of metabolism to slow down the pace at which damage occurs, as near all of that arises from mechanisms related to calorie restriction and insulin or growth hormone metabolism.

One should probably view this sort of work through the lens of scientific interest in mapping and cataloging the way in which aging works at the detail level - why the pace of aging varies somewhat between individuals, which mechanisms are most important, and so forth. Acquisition of knowledge is everything, and application of knowledge to the production of methods of slowing aging in humans is an afterthought. If that was the primary goal, researchers would instead pursue strategies with a much greater expectation of gains in longevity, the potential rejuvenation therapies based on repair of the damage that causes aging.

The enzyme - RNA polymerase III (Pol III) - is present in most cells across all animal species, including humans. While it is known to be essential for making proteins and for cell growth, its involvement in ageing was unexplored until now. A study has found that the survival of yeast cells, and the lifespans of flies and worms were extended by an average of 10% following a modest reduction in Pol III activity in adulthood. "We've uncovered a fundamental role for Pol III in adult flies and worms: its activity negatively impacts stem cell function, gut health, and the animal's survival. When we inhibit its activity, we can improve all these. As Pol III has the same structure and function across species, we think its role in mammals, and humans, warrants investigation as it may lead to important therapies."

The effects of inhibiting Pol III were found to be comparable to the action of the immune-suppressing drug rapamycin, which has previously been shown to extend the lifespans of mice and many other animals. This discovery will help scientists understand the mechanism of action of drugs, such as rapamycin, that show promise for extending the lifespans of mammals. "Understandably, there's a lot of hype around drugs that extend lifespan and promote healthy ageing but very little is known about how they work, which is fundamental knowledge. We now think that Pol III promotes growth and accelerates ageing in response to a signal inhibited by rapamycin, and that inhibiting Pol III is sufficient to result in flies living longer as if they were given rapamycin. If we can investigate this mechanism further and across a wider range of species, we can develop targeted antiaging therapies."

Yeast, flies and worms were used as model organisms as they are not closely related but all contain Pol III. Inhibiting Pol III in the guts of flies and worms, was sufficient to extend lifespan, and when Pol III was inhibited in flies' intestinal stem cells alone, they also lived longer. The team now plan on continuing their work on Pol III to understand its function in an adult organism, and hence shed light on how a reduction in its activity can extend lifespan.

Link: http://www.ucl.ac.uk/news/news-articles/1117/301117-worms-and-flies-live-longer