Fight Aging! Newsletter, October 1st 2018

Fight Aging! provides a weekly digest of news and commentary for thousands of subscribers interested in the latest longevity science: progress towards the medical control of aging in order to prevent age-related frailty, suffering, and disease, as well as improvements in the present understanding of what works and what doesn't work when it comes to extending healthy life. Expect to see summaries of recent advances in medical research, news from the scientific community, advocacy and fundraising initiatives to help speed work on the repair and reversal of aging, links to online resources, and much more.

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  • Clearing Senescent Cells Reduces Tau Aggregation and Cognitive Loss in Mouse Models of Alzheimer's Disease
  • Thoughts on Attending RAADfest 2018 in San Diego
  • Recent Papers Illustrative of Present Efforts to Quantify the Benefits of Exercise
  • A Spotlight on Geroscience
  • New Insights into Liver Regeneration
  • 1.5 Million Raised for Ichor Therapeutics Portfolio Company Auctus Biologics
  • Humanin Improves Cognition in Aged Mice
  • An Update on Dkk1 as a Therapeutic Target in Alzheimer's Disease
  • Researchers Generate Esophagus Organoids from Pluripotent Stem Cells
  • Destroying Mutant Mitochondrial DNA as a Strategy to Treat Mitochondrial Disease
  • Lifespan.io is Crowdfunding a Nicotinamide Mononucleotide Mouse Lifespan Study
  • Searching for Small Molecules that Can Break Down Protein Aggregates Involved in Neurodegenerative Disease
  • Intermittent Living as a Proposal for Enhanced Beneficial Cellular Stress Responses
  • Older Mice Heal Skin Injuries More Slowly, but with Less Scarring
  • A Lower Estimate for the Degree to Which Cancer is Self-Inflicted

Clearing Senescent Cells Reduces Tau Aggregation and Cognitive Loss in Mouse Models of Alzheimer's Disease

Researchers have once again demonstrated that a senolytic therapy capable of selectively destroying senescent cells can reduce tau aggregation and consequent loss of cognitive function in a mouse model of Alzheimer's disease. The research materials noted below report on the use of navitoclax, also known as ABT-263, in mice and follow very closely on the heels of two other studies that produced very similar results using different senolytic treatments, piperlongumine in one study and the dasatinib / quercetin combination in the other. This is very characteristic of research into the removal of senescent cells: any approach that succeeds in destroying a significant fraction of senescent cells produces significant gains in health; there is no shortage of different approaches; the treatments employed cost very little and are easily purchased in the global marketplace; and researchers can readily replicate the findings of other groups. This a very robust intervention in the aging process, producing data that is far more consistent than any other approach I am aware of.

Why does the removal of senescent cells work so well? Firstly, there are few of these cells, perhaps a few percent by number in aged tissues, so selective destruction is not particularly disruptive. It leaves little debris to clean up, and the few lost cells can be rapidly replaced. Secondly, these few senescent cells produce produce sizable harm through the continuous secretion of inflammatory and other harmful signals. A large fraction of that harm is in effect an altered, degraded state of tissue function that is actively maintained via signaling. The moment that this unwanted signaling is cut back, the environment shifts back to a more youthful, less inflammatory, less disrupted state. Regenerative capacity picks up, and many other forms of cellular function improve. This change is rapid. Near any age-related inflammatory condition is mostly likely significantly driven by the accumulation of senescent cells, whether that is arthritis, fibrosis, or Alzheimer's disease. In animal models, removal of senescent cells has been demonstrated to reverse measures of aging in numerous diseases and near all major organs.

It is interesting to compare dosing strategies between the three studies that demonstrated reductions in tau aggregation and cognitive decline. They are illustrative of the behavior of different classes of senolytic drugs, as each of navitoclax, piperlongumine, and the dasatinib / quercetin combination use different mechanisms to kill senescent cells. The navitoclax study here used long-term intermittent administration, five days on and sixteen days off over the full lifetime of the mice. The piperlongumine study used a daily dose over eight weeks. The dastinib study used a bi-weekly schedule of administration over twelve weeks. This is consistent with other data from studies using these compounds, in which dasatinib appears to require far less frequent dosing to achieve more or less the same outcome.

Zombie cells found in brains of mice prior to cognitive loss

Zombie cells are the ones that can't die but are equally unable to perform the functions of a normal cell. These zombie, or senescent, cells are implicated in a number of age-related diseases. In a mouse model of brain disease, scientists report that senescent cells accumulate in certain brain cells prior to cognitive loss. By preventing the accumulation of these cells, they were able to diminish tau protein aggregation, neuronal death, and memory loss.

In the current study, the team used a model that imitates aspects of Alzheimer's disease. "We used a mouse model that produces sticky, cobweb like tangles of tau protein in neurons and has genetic modifications to allow for senescent cell elimination. When senescent cells were removed, we found that the diseased animals retained the ability to form memories, eliminated signs of inflammation, did not develop neurofibrillary tangles, and had maintained normal brain mass." They also report that pharmacological intervention to remove senescent cells modulated the clumping of tau proteins.

"Two different brain cell types called microglia and astrocytes were found to be senescent when we looked at brain tissue under the microscope. These cells are important supporters of neuronal health and signaling, so it makes sense that senescence in either would negatively impact neuron health. We had no idea whether senescent cells actively contributed to disease pathology in the brain, and to find that it's the astrocytes and microglia that are prone to senescence is somewhat of a surprise."

Clearance of senescent glial cells prevents tau-dependent pathology and cognitive decline

Cellular senescence, which is characterized by an irreversible cell-cycle arrest accompanied by a distinctive secretory phenotype, can be induced through various intracellular and extracellular factors. Senescent cells that express the cell cycle inhibitory protein p16INK4A have been found to actively drive naturally occurring age-related tissue deterioration and contribute to several diseases associated with ageing, including atherosclerosis and osteoarthritis. Various markers of senescence have been observed in patients with neurodegenerative diseases; however, a role for senescent cells in the aetiology of these pathologies is unknown.

Here we show a causal link between the accumulation of senescent cells and cognition-associated neuronal loss. We found that the a mouse model of tau-dependent neurodegenerative disease accumulates p16INK4A-positive senescent astrocytes and microglia. Clearance of these cells as they arise using INK-ATTAC transgenic mice prevents gliosis, hyperphosphorylation of both soluble and insoluble tau leading to neurofibrillary tangle deposition, and degeneration of cortical and hippocampal neurons, thus preserving cognitive function. Pharmacological intervention with a first-generation senolytic modulates tau aggregation. Collectively, these results show that senescent cells have a role in the initiation and progression of tau-mediated disease, and suggest that targeting senescent cells may provide a therapeutic avenue for the treatment of these pathologies.

Thoughts on Attending RAADfest 2018 in San Diego

I spent an interesting few days last week attending RAADfest, and came away somewhat optimistic that this strange collision of subcultures may herald an acceleration in the adoption of solid science and working therapies on the part of the anti-aging marketplace, accompanied by a driving out of the ineffective nonsense and fraud of past decades. This sea change is very much a work in process, and there is plenty of that nonsense still to be found. Yet the advent of senolytic therapies to clear senescent cells has clearly invigorated certain groups, who have now turned a sizable amount of their advocacy and attention to the adoption of this first legitimate rejuvenation therapy, an implementation of the SENS model of damage repair.

RAADfest is a stage show of presentations and a floor show of company booths. The core of RAADfest, the presentations on stage, might be best understood as almost a secular church, an adoption of the methods of American revivalism when it comes to firing up an audience, presenting a message, and encouraging people to set forth and tell their friends the good news. The presenters are effusive and largely very charismatic characters, the audience leaps up to applaud and shout encouragement. There are few other places you will see scientists gain a standing ovation and rousing cheers on presenting patient benefits, or explaining how their work will help in the future.

The hosts, the leaders of the Coalition for Radical Life Extension represent a community of long-standing longevity advocates and their followers, associated for decades with the anti-aging marketplace, the original iconoclasts from an era in which the scientific community was much more hostile to the message of longevity. Among them are some of those who built the original businesses such as the Life Extension Foundation because they believed that more could be accomplished than was possible at the time. Where businesses succeeded, they ended up selling at best marginal and ineffective products, hoping for a better future, and coming to be surrounded by an industry in which the fraud of false promises became a way of life. So what happens when real, working rejuvenation therapies start to show up? I hope that the good drives out the bad, and that process seems to be underway. The past generation of longevity advocates, those who built an audience and a logistics pipeline, now have a chance to redeem themselves.

Still, there is an element of the tragic here, in that these people have adopted a mode of advocacy that does not allow them to admit that there is the slightest chance that they will not make it, that the pace of process will be too slow. Technology cannot advance fast enough to save today's oldest demographic, and their only realistic option is cryopreservation (Alcor had a booth, and good for them). There is a certain pathos in folk in late life standing on stage to call for radical life extension, to say that they are fully engaged with living a great life, that they wish to live forever and have fun doing it. In the process they are doing good in the sense of aiding the advance of rejuvenation therapies in their own way, but it is clear that they will be not be around for long enough to see the true flowering of this field of medicine.

On the topic of senolytics, I took a sizable number of handouts to the conference and distributed them all. I feel quite strongly that it is crazy that so little progress is being made in getting the senolytic dasatinib to the tens of millions of older people who might benefit significantly from even a single dose, given that it is a cheap, easily available, FDA-approved generic drug with well characterized pharmacology that can be used off-label. Millions are suffering needlessly, and they and their physicians just need to be told of the opportunity in order to assess it and take advantage of it.

As it turned out, no such effort on my part was actually needed, as the formal conference materials contained a fairly comprehensive section covering senolytics, featuring the dasatinib and quercetin combination front and center. The position put forward by Bill Faloon of the Life Extension Foundation at the conference is that older people should absolutely be taking advantage of NAD+ boosting therapies such as nicotinamide riboside, then senolytics, then mesenchymal stem cell therapies, in that order, envisaged as an ascending stairway of benefits. There is good evidence to suggest that positive results for older individuals will result from all of these, though senolytics are by far the most impressive in animal studies. I'm omitting the presence of basic good health practices and supplements in this stairway picture, but they are still there and being emphasized. That said, I have to think that they will drift away from being as central to the anti-aging message as they have been in the past, as the biotechnologies improve.

I had said this was a collision of cultures. The older longevity advocates of past decades are the organizers, and then into the big tent are invited scientists developing the foundations of real, working rejuvenation therapies; investors funding the latest startups; entrepreneurs commercializing the range of new approaches to treat aging; the transhumanist community with its focus on transcending human limits; health advocates of all varieties; stem cell physicians of the proven and unproven variety, and of course the strange detritus of the anti-aging marketplace, a mix of cynics and true believers offering little more than hope and strangeness, ineffective products wrapped in the veneer of science. It is quite the mix. One might hope that out of this cross-pollination perhaps an acceleration will emerge, a speeding of the otherwise slow process of outreach and awareness in the matter of longevity science. It was certainly the case that I met a couple of interesting new faces, people undertaking or considering what I see to be worthwhile endeavors.

Among the presentations of note, Aubrey de Grey gave an update on the growing number of companies now emerged from or associated with the SENS Research Foundation community (a list that includes the startup Repair Biotechnologies, founded by Bill Cherman and myself). The audience here might find it very interesting to note that Revel Pharmaceuticals, the glucosepane cross-link breaking company in the lengthy process of being founded by David Spiegel is apparently now funded by Juvenescence and Kizoo Technology Ventures. So it looks like we'll be hearing more on that front soon, and a good thing too, as this part of the SENS rejuvenation research agenda is likely to be just as big as senolytics once realized.

Bill Andrews gave an interesting update on progress towards human trials of telomerase gene therapy at Libella Gene Therapeutics; the technology is coming together. Liz Parrish of BioViva was also present at the event to discuss her company and present efforts. Gene therapies are still a pain to develop, to optimize sufficiently to gain high levels of transduction of target cells. This will change in the years ahead, but for now it is still an expensive and complicated business to deal with all of the issues that arise, and every therapy is significantly different in its needs, a hand-crafted product unlike any of its peers. I remain in the camp of wait and see on telomerase therapies; my concern is the sizable difference between mouse and human telomere dynamics. Were I older, the risk/reward calculus would be different, but I have to admire the brave souls who have undergone or will in the near future undergo these therapies. Their risk-taking benefits all of us.

Vocal investor Jim Mellon, who at times appears to be more or less single-handedly driving the funding of our nascent rejuvenation biotechnology industry, gave a rousing presentation. Longevity is a market that will make every past growth trend and bubble seem tiny. Mellon doesn't care about the money, save as a means to an end - "I have enough money" - but rather he wants to see the job accomplished, rejuvenation realized, life spans extended by decades and more. The best way to do that is to build an industry large enough and vibrant enough and sufficiently well known to draw in a flood of capital, packed with enough companies to develop every possible portion of and take on the SENS rejuvenation research portfolio that we can come up with. As he points out, the anti-aging market, selling things that don't work, is worth 140 billion today. How much will it be worth when the products do work? Over the timescale of decades, it is large and healthy industries that truly change the world.

These are interesting times that we live in.

Recent Papers Illustrative of Present Efforts to Quantify the Benefits of Exercise

It is fairly settled in the scientific community, barring the odd few objections here and there, that regular moderate exercise improves health in the long term, relative to a sedentary lifestyle. When it comes to the details of the dose-response curve for exercise, however, the scientists of the field are still somewhere in the midst of a slow and grand debate that has lasted decades and seems likely to last for decades more. Extracting solid conclusions from human epidemiological data is a challenging endeavor at the best of times. The papers noted below are illustrative of a score or more similar efforts published every year, as researchers add ever more analysis to the existing mountain of thought on exercise and health.

Present evidence is leaning in the direction of a big leap in benefits in the transition from no exercise and minimal physical activity. Benefits increase thereafter up to the point of an hour or so a day, and then may or may not decline with further increases. Clearly there is a point at which too much exertion is harmful, but does that occur prior to the level of exercise undertaken by profession athletes? If so, how to account for their longevity compared to the rest of the population? It may be that people who can become professional athletes are just more robust than everyone else to start with, or alternatively it has to do with social status, wealth, and other confounding factors.

Further, even if there ever comes to be solid agreement on how much exercise is best, what about the different forms of exercise? Are repeated short bursts better or worse than extended effort? Can short term effects be separated from long term effects? Is strength training so important as to be worth sacrificing time on aerobic exercise to undertake it? Is cycling better or worse than rowing? Or swimming? Or moving plants around the garden? An endless series of questions might be posed. Few of them will be definitively answered before we find ourselves in an era in which optimizing the effects of exercise is an amusing hobby and little more, because rejuvenation biotechnologies exist. Their effects on health and life span will far exceed anything that might be produced by finding a way to do a little better than the currently recommended level of exercise.

The Goldilocks Zone for Exercise: Not Too Little, Not Too Much

Homo sapiens are evolutionarily adapted to be very physically active throughout life, and thus habitual physical activity (PA) is essential for well-being and longevity. Never the less, middle-aged and older individuals engaging in excessive strenuous endurance exercise appear to be at increased risk for a variety of adverse cardiovascular effects including atrial fibrillation, myocardial fibrosis, and coronary atherosclerosis. An emerging body of evidence indicates U-shaped or reverse J-shaped curves whereby low doses and moderate doses of PA significantly reduce long-term risks for both total mortality and cardiovascular mortality, however, at very high doses of chronic strenuous exercise much of the protection against early mortality and cardiovascular disease is lost.

The optimal dose, or what we term 'Goldilocks Zone,' of PA may be: at least 150 minutes per week of moderate-intensity aerobic exercise or 75 minutes per week of vigorous-intensity aerobic activity, but not more than four to five cumulative hours per week of vigorous (heart-pounding, sweatproducing) exercise, especially for those over 45 years of age. It is also important to take at least one day per week off from vigorous exercise. There appears to be no concerns about an upper threshold for safety for leisure-time low-to-moderate intensity activities such as walking at a comfortable pace, housework, gardening, etc. After every 30 consecutive minutes spent sitting, stand up and move, ideally walking briskly for about five minutes.

Now you just need to remember to exercise!

In a study of 36 healthy young adults, the researchers discovered that a single 10-minute period of mild exertion can yield considerable cognitive benefits. Using high-resolution functional magnetic resonance imaging, the team examined subjects' brains shortly after exercise sessions and saw better connectivity between the hippocampal dentate gyrus and cortical areas linked to detailed memory processing. "The hippocampus is critical for the creation of new memories; it's one of the first regions of the brain to deteriorate as we get older - and much more severely in Alzheimer's disease. Improving the function of the hippocampus holds much promise for improving memory in everyday settings."

While prior research has centered on the way exercise promotes the generation of new brain cells in memory regions, this new study demonstrates a more immediate impact: strengthened communication between memory-focused parts of the brain. "We don't discount the possibility that new cells are being born, but that's a process that takes a bit longer to unfold. What we observed is that these 10-minute periods of exercise showed results immediately afterward."

Mitochondrial changes similar in short sprint exercise versus longer moderate-intensity workouts

A team of researchers studied eight young adult volunteers as they participated in cycling workouts of varying intensity: (a) moderate intensity consisted of 30 minutes of continuous exercise at 50 percent peak effort; (b) high-intensity interval exercise consisted of five four-minute cycling sessions at 75 percent peak effort, each separated by one minute of rest; (c) sprint cycling consisted of four 30-second sessions at maximum effort, each separated by 4.5 minutes of recovery time.

The research team measured the amount of energy the volunteers spent on each workout and compared mitochondrial changes in the participants' thigh muscles before and after each exercise session. The researchers found that fewer minutes of higher-intensity exercise produced similar mitochondrial responses compared to a longer moderate-intensity activity. "A total of only two minutes of sprint interval exercise was sufficient to elicit similar responses as 30 minutes of continuous moderate-intensity aerobic exercise. This suggests that exercise may be prescribed according to individual preferences while still generating similar signals known to confer beneficial metabolic adaptions."

A Spotlight on Geroscience

It isn't entirely fair to categorize geroscience as the worse of the two serious and considered approaches to the treatment of aging as a medical condition, the one that isn't as good as the SENS methodology of rejuvenation through repair of molecular damage. Nor is it entirely the case that geroscience aims only to modestly slow aging to gain a few years while SENS aims at radical life extension and rejuvenation of the old. It is also inaccurate to say that geroscience is concerned only with calorie restriction mimetics and other ways to induce beneficial stress responses, the manipulation of metabolism to resist aging a little better without addressing its root causes.

Yet if you pick a random point in the SENS portfolio and a random point in the geroscience portfolio, the stereotypes above are what you'll likely land upon. Unless, of course, you happened to touch on some portion of the growing interest in senolytics, the selective destruction of senescent cells. This is the major area of overlap between the two at the present time, or - if you choose to look at things the way I do - the most prominent example of the way in which SENS will eventually take over the mainstream of research because it is demonstrably more effective. Senolytics has become a focus for an increasing fraction of the research community as the positive data continues to roll in, and justifiably so. Larger, more reliable effects are what is desired by everyone. Sadly it remains the case that most researchers and sources of funding still need to be persuaded to put aside their geroscience work in favor of the better SENS approach.

The S. Jay Olshansky article I noted a few days back is one of a few interesting position papers from a recent edition of the Journal of the American Medical Association focused on geroscience as an endeavor. The other two are noted below, and each is worth reading as a standalone piece. The bigger picture is that the tenor of the great cultural conversation about aging is changing, has changed significantly, is no longer what it was even a decade ago. The technologies that slow and reverse aging are starting to emerge and be demonstrated in ways that cannot be refuted. Treating aging as a medical condition is no longer mocked in the media - the serious people are convinced. The future is arriving.

Aging as a Biological Target for Prevention and Therapy

Chronic health problems related to the unprecedented aging of the human population in the 21st century threaten to disrupt economies and degrade the quality of later life throughout the developed world. Fortunately, research has shown that fundamental aging processes can be targeted by nutritional, genetic, and pharmacologic interventions to enhance and extend both health and longevity in experimental animal models. These findings clearly demonstrate that the biological rate of aging can be slowed.

The geroscience hypothesis, for which there is abundant evidence in animal models, links these biological discoveries to human health by proposing that targeting biological aging processes will prevent, or at a minimum delay, the onset and progression of multiple chronic diseases and debilities that are typically observed in older adults. For example, interventions that extend the life span of mice often also prevent or slow the progress of several types of cancer, reduce atherosclerotic lesions, improve heart function, alleviate normal age-related cognitive loss, and even improve vaccine response.

One of the main geroscience accomplishments is to highlight a small number of major "pillars," interacting molecular and physiological processes that underlie the biology of aging, for instance, metabolism, proteostasis, macromolecular damage, inflammation, adaptation to stress, epigenetics, and stem cells and their regeneration. The key feature of this conceptual framework is that these processes are understood to be tightly interrelated. These findings have emerged from the remarkable progress made in recent years in dissecting aging processes in model organisms. The discovery of cellular and molecular pathways that modulate healthy aging in diverse species across great evolutionary distances offers an unprecedented opportunity for intervention

Aging, Cell Senescence, and Chronic Disease: Emerging Therapeutic Strategies

Age is the leading predictive factor for most of the chronic diseases that account for the majority of morbidity, hospitalizations, health costs, and mortality worldwide. The fundamental aging processes that contribute to phenotypes characteristic of advanced old age, such as muscle weakness and loss of subcutaneous fat, also appear to underlie the major chronic diseases, geriatric syndromes, and loss of physical resilience. These aging processes can be broadly classified as follows: (1) chronic, low-grade inflammation that is "sterile" (occurring in the absence of known pathogens), together with fibrosis; (2) macromolecular and cell organelle dysfunction (such as DNA damage, dysfunctional telomeres, protein aggregation and misfolding, decreased removal of damaged proteins, or mitochondrial dysfunction); (3) changes in stem cells and progenitors that lead to reduced capacity to repair or replace tissues; and (4) cellular senescence.

Senescence involves essentially irreversible arrest of cell proliferation, increased protein production, resistance to programmed cell death (apoptosis), and altered metabolic activity. Senescent cells accumulate in multiple tissues as a result of chronological aging, especially after middle age, and in tissues central to the pathogenesis of chronic diseases. For example, senescent cells accumulate in and near bone in patients with age-related osteoporosis and in blood vessel walls in patients with vascular disease.

Some senescent cells develop a senescence-associated secretory phenotype (SASP) that entails release of proteins, bioactive lipids, nucleotides, extracellular vesicles, and other factors. The SASP contributes to inflammation and the breakdown of tissues, stem and progenitor cell dysfunction, and the spread of senescence to nonsenescent cells. The SASP, immune cells attracted and activated by the SASP, and spread of senescence contribute to profound local and systemic effects with even small numbers of senescent cells. For example, transplanting small numbers of senescent cells around knee joints in young mice leads to joint pain and pathologic changes closely resembling human osteoarthritis. Transplanting senescent cells into middle-aged mice so that only 1 in 10,000 cells in the recipients is a transplanted senescent cell is sufficient to cause profound physical dysfunction within 2 months, together with early death due to accelerated onset of age-related diseases as a group, compared with transplanting nonsenescent cells.

New Insights into Liver Regeneration

The liver is the most regenerative of organs in mammals, capable of regrowing large amounts of lost tissue following injury. Its strategy for regrowth is somewhat different from that of other tissues, and somewhat different again from the mechanisms employed by species capable of proficient regeneration, such as salamanders. Evolution has produced many approaches to growth and regrowth, it seems. It may or may not be the case that researchers can find ways to make other organs behave more like the liver. I think it is far too early to say just how challenging a proposition this might be; even were there compelling mechanisms in hand and being worked on, that would be a tough prediction to make.

Meanwhile, investigative research continues. In the work noted here, researchers uncover a role for shifts in alternative splicing in liver regeneration. Alternative splicing allows for the production of different proteins from the same genetic blueprint, and is a complex enough epicycle atop all of the other complexity of cellular biochemistry to remain comparatively poorly explored in most specific cases. The researchers tie their findings to the Hippo signaling pathway, something that has attracted attention of late in the context of rejuvenation. A number of research groups are eyeing the Hippo pathway as a target for therapies that might enhance regeneration in various internal organs. This is all largely very early stage work, and it will likely be years before something emerges into the development pipeline.

Study: Damaged liver cells undergo reprogramming to regenerate

The liver is a resilient organ. It can restore up to 70 percent of lost mass and function after just a few weeks. We know that in a healthy adult liver, the cells are dormant and rarely undergo cell division. However, if the liver is damaged, the liver cells re-enter the cell cycle to divide and produce more of themselves. Using a mouse model of a liver severely damaged by toxins, researchers compared injured adult liver cells with healthy cells present during a stage of development just after birth. They found that injured cells undergo a partial reprogramming that returns them to a neonatal state of gene expression.

The team discovered that fragments of messenger RNA, the molecular blueprints for proteins, are rearranged and processed in regenerating liver cells in a manner reminiscent of the neonatal period of development. This phenomenon is regulated through alternative splicing, a process wherein exons (expressed regions of genes) are cut from introns (intervening regions) and stitched together in various combinations to direct the synthesis of many different proteins from a single gene.

"We found that the liver cells after birth use a specific RNA-binding protein called ESRP2 to generate the right assortment of alternatively spliced RNAs that can produce the protein products necessary for meeting the functional demands of the adult liver. When damaged, the liver cells lower the quantity of ESRP2 protein. This reactivates fetal RNA splicing in what is called the Hippo signaling pathway, giving it instructions about how to restore and repopulate the liver with new and healthy cells."

Alternative splicing rewires Hippo signaling pathway in hepatocytes to promote liver regeneration

During liver regeneration, most new hepatocytes arise via self-duplication; yet, the underlying mechanisms that drive hepatocyte proliferation following injury remain poorly defined. By combining high-resolution transcriptome and polysome profiling of hepatocytes purified from quiescent and toxin-injured mouse livers, we uncover pervasive alterations in messenger RNA translation of metabolic and RNA-processing factors, which modulate the protein levels of a set of splicing regulators.

Specifically, downregulation of the splicing regulator ESRP2 activates a neonatal alternative splicing program that rewires the Hippo signaling pathway in regenerating hepatocytes. We show that production of neonatal splice isoforms attenuates Hippo signaling, enables greater transcriptional activation of downstream target genes, and facilitates liver regeneration. We further demonstrate that ESRP2 deletion in mice causes excessive hepatocyte proliferation upon injury, whereas forced expression of ESRP2 inhibits proliferation by suppressing the expression of neonatal Hippo pathway isoforms. Thus, our findings reveal an alternative splicing axis that supports regeneration following chronic liver injury.

1.5 Million Raised for Ichor Therapeutics Portfolio Company Auctus Biologics

The folk at Ichor Therapeutics are spinning off subsidiary companies at a fair pace, each devoted to either SENS rejuvenation biotechnology or life science infrastructure technologies: LysoClear; Antoxerene; Auctus Biologics; RecombiPure. At this point, the staff at Ichor Therapeutics are quietly turning their portion of Upstate New York into a biotech hub pretty much all by themselves. I'm doing my small part to help by situating Repair Biotechnologies right next door. This growth seems likely to continue, as there is no shortage of work to be done when it comes to realizing the SENS portfolio of rejuvenation therapies.

The latest funding round for this collection of companies, just closed, puts 1.5 million into Auctus Biologics, which is for now starting out with the aim of commercializing a most interesting infrastructure technology. But then Antoxerene also started out this way, and that company is now using their infrastructure technology to produce new senolytic drugs, a way to selectively remove senescent cells and thus turn back that contribution to aging. The Auctus Biologics platform initially offers the promise of being able to replace injections with pills for a range of therapies; if realized it will be a big deal for everyone in the industry who cares deeply about the logistics and cost of delivery therapies to patients.

Auctus Biologics, Inc., a new portfolio company of Ichor Therapeutics, Inc., announced today the closure of 1.5 million in seed funding. The company will develop RPtag, a hyper-stable antibody mimetic scaffold published earlier this year, to take on conventional clinical antibody therapy as an orally bioavailable formulation. New high priority immunosenescence and gastrointestinal targets will also be pursued. "Although there may be significant opportunities to develop this platform as an oral formulation to replace the need for conventional intravenous infusions, we are also very excited about the prospect of deploying this technology to modulate gut micro-flora and to go after other gut targets that may drive age-associated disease and related processes."

"This program is a testament to the excellence of our research teams and their ability to identify unique value in all its manifestations. This technology was originally developed for protein expression applications. By following the data and affording the team an appropriate level of scientific freedom, we have created a robust therapeutic platform that can operate in environments where biologics are traditionally limited."

Humanin Improves Cognition in Aged Mice

Researchers here demonstrate that delivery of humanin to aged mice can improve cognitive function. Humanin appears to trigger increased levels of autophagy, the collection of processes responsible for recycling damaged proteins and cell structures. Increased autophagy is associated with many of the approaches shown to modestly slow aging in short-lived species such as nematodes, flies, and mice. These approaches largely involve applying mild stress to cells, such as via heat, lack of nutrients, or other methods, or directly triggering the signals that normally result from such stress. Increased autophagy for some period of time is the primary outcome.

One of the more important mechanisms by which autophagy influences aging may be the removal of damaged mitochondria. Swarms of mitochondria act as the power plants of the cell, producing chemical energy store molecules, but their function degrades with age. This is in part a reaction to rising levels of cellular damage, but it is also the case that a tiny fraction of mitochondria can malfunction dramatically due to DNA damage. This leads to errant behavior in cells that can damage the tissue environment. Greater recycling of mitochondria appears to reduce their dysfunction in aging, though nowhere near as much as we'd like it to. We have a good guide as to what happens when autophagy is upregulated in humans, namely the practice of calorie restriction. Far greater benefits than those realized via calorie restriction seem unlikely to arise through this set of mechanisms.

Humanin is the first member of a new class of peptides originating from small, alternative open reading frames within the mitochondrial genome. Since it was discovered, humanin has been shown to be neuroprotective in multiple in vitro and animal studies. The importance of the mitochondria in the etiology of Alzheimer's disease is becoming more apparent and evidence suggests that humanin protects from various insults both in cellular models and in vivo models of Alzheimer's disease. Because circulating humanin levels have been shown to decrease in humans as they age, humanin could also play a role in age-related cognitive decline although this has not been investigated.

Because humanin is encoded within the mitochondrial genome, mitochondrial genetics may influence the expression of humanin, which in turn may directly influence cognition during aging. In fact, many of the differences in disease incidence between haplogroups and ethnicities are in diseases that have been linked to humanin in animal models such as Alzheimer's, diabetes, and cardiovascular disease. Thus, in this study we examined the role of humanin in cognition and its use as a possible intervention across several experimental models and paradigms.

We show that humanin has neuroprotective effects both in vitro and in vivo. We further show that humanin administration is sufficient to prevent some of the normal behavioral and cognitive deficits that occur with age in common laboratory mice. This suggests that the decline in humanin seen with increasing age may be one of the reasons for the age-related decline in cognition and related physiological parameters.

An Update on Dkk1 as a Therapeutic Target in Alzheimer's Disease

Six years ago, researchers reported that dkk1 appears to be involved in the destruction of synapses in Alzheimer's disease. More recent work expands the understanding of dkk1 in this context, placing it in a positive feedback loop related to amyloid-β, in which synaptic damage drives more synaptic damage. The researchers provide evidence to suggest that dkk1 protein can be a therapeutic target for treatments that slow the progression of Alzheimer's disease. Fortunately, there is an existing approved drug that might be used to produce a proof of concept in human patients, so it seems likely that we will be hearing more from this line of research in the years ahead.

Overproduction of the protein beta-amyloid is strongly linked to development of Alzheimer's disease but many drugs targeting beta-amyloid have failed in clinical trials. Beta-amyloid attacks and destroys synapses - the connections between nerve cells in the brain - resulting in memory problems, dementia, and ultimately death. In a new study researchers found that when beta-amyloid destroys a synapse, the nerve cells make more beta-amyloid driving yet more synapses to be destroyed. "We show that a vicious positive feedback loop exists in which beta-amyloid drives its own production. We think that once this feedback loop gets out of control it is too late for drugs which target beta-amyloid to be effective, and this could explain why so many Alzheimer's drug trials have failed."

The researchers also found that a protein called Dkk1, which potently stimulates production of beta-amyloid, is central to the positive feedback loop. Previous research identified Dkk1 as a central player in Alzheimer's, and while Dkk1 is barely detectable in the brains of young adults its production increases as we age. Instead of targeting beta-amyloid itself, the researchers believe targeting Dkk1 could be a better way to halt the progress of Alzheimer's disease by disrupting the vicious cycle of beta-amyloid production and synapse loss. "Importantly, our work has shown that we may already be in a position to block the feedback loop with a drug called fasudil which is already used in Japan and China for stroke. We have convincingly shown that fasudil can protect synapses and memory in animal models of Alzheimer's, and at the same time reduces the amount of beta-amyloid in the brain."

Researchers Generate Esophagus Organoids from Pluripotent Stem Cells

Every tissue requires a different recipe for the production of a functioning structure from the starting point of a few cells: different signals, different environment, different timing. Researchers in the heavily funded tissue engineering community are working their way through the lengthy and costly task of establishing those recipes for every type of organ that might be replaced or repaired. At the same time, there is at present no reliable way to produce the capillary networks needed to support tissues thicker than a few millimeters. The result is an era of organoids, tiny functional sections of organ tissue that are primarily used to accelerate research rather than for the production of therapies. Therapies are nonetheless possible in some cases: sheets of functional tissue can in principle be transplanted onto or into an organ, or even used to generate free-standing tiny assistive organs elsewhere in the body, as demonstrated by the ongoing work at Lygenesis. The set of organoid recipies is expanding and the quality of the end results are improving, with the report here being a representative example of the state of progress in this field.

Scientists working to bioengineer the entire human gastrointestinal system in a laboratory now report using pluripotent stem cells to grow human esophageal organoids. The newly published research is the first time scientists have been able to grow human esophageal tissue entirely from pluripotent stem cells (PSCs), which can form any tissue type in the body. Scientists have already used PSCs to bioengineer human intestine, stomach, colon, and liver. "Disorders of the esophagus and trachea are prevalent enough in people that organoid models of human esophagus could be greatly beneficial. In addition to being a new model to study birth defects like esophageal atresia, the organoids can be used to study diseases like eosinophilic esophagitis and Barrett's metaplasia, or to bioengineer genetically matched esophageal tissue for individual patients."

The scientists based their new method for using human PSCs to general esophageal organoids on precisely timed, step-by-step manipulations of genetic and biochemical signals that pattern and form embryonic endoderm and foregut tissues. They focused in part on the gene Sox2 and its associated protein - which are already known to trigger esophageal conditions when their function is disrupted. The scientists used mice, frogs, and human tissue cultures to identify other genes and molecular pathways regulated by Sox2 during esophagus formation. The scientists report that during critical stages of embryonic development, the Sox2 gene blocks the programming and action of genetic pathways that direct cells to become respiratory instead of esophageal. In particular, the Sox2 protein inhibits the signaling of a molecule called Wnt and promotes the formation and survival of esophageal tissues.

After successfully generating fully formed human esophageal organoids - which grew to a length of about 300-800 micrometers in about two months - the bioengineered tissues were compared biochemically to esophageal tissues from patient biopsies. Those tests showed the bioengineered and biopsies tissues were strikingly similar in composition. The research team is continuing its studies into the bioengineering process for esophageal organoids and identifying future projects to advance the technology's eventual therapeutic potential.

Destroying Mutant Mitochondrial DNA as a Strategy to Treat Mitochondrial Disease

The herd of bacteria-like mitochondria in each of our cells are vital cellular components, and come equipped with their own small genome, the mitochondrial DNA, one or more copies in each mitochondrion. If that DNA is broken, then harm results. Mitochondrial diseases bear only superficial similarities to the mitochondrial DNA damage that is a root cause of degenerative aging; while it is the case that mitochondrial DNA is mutated in both cases, the distribution of those mutations in cells and tissues is quite different. Nonetheless, it seems a reasonable proposition that a strategy of selectively destroying damaged mitochondrial DNA may work in each situation, though for different reasons.

In inherited mitochondrial disease, there is some split between healthy and damaged copies of mitochondrial DNA in cells. Destroy the bad genome copies and the good ones will hopefully replicate to make up that loss. In aging, just a few cells become entirely overtaken by clones of mitochondria with damaged genomes, but they exert a sizable negative influence on health via generation of oxidative molecules. Destroying all of the mitochondrial DNA in those cells might be expected to kill them, for all of the obvious reasons. Since there are few of them, destroying them is probably the most expedient approach to dealing with the issue. In both cases, effectiveness would be determined by how clean a sweep is made, though one might imagine temporary or partial benefits resulting from removing even half of the damaged mitochondrial genomes.

"Mitochondrial replacement therapy is a promising approach to prevent transmission of mitochondrial diseases, however, as the vast majority of mitochondrial diseases have no family history, this approach might not actually reduce the proportion of mitochondrial disease in the population. One idea for treating these devastating diseases is to reduce the amount of mutated mitochondrial DNA by selectively destroying the mutated DNA, and allowing healthy DNA to take its place."

To test an experimental gene therapy treatment, which has so far only been tested in human cells grown in petri dishes in a lab, the researchers used a mouse model of mitochondrial disease that has the same mutation as some human patients. The gene therapy treatment, known as the mitochondrially targeted zinc finger-nuclease, or mtZFN, recognises and then eliminates the mutant mitochondrial DNA, based on the DNA sequence differences between healthy and mutant mitochondrial DNA. As cells generally maintain a stable number of mitochondrial DNA copies, the mutated copies that are eliminated are replaced with healthy copies, leading to a decrease in the mitochondrial mutation burden that results in improved mitochondrial function.

The treatment was delivered into the bloodstream of the mouse using a modified virus, which is then mostly taken up by heart cells. The researchers found that the treatment specifically eliminates the mutated mitochondrial DNA, and resulted in measures of heart metabolism improving. Following on from these results, the researchers hope to take this gene therapy approach through clinical trials, in the hope of producing an effective treatment for mitochondrial diseases.

Lifespan.io is Crowdfunding a Nicotinamide Mononucleotide Mouse Lifespan Study

Lifespan.io has launched their latest crowdfunded study, and seeks more donors to join the more than 100 philanthropists of our community who have pledged already in the first few days. It is an assessment of the capacity of nicotinamide mononucleotide (NMN) to slow aging in mice, treating both normal mice and a lineage exhibiting accelerated aging. The final stretch goal in this fundraiser will provide enough funding to kick off a full life span study. This work is carried out in partnership with David Sinclair's lab, home of the past fifteen years of work on calorie restriction mimetics associated with sirtuins, a line of research that has evolved to these days to focus instead on nicotinamide adenine dinucleotide, NAD+.

NMN is one of a number of options that can be used to treat the loss of NAD+ in older individuals. While this approach doesn't address any of the causes of aging, meaning the rising levels of molecular damage that take throughout the body, it does serve to boost mitochondrial function. Mitochondrial function is well known to falter with age, and researchers consider this important in a range of age-related conditions. The evidence to date suggests that enhancing NAD+ levels may to some degree diminish measures of aging. To pick one recent example from the data, a small human trial of nicotinamide riboside, another of the options to raise NAD+ levels, demonstrated a reduction in blood pressure in hypertensive older patients.

One of the best studied anti-aging treatments is a diet reduced in calories, yet high enough in nutrients to avoid malnutrition. Known as calorie restriction (CR), this dietary regimen provides irrefutable evidence of the importance of metabolism in the aging process. While CR has been studied extensively and even tested in human trials, long term adherence to a CR dietary regimen is extremely difficult for most individuals to maintain.

One method to achieve the benefits of CR for everyone would be to administer compounds which act as "CR mimetics". A major metabolic signaling molecule that we and others have shown to exhibit significant declines with increasing age is NAD+. Importantly, CR reverses the age-related decline of bioavailable NAD+. This key metabolite plays a crucial role in regulating the activity of many important signaling molecules involved in age-related diseases.

However, feeding or administering NAD+ directly to organisms is not a practical option. The NAD+ molecule cannot readily cross cell membranes to enter cells, and therefore would be unavailable to positively affect metabolism. Instead, precursor molecules to NAD+ must be used to increase bioavailable levels of NAD+. Recently, we have shown that by administering the NAD+ precursor NMN (Nicotinamide Mononucleotide) in drinking water to older mice, NAD+ levels were restored to those normally associated with younger healthy animals. By administering NMN to mice for just one week, our lab demonstrated a robust correction in age-associated metabolic dysfunction and restored muscle mitochondrial function in old mice to levels seen in younger control mice.

Although the restorative properties of NMN treatment drive many of the same cellular signaling pathways which underlie CR, trials of greater than one week or two months are needed to properly evaluate whether NMN can reverse the aging process. Starting with mice that are 20 months old (roughly equivalent to a 50 year old human), longer-term NMN treatments will be applied in order to restore levels of cellular NAD+ to those found in youthful mice. Along with a large cohort of normal mice, we will also use a cohort of our novel genetically engineered mouse, termed the ICE mouse (Induced Changes In Epigenome). These ICE mice manifest an accelerated aging phenotype.

Your donations will not only allow us to purchase the materials necessary to perform this experiment, but also pave the way for human clinical trials aimed at showing, for the first time, that we can actually slow down human aging. We find ourselves at a turning point in history, and together we have the chance to accelerate technologies that will allow us to live healthfully at any age. This is a future that is coming, and whether it arrives in our lifespan or only for future generations is up to us.

Searching for Small Molecules that Can Break Down Protein Aggregates Involved in Neurodegenerative Disease

Considerable effort in the research community is devoted to the search for small molecule drugs that can break down or inhibit formation of the protein aggregates associated with various forms of neurodegenerative disease. One of these is α-synuclein, a prominent feature of Parkinson's disease. Potential treatments based on clearance of α-synuclein are at varying points in the development and regulatory approval pipeline. The materials here provide one of many examples of continued efforts to produce new drug candidates that can enter that pipeline. This is an uncertain process: scanning the compound libraries for new possibilities has unknown (but certainly low) odds of success in any given case. It is expensive and slow besides, and few sources of funding are willing to roll the dice given those points.

Parkinson's disease (PD) is characterized by a progressive loss of dopaminergic neurons, a process that current therapeutic approaches cannot prevent. In PD, the typical pathological hallmark is the accumulation of intracellular protein inclusions, known as Lewy bodies and Lewy neurites, which are mainly composed of α-synuclein. Recently, we have developed an accurate and robust high-throughput screening methodology to identify α-synuclein aggregation inhibitors. Here, we exploited this methodology to identify a small molecule (SynuClean-D) able to inhibit α-synuclein aggregation.

SynuClean-D significantly reduces the in vitro aggregation of wild-type α-synuclein and familiar variants in a substoichiometric molar ratio. This compound prevents fibril propagation in protein-misfolding cyclic amplification assays and decreases the number of α-synuclein inclusions in human neuroglioma cells. Computational analysis suggests that SynuClean-D can bind to cavities in mature α-synuclein fibrils and, indeed, it displays a strong fibril disaggregation activity. The treatment with SynuClean-D of two PD Caenorhabditis elegans models, expressing α-synuclein either in muscle or in dopaminergic neurons, significantly reduces the toxicity exerted by α-synuclein.

SynuClean-D-treated worms show decreased α-synuclein aggregation in muscle and a concomitant motility recovery. More importantly, this compound is able to rescue dopaminergic neurons from α-synuclein-induced degeneration. Overall, SynuClean-D appears to be a promising molecule for therapeutic intervention in Parkinson's disease.

Intermittent Living as a Proposal for Enhanced Beneficial Cellular Stress Responses

Intermittent fasting, particularly in the form of fasting mimicking diets that enhance autophagy and last long enough to trigger significant reduction and replacement of immune cells, is growing in popularity as a way to activate the range of cellular stress responses known to modestly improve health. It isn't the only way to alter behavior and the environment to upregulate beneficial cellular stress responses such as autophagy, however. Thus the authors of this open access paper propose that a broader program of periodic challenges should be introduced as a best practice for human health, and be as strongly recommended as regular exercise. The health benefits may be in the same ballpark. They choose to call this "intermittent living." A great deal of gathering and analysis of data lies between here and the realization of their vision, of course.

The number of people with chronic diseases such as cardiovascular diseases (CVD), diabetes, respiratory diseases, mental disorders, autoimmune diseases and cancer has increased dramatically over the last three decades. The increasing rates of these chronic systemic illnesses suggest that inflammation, caused by excessive and inappropriate innate immune system activity, is unable to respond appropriately to danger signals that are new from the perspective of evolution.

These, mostly environment-driven, risk factors seem inevitable in current Western societies and their shares and intensities are most likely destined to further increase in the future. Importantly, many of these risk factors exhibit interaction, while contemporary humans are likely to suffer from these challenges in concert. This contrasts with the stress factors experienced by traditionally living populations who still live in the environment of our ancestors. In that environment, they had to cope with short-term mono-metabolic danger factors (e.g. hunger, thirst, cold, heat), whereas modern humans are exposed to multi-metabolic risk factors that stimulate an energy conflict between organs and major systems. The ensuing conflict between current experience and to what our genes and stress systems are adapted is the basis of the so-called 'mismatch hypothesis' of 'typically Western' diseases.

Mono-metabolic stress factors have shaped adaptive mechanisms for survival and reproduction, such as short-lasting inflammation, insulin resistance, activation of the sympathetic nervous system and others. Mild triggers might at least in part reset physiologic and metabolic dysfunctioning in patients with 'typically Western' diseases. In other words they may provide low-cost opportunities for secondary prevention. Conversely, the chronic absence of mild stress factors may have rendered modern 21st century humans less resistant to major toxic insults and susceptible to the development of many, 'typically Western', chronic diseases of affluence, including metabolic disorders.

Several of our studies showed that the combination of certain intermittent stress factors produce a hormetic early stress response with a compensatory improvement of multiple metabolic and immunological indices, and wellbeing. The employed hormetic triggers included: intermittent fasting, intermittent heat, intermittent cold, intermittent hypoxia, intermittent drinking, and the consumption of a great number of nutrients with hormetic effects. The use of intermittent challenges, combined in a homework-protocol, could serve as a vaccine against the deleterious effects of modern life. We named this concept "intermittent living", defined as the daily intermittent use of known ancient triggers for a period of seven days per month. We propose to use this concept as a basis for interventions for individuals with chronic disease and/or its prevention. Intermittent living is no more than the reintroduction of mild environmentally-based short lasting stress (including cold, heat, hunger, thirst).

Older Mice Heal Skin Injuries More Slowly, but with Less Scarring

Researchers have recently provided evidence for regeneration of skin injuries in old mice to result in lesser degrees of scarring than is the case in young mice. The usual consideration of regeneration with age is that it is disrupted by rising levels of inflammation. Further, the same set of inflammatory mechanisms appear to cause the formation of inappropriate scar-like tissue in organs, the process of fibrosis that contributes to loss of function and organ failure. Finding a way to align those well established results with the data from this study should keep research groups busy for some years. Nothing is simple in mammalian biochemistry.

Organisms repair wounds using a combination of two biological processes: scar formation and tissue regeneration. Scar formation results in deposition of fibrous tissue that disrupts the original tissue architecture. Tissue regeneration results in reconstitution of the original and functional tissue architecture, including all cellular subtypes and absence of scar formation. Although amphibians regenerate lost limbs, mammals generally repair injured tissue with scar formation. However, limited examples of human tissue regeneration do exist, including adult liver regeneration, pediatric traumatic digit tip amputations, and fetal skin wounds. These examples suggest that the mechanisms mediating tissue regeneration remain conserved in mammals.

Human skin wounds invariably form scars. Aging slows the speed of skin re-epithelialization and the subsequent rate of wound repair, but the strength of re-epithelized skin remains roughly the same at any age. Researchers have observed that skin wounds in the elderly close with thinner scars. Indeed, the incidence of keloid and hypertrophic scar formation peaks in the second decade of life and decreases with age. These surprising and somewhat counterintuitive clinical observations suggest that the tissue-regenerative pathway in the skin, instead of being diminished, may be more effective in the elderly. Here we investigated the role of aging as a regulator of mammalian tissue regeneration.

We show that full-thickness skin wounds in aged but not young mice fully regenerate. This aging-induced switch between scar formation and tissue regeneration appears to be a gradual process rather than a binary decision. Exposure of aged animals to blood from young mice by parabiosis counteracts this regenerative capacity. The secreted factor, stromal-derived factor 1 (SDF1), is expressed at higher levels in wounded skin of young mice. Genetic deletion of SDF1 in young skin enhanced tissue regeneration. Our results counter the current dogma that tissue function inevitably worsens with age and uncovers potential mechanisms to explain the paradoxical effect of aging on skin tissue regeneration.

A Lower Estimate for the Degree to Which Cancer is Self-Inflicted

The consensus among researchers has long been that a sizable fraction of all cancers could be avoided, given more exercise, better diet, less excess fat tissue. This is even setting aside the matter of smoking and its significant relationship to cancer. The study here is notable for adopting a slightly different approach from most other analyses, and arriving at lower numbers when it comes to the risk of a poor lifestyle. Whether or not one concurs, it is worth bearing in mind that aging remains the greatest risk factor for cancer incidence.

Cancer is a numbers game, risk over time: the wrong mutation in the wrong place; a mutated cell failing to destroy itself; the immune system failing to save the day by destroying the errant cell; the local tissue environment dysfunctional enough to support cancerous growth of that cell. Live long enough and cancer will happen, even given rejuvenation therapies capable of restoring the immune system, damping down chronic inflammation, and addressing the other most important mechanisms relating to cancer. A comprehensive, robust cure for all cancer is a vital part of the planned future toolkit of longevity assurance treatments.

Excess weight, low physical activity, and unhealthy diet contribute substantially to the development of cancer. However, no information on the attributable cancer incidence is available for the general population in Germany. By applying the concept of population-attributable fractions, we estimated the incidence of cancers attributable to excess weight, low physical activity, and unhealthy diet. Our definitions of normal body weight, recommended level of physical activity and a healthy diet followed the cancer prevention guidelines of the World Cancer Research Fund. We considered all cancer types that have been shown to be related to those lifestyle factors in published meta-analyses of prospective studies comprising 5000 or more cancer cases.

Our study revealed a high prevalence of excess weight, low physical activity, and unhealthy diet among the population in Germany in the period 2008 to 2011. For the population aged 35 to 84 years in 2018 in Germany, we therefore estimated that 30,567 incident cancers will be attributable to excess weight and 27,081 to low physical activity in 2018, corresponding to 7% and 6%, respectively, of the expected total of 440,373 incident cancers in this population. 9,000 to 14,000 cancers (2-3%) will be attributable to low intakes of dietary fiber, fruit, and non-starchy vegetables and high consumption of processed meat, and some 1,000 to 2,000 cases (less than 1%) to high intakes of salt and red meat.


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