Fight Aging! Newsletter, June 20th 2016

June 20th 2016

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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  • New Organ and Organ Preservation Alliance Announce the Vascular Tissue Challenge and Other Initiatives in Organ Engineering
  • Crowdfunding Steps Towards a Universal Cancer Therapy: Help the SENS Research Foundation to Identify Drug Candidates and Mechanisms to Suppress ALT
  • Matching Fund Announced for the Major Mouse Testing Program Fundraiser: Help Reach the Goal in the Final Week Ahead
  • Replacing Neural Stem Cells in the Aging Hippocampus
  • To What Degree is Alzheimer's a Lifestyle Disease?
  • Latest Headlines from Fight Aging!
    • Life Extension Foundation Interview with George Church
    • Aging of Human Egg Cells Associated with Falling Oxygen Levels
    • Subverting Tumor Associated Macrophages in Order to Attack Cancer
    • 15 Minutes of Daily Exercise Associated with 22% Lower Mortality for Older People
    • A Cell Cycle Hypothesis for the Development of Alzheimer's Disease
    • Generating New Pituitary Tissue in Mice
    • Restoring Osteocalcin Levels Reverses Age-Related Decline in Exercise Capacity
    • Human GDF11 Does Not Decline With Age
    • Progress in Tissue Engineered Bone, Matching Natural Bone Structure
    • Stem Cells from Young Mice Heal Stomach Ulcers in Old Mice


The US government is beginning to make more of an overt show of supporting tissue engineering, cryobiology, and other areas that can help move the needle in the field of organ transplantation, as demonstrated by today's White House Organ Summit. It will take some time to see how this pans out; typically the immediate outcome of this sort of public-private partnership is that it becomes easier for private and philanthropic initiatives at the cutting edge to raise funds for projects that can advance the state of the art. Familiarity with the field and its goals spreads, and that helps, as fundraising is always slower when you have to start with an explanation of the basics of what it is you are actually doing. Government funding sources tend to get directly involved only in the much less risky and much later stages of development, however, and that funding typically has much more to do with delivery of existing technology than implementation of new technology. You can look back at comparable US government efforts from past decades, such as the nanotechnology initiative back in 2004, and draw your own conclusions.

For biotechnology, one high level goal for the next twenty years is to generate a much larger and more reliably, high-quality supply of organs and tissues for transplantation. That could be achieved to some degree through better storage methodologies, such as reversible vitrification that would allow indefinite storage of large tissue sections, or through improvements in the ability to repair and make use of donor organs that are presently rejected, perhaps using decellarization approaches presently under development. Further down the line, constructing organs to order from the starting point of cells, preferably a patient's own cells, will completely remove limits on the availability of tissues for transplantation, but a lot of work remains to be accomplished in order to reach that goal. Still, there are many plausible options for near-future development when it comes to making the present situation incrementally better.

The New Organ initiative, run by the Methuselah Foundation, is one of a number of non-profits and advocacy efforts that are each independently focused on progress in tissue engineering. Another organization active in this field and mentioned here today is the Organ Preservation Alliance, for example. These groups are focused on a range of technologies that could reduce the waiting lists and risks for transplants in one way or another. Today, tissue engineering advocates are using the White House meeting on organ shortage issues as a springboard to announce a range of initiatives. This is the way publicity works: it always helps to stand beside the biggest megaphone in the room. For my money, the greater sign of progress is activity in the non-profit sector, the growth in advocacy, rather than purely government initiatives. The leadership here is provided by the non-profits and the advocates. Government agencies only follow years down the line, when the crowds grow large enough - so in a way it is reassuring to see that we seem to have reached that point in the development cycle.

Saving Lives and Giving Hope by Reducing the Organ Waiting List

There are currently more than 120,000 people on the waiting list for an organ in the United States. Every 10 minutes, someone is added to the national waiting list for a life-saving organ transplant. This is despite advances in clinical science and medical innovation over the last decade and widespread recognition by Americans that organ donation and transplantation make a real difference in people's lives. Twenty-two people die every day in the United States while waiting for a life-saving transplant.

We must and can do more. The good news is that reducing the organ waiting list is a problem that can be solved - and that's why today, the Obama Administration and dozens of companies, foundations, universities, hospitals, and patient advocacy organizations are taking steps to change that by announcing a new set of actions that will build on the Administration's efforts to improve outcomes for individuals waiting for organ transplants and support for living donors.

NASA Challenge Aims to Grow Human Tissue to Aid in Deep Space Exploration

NASA, in partnership with the nonprofit Methuselah Foundation's New Organ Alliance, is seeking ways to advance the field of bioengineering through a new prize competition. The Vascular Tissue Challenge offers a 500,000 prize to be divided among the first three teams that successfully create thick, metabolically-functional human vascularized organ tissue in a controlled laboratory environment. Competitors must produce vascularized tissue that is more than .39 inches (1 centimeter) in thickness and maintains more than 85 percent survival of the required cells throughout a 30-day trial period. Teams must demonstrate three successful trials with at least a 75 percent success rate to win an award. In addition to the laboratory trials, teams also must submit a proposal that details how they would further advance some aspect of their research through a microgravity experiment that could be conducted in the U.S. National Laboratory on the International Space Station.

The new challenge was announced as part of White House Organ Summit, which highlighted efforts to improve outcomes for individuals waiting for organ transplants and support for living donors. In a related initiative, the Center for the Advancement of Science in Space (CASIS), which manages the International Space Station U.S. National Laboratory, announced a follow-on prize competition in partnership with the New Organ Alliance and the Methuselah Foundation that will provide researchers the opportunity to conduct research in microgravity conditions. CASIS will provide one team up to 200,000 in flight integration support costs, along with transportation to the ISS National Laboratory, support on station and return of experimental samples to Earth.

Launching Programs to "Stop Biological Time" at the White House Summit on Ending the Organ Shortage

Today, on the shoulders of recent progress suggesting that true organ cryobanking for the first time may be within reach and in partnership with the Thiel Foundation, Association of Organ Procurement Organizations, American Society of Mechanical Engineers, Society for Cryobiology, and New Organ Alliance, the Organ Preservation Alliance is launching:

1) A National Roadmap to Organ Banking Program to develop a consensus national strategy to advance organ and tissue preservation technologies, announced by the White House.

2) The official report from the year long NSF-funded "beta technology roadmapping process" with participation from world leading scientists, physicians and government.

3) A follow-up Dept. of Defense funded Complex Tissue Cryobanking Analysis and Report Process, reflecting the conclusions of the recent workshop at the West Point Military Academy with DARPA and others on the topics of Organs On-Demand and Biological Time control.

4) A companion Global Summit on Organ Banking through Converging Technologies in partnership with the Center for Engineering in Medicine at Massachusetts General Hospital/Harvard/MIT, announced by the White House.

5) A Breakthrough Ideas in Organ Banking Hackathon Program to bring together teams of young scientists, engineers and technology entrepreneurs working on solving the remaining challenges, announced by the White House.

Through these programs and others, scientists, surgeons and leaders are coming together from all over the world to work on the mission to save millions of lives through enabling breakthroughs in complex tissue cryopreservation and transforming transplant, trauma, and regenerative medicine.


The next stage in this year's SENS rejuvenation research funding initiatives launches today: the SENS Research Foundation is crowdfunding a search for drug candidates and mechanisms that can attack all ALT cancers, those that abuse the alternative lengthening of telomeres (ALT) processes to grow. This is a part of the OncoSENS program, which seeks to produce the grounding for a universal cancer treatment platform, based on the one commonality known to be shared by all cancers, which is that cancer cells must lengthen their telomeres, one way or another. You may recall coverage of the SENS Research Foundation ALT research in the scientific press last year. Given the ability to turn off telomere lengthening, then that is also the ability to turn off cancer, any cancer. The cost of mitigating the potential side-effects of this approach, such as loss of stem cell activity, is a small line item in comparison to the cost of present cancer research strategies, as they produce treatments that are expensive to develop, but more importantly can usually only be used for one of the hundreds of subtypes of cancerous growth. To make real progress in cancer, the research community must instead attack the shared vulnerabilities in all cancers, so as to greatly reduce the cost of building viable treatments that will work for many patients, not just a few.

Like other SENS initiatives, OncoSENS, and ALT targeting in particular, is focused on funding an area of research important to aging and longevity science that is presently languishing, largely neglected by the mainstream of the scientific community. There are many such dead zones in the sciences, where the potential for great progress is left untended, usually for no good reason, and too few people are willing to step in to do something about it. The SENS Research Foundation and Methuselah Foundation before it have in a number of cases helped to generate active research and development communities from these dead zones through advocacy and targeted philanthropic funding, and seek to do the same here. A robust and cost-effective cure for cancer is a necessary part of the future rejuvenation toolkit, and prevention of telomere lengthening is a good candidate for the job. The ALT cancer research crowdfunding campaign can be found at, and I encourage you to show your support; this is yet another field that might blossom in the years ahead thanks to exactly this sort of effort.

OncoSENS: Control ALT, Delete Cancer

Of all the risk factors associated with cancer: obesity, smoking, sun exposure etc., there is none more universal than aging. Therefore it is of paramount importance to develop new anti-cancer approaches to meet the humanitarian and economic challenges associated with our aging global population. One such approach is to target cancers that employ a particular mechanism to achieve cellular immortality - Alternative Lengthening of Telomeres, or "ALT".

Every time a normal somatic cell divides, the DNA at the ends of its chromosomes, called telomeres, gets shorter. When the telomeres shorten too much, the cell permanently stops dividing and either enters senescence or undergoes apoptosis (programmed cell death). Telomere shortening thus acts as a biological mechanism for limiting cellular life span. Most cancer cells bypass this failsafe by synthesizing new telomeres using the enzyme telomerase. Several therapies targeting this well-described telomerase-based pathway are in the advanced stages of clinical development, but as with any cancer therapy there is the potential for development of resistance against telomerase-based strategies to defeat cancer. Studies using mice and human cancer cell lines have demonstrated that cancer can overcome the loss of telomerase by using a telomerase-independent mechanism called alternative lengthening of telomeres (ALT). Furthermore, existing tumor cells in mice have also been observed to switch over to the ALT pathway as a result of telomerase-inhibiting treatment. It is therefore plausible that telomerase-dependent cancer treatments will introduce selective pressures in human tumors to activate the ALT pathway and/or select for cells already using ALT within the tumor. This makes the development of ALT-specific therapies imperative for the success of complete anti-cancer approaches.

There are currently no ALT-targeted anti-cancer therapeutics, however, largely because this process is much less well understood. A key step towards the development of ALT-targeted cancer therapeutics and diagnostics was the discovery of the first ALT-specific molecule, the telomeric C-circle, by our collaborator, Dr. Jeremy Henson, back in 2009. C-circles are an unusual type of circular DNA sequences that are created from telomeres. The level of C-circles in cancer cells accurately reflects the level of ALT activity, and this biomarker can be found in the blood of patients who have bone cancers positive for ALT activity. The OncoSENS research team at the SENS Research Foundation, in collaboration with Dr. Jeremy Henson at the University of New South Wales in Australia, has developed a novel version of the C-circle assay that can be fully automated using robotic liquid handlers, making it now feasible to perform robust high-throughput screenings to search for chemical modulators of the ALT pathway.

The goal of this project is to screen a library of about 115,000 compounds containing structurally diverse, medicinally active, and cell permeable drugs from a variety of fields of medicine (oncology, cardiology, and immunology, etc.), for inhibitors of the ALT pathway. The crucial advantage of making use of such drug libraries, which are richly documented and contain some FDA approved compounds, is that once hits are identified and validated using our ALT-specific assays they can potentially be repurposed for the treatment of patients with ALT cancers through cheaper, faster and safer preclinical and clinical validation protocols. Our initial goal of 60,000 will allow us to test a significant subgroup of this library, and reaching a stretch goal of 200,000 will allow us to test them all.

While a few groups are presently working on inhibition of telomerase-based telomere lengthening in cancer, and the majority of cancers use telomerase rather than ALT when left to their own devices, as noted above it is clearly the case that ALT inhibition is an essential part of this approach to a universal cancer therapy. Unfortunately, the SENS Research Foundation is one of the very few groups funding any significant work in this area of cancer research. Still, there is a real opportunity here, and with the falling cost of early stage research, a great deal of useful work can be accomplished with comparatively little funding. Working through the most promising parts of standard drug libraries should produce leads on drug candidates and mechanisms for interfering with ALT that will attract the interest of other investigators. Taking this step is necessary if the telomere interdiction approach to cancer is to grow, and funding the important work that others do not is exactly how the SENS Research Foundation has produced considerable success in other areas of aging research.

I really can't overstate how important it is to change the nature of cancer research, steering the scientific community away from the approach of one costly research project per subtype of cancer and towards the production of a single technology that can attack all cancers with minimal adjustment. I will be donating to this OncoSENS crowdfunding initiative, and I encourage you to do so as well. It is an rare chance to nudge cancer researchers towards a better, more effective strategic direction, to help start an avalanche that will pay off greatly in the years ahead, with therapies that can target all forms of cancer.


The clock is counting down on the Major Mouse Testing Program (MMTP) fundraiser at With just over a week to go, more than 400 donors have given a total of nearly 40,000 so far. These funds will be used to run tests of senolytic drugs to clear senescent cells in aged mice, the first of what will hopefully be a series of useful studies carried out by this group, working to push treatments for the causes of aging closer to the clinic. The initial goal for the fundraiser is 45,000, and a matching fund has been announced to help close the gap in the next few days. Donate, and your donation will be matched:

Hello dear friends! There are 10 days left before the Senolytics campaign ends, and it is time to make a final dash to the finish line!

Some great news from Healthy Life Extension Society (Heales) leader Didier Coeurnelle. He has offered a FUND MATCH! Whatever we will raise from Tuesday, June 14, 11 AM UTC (6 AM EST) to Thursday, June 16, 11 AM UTC (6 AM EST) up to 2500 will be doubled! Didier is Co-chair of Heales, the largest non-profit organization in Continental Europe promoting and advocating scientific research into longevity and biogerontology, and vice-president of the French association AFT-Technoprog, that aims to spread the themes and questions related to technologies that could extend and enhance the lives of individuals and of humankind.

If you will contribute during this period, every donation will be doubled - and the project will receive a nice push to get us to our goal!

It is generally agreed upon now in the broader research community that senescent cells are a meaningful component of degenerative aging. They accumulate over time in all tissues, and secrete a mix of signals that, among other things, spurs greater inflammation, damages tissue structure, and increases the odds of nearby cells also becoming senescent. Their presence accelerates the development of all of the major age-related diseases - but all of this could be removed given a way to selectively destroy these cells. Fortunately senescent cells are already primed to self-destruction, and all that needs to be done is to nudge them in that direction, something that can be achieved through drugs. A senolytic drug can issue a modest prompt to destruction to all cells, and only senescent cells will be pushed across the line. The Major Mouse Testing Program volunteers have an active YouTube channel, and over the past few weeks have conducted a number of video interviews with members of the research and advocacy community on the value of senescent cell clearance and mouse testing in this field. You'll find a few of these linked below:

MMTP - Major Mouse Testing Program - Interview with Joao Pedro de Magalhaes

Today we would like to help you learn more about mice. Yes, mice are nice, but apart from that they are one of the best models for aging research. Here is one of our scientific advisors Dr. Aubrey de Grey from SENS speaking about the importance and relevance of mouse studies in the research of aging and interventions against it.


Today I'll point out progress towards an as yet unrealized category of stem cell treatments involving the wholesale replacement of entire stem cell populations and their niches, to remove age-related damage and sustain tissue maintenance for the long term. This will become an essential component for any future rejuvenation toolkit. From a stem cell perspective, rejuvenation has two components: firstly revert the root causes of signaling changes in blood and tissues that result in stem cell populations becoming less active; secondly, replace the stem cells themselves, scores of different types in different locations, to clear out damaged cells. The root cause of signaling changes in old individuals is, collectively, all of the forms of damage listed in the SENS proposals for rejuvenation treatments - a lot of work is yet to be accomplished there to reach even the initial goals of prototype treatments across the board. Nonetheless, it is still the case that replacement of aged stem cell populations with undamaged, pristine stem cells created from the patient's own cells is an important target for future development in the stem cell field.

Most stem cell therapies in use today are actually far removed from this goal: the transplanted cells do not live long, and do not integrate with recipient tissues. They achieve beneficial effects through a temporary alteration of the signaling environment that spurs regeneration and reduces inflammation. In effect the transplant temporarily overrules the evolved reaction to being aged and damaged and puts sleeping cells back to work - but without fixing that low level damage. So there can be some degree of rebuilding of worn tissues and organs, but the causes of aging are still present and continue to cause harm: cross-links, mitochondrial mutations, and so forth.

There are exceptions to the outcome of benefits through signaling mechanisms, however, and these exceptions include types of therapy in which cells are transplanted into the brain. Some of the earliest stem cell transplants trialed in humans aimed to treat Parkinson's disease, for example, and at least some of the transplanted cells survived and integrated into the brains of patients for the long term. This is still a considerable distance removed from a controlled repopulation of stem cell niches in all of the right places and with cells that will pick up tissue maintenance activities in exactly the right ways, but it is a step in the right direction. In the research materials linked below, scientists report on further progress along these lines, and that they were able to create new stem cell niches in brain tissue seems like an important advance:

Regenerating Memory with Neural Stem Cells

Although brains - even adult brains - are far more malleable than we used to think, they are eventually subject to age-related illnesses, like dementia, and loss of cognitive function. Someday, though, we may actually be able to replace brain cells and restore memory. Recent work hints at this possibility with a new technique of preparing donor neural stem cells and grafting them into an aged brain. The team took neural stem cells and implanted them into the hippocampus - which plays an important role in making new memories and connecting them to emotion - of an animal model, essentially enabling them to regenerate tissue.

"We're very excited to see that the aged hippocampus can accept grafted neural stem cells as superbly as the young hippocampus does and this has implications for treating age-related neurodegenerative disorders. It's interesting that even neural stem cell niches can be formed in the aged hippocampus." The team found that the neural stem cells engrafted well onto the hippocampus in the young animal models (which was expected) as well as the older ones that would be, in human terms, about 70 years old. Not only did these implanted cells survive, they divided several times to make new cells. "They had at least three divisions after transplantation. So the total yield of graft-derived neurons and glia (a type of brain cell that supports neurons) were much higher than the number of implanted cells, and we found that in both the young and aged hippocampus, without much difference between the two. What was really exciting is that in both old and young brains, a small percentage of the grafted cells retained their 'stemness' feature and continuously produced new neurons."

This is called creating a new 'niche' of neural stem cells, and these niches seemed to be functioning well. "They are still producing new neurons at least three months after implantation, and these neurons are capable of migrating to different parts of the brain. Next, we want to test what impact, if any, the implanted cells have on behavior and determine if implanting neural stem cells can actually reverse age-related learning and memory deficits. That's an area that we'd like to study in the future."

Grafted Subventricular Zone Neural Stem Cells Display Robust Engraftment and Similar Differentiation Properties and Form New Neurogenic Niches in the Young and Aged Hippocampus

As clinical application of neural stem cell (NSC) grafting into the brain would also encompass aged people, critical evaluation of engraftment of NSC graft-derived cells in the aged hippocampus has significance. We examined the engraftment and differentiation of alkaline phosphatase-positive NSCs expanded from the postnatal subventricular zone (SVZ), 3 months after grafting into the intact young or aged rat hippocampus. Graft-derived cells engrafted robustly into both young and aged hippocampi. Although most graft-derived cells pervasively migrated into different hippocampal layers, the graft cores endured and contained graft-derived neurons.

The results demonstrate that advanced age of the host at the time of grafting has no major adverse effects on engraftment, migration, and differentiation of grafted subventricular zone-neural stem cells (SVZ-NSCs) in the intact hippocampus, as both young and aged hippocampi promoted excellent engraftment, migration, and differentiation of SVZ-NSC graft-derived cells in the present study. Furthermore, SVZ-NSC grafts showed ability for establishing neurogenic niches in non-neurogenic regions, generating new neurons for extended periods after grafting. This phenomenon will be beneficial if these niches can continuously generate new neurons and glia in the grafted hippocampus, as newly generated neurons and glia are expected to improve, not only the microenvironment, but also the plasticity and function of the aged hippocampus. Overall, these results have significance because the potential application of NSC grafting for treatment of neurodegenerative disorders at early stages of disease progression and age-related impairments would mostly involve aged persons as recipients.


Type 2 diabetes is the archetypal lifestyle disease, a metabolic dysfunction run out of control to the point at which it disrupts the crucial mechanisms of insulin metabolism. Diabetes isn't accelerated aging, but it has many of the same consequences when viewed from the high level: more damage, more disease, higher mortality. The vast majority of type 2 diabetics have this condition as a result of the choices they made. It is easy to become fat in a world of low-cost calories and increasing wealth, but it is still a choice. We can turn a questioning eye to Alzheimer's disease, a progressive age-related dementia characterized by a range of changes in the biochemistry of the brain, such as amyloid and tau deposits, and ask to what degree it is a lifestyle condition, driven by visceral fat tissue, lack of exercise, and the like. When looking at lifestyle choices and risk, the answers are more ambiguous than is the case for type 2 diabetes, however. Consider cardiovascular disease, for example. You can lead a life that makes you much more likely to die young from a heart attack, but equally everyone will suffer cardiovascular failure if they live long enough - the processes that weaken the heart and corrode our blood vessels operate in everyone, just more rapidly in the obese.

Is Alzheimer's more like type 2 diabetes, 90% avoidable over a normal human life span for the diligent, or is it more like cardiovascular disease, inevitable for all of us, absent radical progress in medical science, but arriving sooner for the less diligent? You'll see arguments either way if you wander the literature, most of which lean in the direction of Alzheimer's as a lifestyle condition, but not to the same degree as type 2 diabetes. A good meta-analysis from last year puts some numbers to that summary: if nine-tenths of type 2 diabetes is self-inflicted, then one can argue for two-thirds of Alzheimer's to be self-inflicted by the same types of statistical approach. Being overweight is definitely on the list: the distortions of metabolism caused by excess visceral fat tissue impact the brain. There is even a faction within the research community who argue that Alzheimer's is a type 3 diabetes, in effect.

Perhaps a better measure of the degree to which a medical condition is a lifestyle condition is whether or not it can be effectively treated, reversed, or cured by lifestyle changes alone. This is the case for type 2 diabetes. Even fairly late in its progression, calorie restriction and consequent loss of fat tissue can turn things around for a majority of patients, to the point of a cure. It is somewhat amazing that so many people continue down the road of disability when they could turn back at any time. For cardiovascular disease, lifestyle interventions like increased regular moderate exercise are beneficial, but in the way of a delaying tactic. You can improve the present poor situation, but you can't choose your way to back to full health for your age given the tools available. When it comes to the option to turn back, is Alzheimer's disease more like type 2 diabetes or more like cardiovascular disease, once it has taken hold?

The publicity materials and paper I'll point out today add a little more data from a small set of patients to the present evidence on this topic, putting Alzheimer's more in line with what one might expect from comparing the risk factors. Note the date on the paper, two years ago, versus the date on the publicity, however, this week. These results have been languishing for a few years, and by the look of it the researchers involved are now attempting another angle to broaden support for their approach - whenever book publication is mentioned in a release, it's a fair guess that the forthcoming book is why the release exists. Pitching a strategy of lifestyle changes to the usual panoply of research funding sources has ever had the problem that lifestyle changes are a poor foundation for a for-profit business, and are in any case well outside the area of interest for most for-profit funding sources relevant to medical research. It took some years for the calorie restriction research community to figure out a way to get for-profit interests involved, for example. That sort of challenge may well be what is taking place behind the scenes here, but equally it could simply be a mundane case of business failure for reasons unrelated to the science.

Pre and post testing show reversal of memory loss from Alzheimer's disease in ten patients

Results from quantitative MRI and neuropsychological testing show unprecedented improvements in ten patients with early Alzheimer's disease (AD) or its precursors following treatment with a programmatic and personalized therapy dubbed metabolic enhancement for neurodegeneration (MEND). The study is the first to objectively show that memory loss in patients can be reversed, and improvement sustained, using a complex, 36-point therapeutic personalized program that involves comprehensive changes in diet, brain stimulation, exercise, optimization of sleep, specific pharmaceuticals and vitamins, and multiple additional steps that affect brain chemistry. "All of these patients had either well-defined mild cognitive impairment (MCI), subjective cognitive impairment (SCI) or had been diagnosed with Alzheimer's disease before beginning the program. Follow up testing showed some of the patients going from abnormal to normal."

All but one of the ten patients included in the study are at genetic risk for AD, carrying at least one copy of the APOE4 allele. Five of the patients carry two copies of APOE4 which gives them a 10-12 fold increased risk of developing AD. "We're entering a new era. The old advice was to avoid testing for APOE because there was nothing that could be done about it. Now we're recommending that people find out their genetic status as early as possible so they can go on prevention." Sixty-five percent of the Alzheimer's cases in this country involve APOE4; with seven million people carrying two copies of the ApoE4 allele. "The magnitude of improvement in these ten patients is unprecedented, providing additional objective evidence that this programmatic approach to cognitive decline is highly effective. Even though we see the far-reaching implications of this success, we also realize that this is a very small study that needs to be replicated in larger numbers at various sites."

Reversal of cognitive decline in Alzheimer's disease

Effective treatment of Alzheimer's disease has been lacking, but recently a novel programmatic approach involving metabolic enhancement was described, with promising anecdotal results. This treatment is based on connectomic studies and previous transgenic findings as well as epidemiological studies of various monotherapeutic components of the overall program. The approach is personalized, responsive to suboptimal metabolic parameters that reflect a network imbalance in synaptic establishment and maintenance vs. reorganization, and progressive in that continued optimization is sought through iterative treatment and metabolic characterization.

Here we report the initial follow-up of ten patients who were treated with this metabolic programmatics approach. One patient had well documented mild cognitive impairment (MCI), with a strongly positive amyloid-PET (positron emission tomography) scan, positive FDG-PET scan (fluorodeoxyglucose PET scan), abnormal neuropsychological testing, and hippocampal volume reduced to 17th percentile; after 10 months on the MEND protocol, his hippocampal volume had increased to 75th percentile, in association with a reversal of cognitive decline. Another patient had well documented early Alzheimer's disease, with a positive FDG-PET scan and markedly abnormal neuro-psychological testing. After 22 months on the MEND protocol, he showed marked improvement in his neuropsychological testing, with some improvements reaching three standard deviations from his earlier testing.

The initial results for these patients show greater improvements than have been reported for other patients treated for Alzheimer's disease. The results provide further support for the suggestion that such a comprehensive approach to treat early Alzheimer's disease and its precursors, MCI and SCI, is effective. The results also support the need for a large-scale, personalized clinical trial using this protocol.



Here, Greg Fahy interviews George Church on the topic of gene therapies, gene expression changes in aging, and the aim of treating aging as a medical condition in a recent issue of Life Extension Magazine. Both of these researchers are enthusiastic about the path of identifying and reverting age-related changes in gene expression, something I consider to be most likely less useful than targeting root cause damage after the SENS model for rejuvenation therapies. Still, present day stem cell therapies are probably a good indication of the sort of result that can be achieved through gene expression alteration, as they largely work through signaling changes: putting damaged machinery back to work without fixing the underlying damage that causes aging. It can be argued that these gains are large enough to pursue, and we should just be aware that it isn't the path to controlling and halting aging, only the path to a class of therapies for age-related disease that are incrementally better than existing ones.

Fahy: If aging is driven by changes in gene expression, then the ability to control gene expression using CRISPR technology could have profound implications for the future of human aging. Why do you think aging may be at least partly driven by changes in gene expression?

Church: We know that there are cells that deteriorate with age in the human body and that we have the ability to turn those back into young cells again. This means we can effectively reset the clock to zero and keep those cells proliferating as long as we want. For example, we can take old skin cells, which have a limited lifetime, and turn them into stem cells (stem cells are cells that can turn into other kinds of cells) and then back into skin cells. This roundtrip results in the skin cells being like baby skin cells. It's as if my 60-year-old cells become 1-year-old cells. There are a variety of markers that are associated with aging, and those all get reset to the younger age.

Fahy: There are several very exciting stories in aging intervention these days. In 2013, the Sinclair lab at Harvard came out with the revelation that the aging of mitochondria (which are the producers of usable energy within cells) is driven in significant part by reduced levels of one particular molecule in the cell nucleus: oxidized NAD (NAD+). Now your lab showed that there is a very exciting gene engineering alternative involving TFAM (Transcription Factor A, Mitochondrial). Why is TFAM important, and what have you done with it?

Church: TFAM is a key regulatory protein that is in this pathway of NMN and NAD+. It allows cells to manufacture the NMN precursor on their own, so you don't have to manufacture it outside the cell and then try to get it into the cell from outside. Ideally, you don't want to have to take NMN for the rest of your life, you want to fix the body's ability to make its own NMN and buy yourself rejuvenation for at least a few decades before you have to worry about NMN again. In order to accomplish this on a single cell level, we've used CRISPR to activate a TFAM activator, and we made it semi-permanent. When we activated TFAM, these changes returned to what you would expect of a younger cell state. And we built this anti-aging ability into the cell, so it's self-renewing and eliminates the need to take pills or injections.

Fahy: GDF11 has been reported to rejuvenate the heart, muscles, and brain. It restores strength, muscle regeneration, memory, the formation of new brain cells, blood vessel formation in the brain, the ability to smell, and mitochondrial function. All of this is done by just one molecule. Infusing young plasma, which contains GDF11, into older animals also provides benefits in other tissues, such as the liver and spinal cord, and improves the ability of old brain cells to form connections with one another. How would you use CRISPR to make sure that GDF11 blood levels never go down?

Church: The CRISPR-regulating GDF11 could be delivered late in life, which is exactly when such an increase would be welcome. If you really wanted to stay at a certain level, you might want to put in a GDF11 sensor to provide feedback so you could automatically control GDF11 production so as to lock in a specific GDF11 level. If necessary, you could recalibrate and fine-tune this maybe once every few decades with another dose of CRISPR. But yes, it's a great molecule, and we've got a handle on it. We are also doing a number of other projects now, dealing with a range of muscle diseases such as muscle wasting. We're working on possible treatments involving proteins such as myostatin and follistatin.

Fahy: Speaking of myostatin, the lack of which causes super-development of muscles, you mentioned in your 2014 SENS talk that you are interested in the possibility of enabling better muscle strength and less breakable bones. Is this another good treatment path for aging?

Church: Muscle wasting and osteoporosis are symptoms of aging. The key to dealing with them is to get at the core causes, even if they're complicated. There are genes known to be involved in muscle wasting and genes that can overcome that.

Fahy: What about going beyond just correcting aging and actually super-protecting people by making them augmented with stronger bones or muscles than what they would normally have?

Church: Rather than waiting until the muscles are wasting and then trying to correct the problem, or waiting until someone breaks a bone and putting a cast on, the idea is to make the muscles and bones stronger to begin with. Think of it as preventive medicine. You have to be careful, but there are people naturally walking around with much denser bones and much stronger muscles that have no particularly bad consequences, so we know such things are possible. I would say osteoporosis definitely could be reversed. The process of bone building and bone breaking down is a regulated process that responds to conditions such as the good stress of standing or running. So yes, it's an example of something that's reversible.

Fahy: Using your most favorable pathway for intervention, how long will it take before a human trial might be possible?

Church: I think it can happen very quickly. It may take years to get full approval, but it could take as little as a year to get approval for phase one trials. Trials of GDF11, myostatin, and others are already underway in animals, as are a large number of CRISPR trials. I think we'll be seeing the first human trials in a year or two.


Researchers here identify a possible proximate mechanism associated with the age-related decline of human fertility. It is a little early in the research process to say what might be made of this, or how it connects to the underlying causes of degenerative aging, however.

Researchers have examined the sharp decline in egg quality in women 40 and older and found that egg damage is linked to oxygen-deprived cells. "More women are postponing childbearing, but with age, the cumulus cells that surround and nurture the eggs begin dying; we've found that this is caused by lack of oxygen. This follicular hypoxia triggers a cascade of biochemical changes in the cumulus cells. This may ultimately affect chromosomal abnormalities seen in eggs of older patients."

The researchers studied samples from 20 cumulus cells in 15 patients younger than age 35 and in those age 40 and older. The team looked for differences in RNA expression in both sets of patients. They found significant differences in RNA molecules in the cumulus cells of older patients when compared to RNA expressed in cells of patients younger than 35. Changes in the ovarian microenvironment, such as reduced oxygen supply to the growing follicles are likely causes of ovarian aging. "Our data show that cumulus cells from older women are affected by a chronic exposure to suboptimal oxygen levels, as indicated by an increased expression of hypoxia-induced genes when compared to the same cells collected in younger patients. Our findings shed light on the mechanisms responsible for human egg aging. We have always been intrigued by the questions, 'Who is the time keeper of egg aging?' and 'How are the eggs informed of the biological clock?' Now we know that changes in RNA of the cumulus cells triggered by aging-induced hypoxia, are the key messengers. The ability to screen cumulus cells for oxygen deprivation may help us identify healthier eggs, modify ovarian stimulation protocols, and ultimately lead to more successful in vitro fertilization treatments."


Potential cancer therapies that can address many types of cancer should be a primary focus of the cancer research community. There are far too many varieties of cancer to do otherwise if the goal is rapid progress towards the control of cancer. In this early stage research, researchers report on an approach to using immune cells hijacked by cancerous tissue as a way to attack the cancer. This could in principle be applied to numerous types of cancer:

Along with attacking foreign pathogens like bacteria, macrophages also help the body's organs develop and its wounds heal. Their own behavior is fine-tuned by small molecules that they produce, called microRNAs. When a tumor begins to develop, macrophages attempt to block its growth. But often tumors hijack them and convert them into what are known as "tumor-associated macrophages", or TAMs for short. Now corrupted, TAMs use their microRNAs to shield the tumor from the patient's immune system, helping it grow and metastasize. This phenomenon is common across many tumor types. It is one of the major obstacles in treating cancer, and often leads to a poor prognosis for the patient.

Researchers have now found how to reclaim TAMs. The researchers genetically modified TAMs to remove their ability to produce microRNAs. As a result, the TAMs were reprogrammed dramatically. Instead of protecting the tumor, the TAMs now signaled the presence of the tumor to the immune system, triggering attacks against it - and did so very efficiently. Using a bioinformatics approach, the researchers found that the most likely culprit was a small family of microRNAs, called Let-7. This offers a more specific target: blocking Let-7 microRNAs may help instruct the TAMs to stimulate anti-tumor immunity. Interestingly, the researchers observed that reprogramming TAMs also stops cancer cells from leaving the primary tumor. This could mean that the approach can also prevent tumor metastasis, the most threatening aspect of cancer. Moreover, the researchers found that the re-educated TAMs could enhance the anti-tumoral efficacy of certain cancer immunotherapies, some of which are already approved for patients. However, more work is needed to translate all these findings to actual therapies, especially since there is currently no way to block the Let-7 microRNAs selectively in TAMs. But researchers are now working to design drugs that can target the Let-7 microRNAs specifically in the TAMs.


The study linked here is one of many examples of the correlation between regular moderate exercise and mortality rate found in human epidemiological data. In animal studies it can be proven that exercise causes reduced mortality, but that is very hard to demonstrate directly in human populations - researchers can't just set up the same experimental groups and wait. So statistical methods are used, and the combination of those and the animal studies gives a good level of confidence to suggest that yes, it is a matter of exercise providing benefits rather than a matter of people more likely to live longer regardless also being more likely to exercise.

Fifteen minutes of daily exercise is associated with a 22% lower risk of death and may be a reasonable target for older adults. The authors studied two cohorts. A French cohort of 1011 subjects aged 65 in 2001 was followed over a period of 12 years. An international cohort of 122,417 subjects aged 60 was included from a systematic review and meta-analysis, with a mean follow up of 10 years. Physical activity was measured in Metabolic Equivalent of Task (MET) minutes per week, which refers to the amount of energy (calories) expended per minute of physical activity. One MET minute per week is equal to the amount of energy expended just sitting. The number of MET minutes an individual clocks up every week depends on the intensity of physical activity. For example, moderate intensity activity ranges between 3 and 5.9 MET minutes while vigorous intensity activity is classified as 6 or more. The recommended levels of exercise equate to between 500 and 1000 MET minutes every week. The authors looked at the associated risk of death for four categories of weekly physical activity in MET minutes, defined as inactive (reference for comparison), low (1-499), medium (500-999) or high (≥1000).

During the follow up there were 88 (9%) and 18,122 (15%) deaths in the French and international cohorts, respectively. The risk of death reduced in a dose response relationship as the level of exercise increased. Compared to those who were inactive, older adults with low, medium and high activity levels had a 22%, 28% and 35% lower risk of death, respectively. "These two studies show that the more physical activity older adults do, the greater the health benefit. The biggest jump in benefit was achieved at the low level of exercise, with the medium and high levels bringing smaller increments of benefit. We think that older adults should progressively increase physical activity in their daily lives rather than dramatically changing their habits to meet recommendations. Fifteen minutes a day could be a reasonable target for older adults. Small increases in physical activity may enable some older adults to incorporate more moderate activity and get closer to the recommended 150 minutes per week."


The development of treatments for Alzheimer's disease based on clearance of amyloid continues to be a struggle, and it is still unclear as to whether this is because it is an inherently hard task, or because amyloid aggregates are not the most important contributing cause of this condition. Given that theorizing is a lot easier than building therapies, all delays in evident progress tend to give rise to a lot of theorizing. There is a prolific construction of alternative hypotheses regarding the biochemistry of Alzheimer's disease, its causes and progression. This example of one such a hypothesis has little support for its thesis in the broader research community, but is interesting as an example of the range of thinking taking place on this topic:

Early-onset familial Alzheimer's disease (EOFAD) and late-onset sporadic AD (LOSAD) both follow a similar pathological and biochemical course that includes: neuron and synapse loss and dysfunction, microvascular damage, microgliosis, extracellular amyloid-β deposition (Aβ), and the deposition of phosphorylated tau protein in the form of intracellular neurofibrillary tangles in affected brain regions. Any mechanistic explanation of AD must accommodate these biochemical and neuropathological features for both forms of the disease.

Cell cycle abnormalities represent another major biochemical and neuropathological feature common to both EOFAD and LOSAD, and 1) appear very early in the disease process, prior to the appearance of plaques and tangles, and 2) explain the biochemical (e.g., tau phosphorylation), neuropathological (e.g., neuron hypertrophy) and cognitive changes observed in EOFAD and LOSAD. Since neurogenesis after the formation of a memory is sufficient to induce forgetting, any stimulus that promotes cell cycle re-entry will be a negative event for memory. In this insight paper, we propose that aberrant re-entry of terminally differentiated, post-mitotic neurons into the cell cycle is a common pathway that explains both early and late-onset forms of AD. In the case of EOFAD, mutations in APP, PSEN1, and PSEN2 that alter AβPP and Notch processing drive reactivation of the cell cycle, while in LOSAD, age-related reproductive endocrine dyscrasia that upregulates mitogenic TNF signaling, AβPP processing toward the amyloidogenic pathway and tau phosphorylation drives reactivation of the cell cycle. Inhibition of cell cycle reentry of post-mitotic neurons may be a useful therapeutic strategy to prevent or halt disease progression.


Researchers have announced another step forward in the development of methods of regeneration that should one day encompass all tissue types and organs in the body. This time the pituitary gland is the target, and the approach used here well illustrates the point that engineered replacements do not have to be in any way similar to the organ they are replacing. They just have to carry out the same functions.

Researchers have successfully used human stem cells to generate functional pituitary tissue that secretes hormones important for the body's stress response as well as for its growth and reproductive functions. When transplanted into rats with hypopituitarism the lab-grown pituitary cells promoted normal hormone release. "The current treatment options for patients suffering from hypopituitarism, a dysfunction of the pituitary gland, are far from optimal. Cell replacement could offer a more permanent therapeutic option with pluripotent stem cell-derived hormone-producing cells that functionally integrate and respond to positive and negative feedback from the body. Achieving such a long-term goal may lead to a potential cure, not only a treatment, for those patients."

The pituitary gland is the master regulator of hormone production in the body, releasing hormones that play a key role in bone and tissue growth, metabolism, reproductive functions, and the stress response. Hypopituitarism can be caused by tumors, genetic defects, brain trauma, immune and infectious diseases, or radiation therapy. The consequences of pituitary dysfunction are wide ranging. Currently, patients with hypopituitarism must take expensive, lifelong hormone replacement therapies that poorly mimic the body's complex patterns of hormone secretion that fluctuates with circadian rhythms and responds to feedback from other organs. By contrast, cell replacement therapies hold promise for permanently restoring natural patterns of hormone secretion while avoiding the need for costly, lifelong treatments.

Recently, scientists developed a procedure for generating pituitary cells from human pluripotent stem cells - an unlimited cell source for regenerative medicine - using organoid cultures that mimic the 3D organization of the developing pituitary gland. However, this approach is inefficient and complicated. To address these limitations, researchers developed a simple, efficient, and robust stem cell-based strategy for reliably producing a large number of diverse, functional pituitary cell types suitable for therapeutic use. Instead of mimicking the complex 3D organization of the developing pituitary gland, this approach relies on the precisely timed exposure of human pluripotent stem cells to a few specific cellular signals that are known to play an important role during embryonic development. Exposure to these proteins triggered the stem cells to turn into different types of functional pituitary cells.

To test the therapeutic potential of this approach, the researchers transplanted the stem cell-derived pituitary cells under the skin of rats whose pituitary gland had been surgical removed. The cell grafts not only secreted adrenocorticotropic hormone, prolactin, and follicle-stimulating hormone, but they also triggered appropriate hormonal responses in the kidneys. The researchers were also able to control the relative composition of different hormonal cell types simply by exposing human pluripotent stem cells to different ratios of two proteins: fibroblast growth factor 8 and bone morphogenetic protein 2. This finding suggests their approach could be tailored to generate specific cell types for patients with different types of hypopituitarism.


Osteocalcin levels decline with age, one of many age-related changes in production of specific proteins. Researchers here demonstrate that introducing additional osteocalcin restores age-related loss of exercise capacity in mice. This is yet another possibility to add to the list of potential gene therapies that might be developed to offset some of the changes that occur with aging, though as for all such alterations, it doesn't address root causes. Though not mapped at the present time, the view of aging as damage accumulation expects there to be a chain of cause and effect leading from increased cell and tissue damage at the root of aging to a series of consequent changes that leads to a reduction in the gene expression of ostoeclastin.

When we exercise, our bones produce a hormone called osteocalcin that increases muscle performance. Osteocalcin naturally declines in humans as we age, beginning in women at age 30 and in men at age 50. During exercise in mice and humans, the levels of osteocalcin in the blood increase depending on how old the organism is. The researchers observed that in 3-month-old adult mice, osteocalcin levels spiked approximately four times the amount that the levels in 12-month-old mice did when the rodents ran for 40 minutes on a treadmill. The 3-month-old mice could run for about 1,200 meters before becoming exhausted, while the 12-month-old mice could only run half of that distance.

To investigate whether osteocalcin levels were affecting exercise performance, researchers tested mice genetically engineered so the hormone couldn't signal properly in their muscles. Without osteocalcin muscle signaling, the mice ran 20%-30% less time and distance than their healthy counterparts before reaching exhaustion. Surprisingly, when healthy mice that were 12 and 15 months old - whose osteocalcin levels had naturally decreased with age - were injected with osteocalcin, their running performance matched that of the healthy 3-month-old mice. The older mice were able to run about 1,200 meters before becoming exhausted. "It was extremely surprising that a single injection of osteocalcin in a 12-month-old mouse could completely restore its muscle function to that of a 3-month-old mouse."

To determine the cellular mechanisms behind osteocalcin's effects, the team measured levels of glycogen, glucose, and acylcarnitines (an indicator of fatty-acid use) in mice with and without osteocalcin. The researchers determined that the hormone helps muscle fibers uptake and catabolize glucose and fatty acids as nutrients during exercise. "It's never been shown before that bone actually influences muscle in any way. Osteocalcin is not the only hormone responsible for adaptation to exercise in mice and humans, but it is the only known bone-derived hormone that increases exercise capacity. This may be one way to treat age-related decline in muscle function in humans."


Researchers have in the past couple of years shown that GDF11 levels decline with age in mice, and that restoring youthful GDF11 in old mice improves numerous measures of health. The mechanism involved may be increased stem cell activity. There has been some debate over whether the teams involved are in fact measuring what they think they are measuring, however. New human data in the research noted here today muddies the water some more, though these researchers are also claiming an improvement in the approach to measurement of GDF11 levels. This suggests that either mice and humans are different in this aspect of aging, or that the issues in prior methods of measurement were more prevalent than thought, or both. The outcome of improved health in aged mice following introduction of additional GDF11 isn't disputed, so it will be interesting to see how these various results are reconciled:

Researchers have developed an accurate way to measure a circulating factor, called GDF11, to better understand its potential impact on the aging process. They found that GDF11 levels do not decline with chronological age, but are associated with signs of advanced biological age, including chronic disease, frailty and greater operative risk in older adults with cardiovascular disease. "Aging is the primary risk factor for the majority of chronic diseases, so it is critical to identify and understand the biomarkers, or indicators, in the body that are linked to this process. The role of GDF11 as a biomarker of aging and its association with age-related conditions has been largely contradictory, in part, because of how difficult it has been to measure. We have developed a new way to measure GDF11 that is accurate and effective."

A challenge of previous measurements was differentiating between the circulating levels of GDF11 and those of a highly-related protein, myostatin. To overcome this, researchers developed an extremely precise assay that can distinguish between unique amino acid sequence features, or "fingerprints" of GDF11 and myostatin. Using this platform, researchers compared age-associated changes in GDF11 and myostatin in healthy men and women between 20 and 94 years old. They discovered that although myostatin is higher in younger men than younger women and declines in healthy men throughout aging, GDF11 levels do not differ between sexes nor decline throughout aging. In an independent cohort of older individuals with severe aortic stenosis, researchers found that those with higher GDF11 levels were more likely to be frail and have diabetes or prior cardiac conditions. Following valve replacement surgery, increased GDF11 was associated with a higher prevalence of re-hospitalization and multiple adverse events.


Researchers have announced progress in the production of larger sections of bone for transplantation. Once transplanted, the new bone serves as a template to provoke further regeneration to match the structure of the natural bone that is replaced. Based on results from animal studies, this seems a promising approach:

A new technique repairs large bone defects in the head and face by using lab-grown living bone, tailored to the patient and the defect being treated. This is the first time researchers have grown living bone that precisely replicates the original anatomical structure, using autologous stem cells derived from a small sample of the recipient's fat. "We've been able to show, in a clinical-size porcine model of jaw repair, that this bone, grown in vitro and then implanted, can seamlessly regenerate a large defect while providing mechanical function. The need is huge, especially for congenital defects, trauma, and bone repair after cancer surgery. The quality of the regenerated tissue, including vascularization with blood perfusion, exceeds what has been achieved using other approaches. So this is a very exciting step forward in improving regenerative medicine options for patients with craniofacial defects, and we hope to start clinical trials within a few years."

Researchers fabricated a scaffold and bioreactor chamber based on images of the weight-bearing jaw defect, to provide a perfect anatomical fit. The scaffold they built enabled bone formation without the use of growth factors, and also provided mechanical function, both of which are unique advantages for clinical application. They then isolated the recipient's own stem cells from a fat sample and, in just three weeks, formed the bone within a scaffold made from bone matrix, in a custom-designed perfused bioreactor. An unexpected outcome was that the lab-grown bone, when implanted, was gradually replaced by new bone formed by the body, a result not seen with the implantation of a scaffold alone, without cells. "Our lab-grown living bone serves as an 'instructive' template for active bone remodeling rather than as a definitive implant. This feature is what makes our implant an integral part of the patient's own bone, allowing it to actively adapt to changes in the body throughout its life."

The team are now including a cartilage layer in the bioengineered living bone tissue to study bone regeneration in complex defects of the head and face. They are also advancing their technology through advanced preclinical trials, and in planning stages with the FDA for clinical trials, through the company epiBone.


When it comes to the question of whether young stem cells and a young tissue environment are necessary for the success of stem cell therapies, there is evidence to support all of the possible answers. It is a confusing picture at the moment, and it is very possible that the answer varies by cell type. Since the best option for therapy is to use the patient's own cells, it would be good to find that cell therapies can work effectively and produce meaningful benefits even when both cells and patient are old. In some studies researchers have seen little difference in short term outcomes between young and old individuals, which is the more surprising of the possible results: the intuitive expectation is that age-related damage and the signaling changes that suppress stem cell activity in response to that damage will make all forms of cell therapy less effective in old individuals. In the research linked here, the results are more in line with expectations, in that young stem cells work to promote regeneration where old stem cells do not. This sort of experimentation will in time lead to a list of things that must be changed and corrected in stem cells, probably differing by tissue type, in order to make them more effective when transplanted into older individuals:

During aging, changes in the stomach result in gastric tissue that is less capable of repairing injury correctly. These changes include decreased gastric acid secretion, cell motility, and proliferation. In addition, angiogenesis, a fundamental process essential for wound healing, is impaired with advanced age. Such pathophysiological changes are believed to result in disrupted repair in response to chronic ulceration in the elderly that can be exacerbated during chronic insults such as Helicobacter pylori infection or nonsteroidal anti-inflammatory drug administration. In elderly patients there is a strong association between ulceration with cancer or evolution of dysplasia into neoplasia. Renewal of gastric stem cells to produce committed progenitor cells that differentiate further into adult epithelial cell types is important for the structural integrity of the mucosa. However, relatively little is known regarding the age-related changes affecting gastric epithelial stem cells. Early studies have shown that in aged rats, stem cell proliferation and epithelial cell numbers are decreased compared with young animals, thus suggesting impaired tissue integrity in the aged stomach.

The origin of cells for repair of severe gastric epithelial injury has not received extensive attention. Recent investigations have indicated that loss of parietal cells, either from acute toxic injury or chronic Helicobacter infection, leads to the development of spasmolytic polypeptide/trefoil factor (TFF) 2-expressing metaplasia (SPEM) through transdifferentiation of chief cells into mucous cell metaplasia. In the face of continued inflammation and M2-macrophage influence, SPEM may progress to a more proliferative preneoplastic metaplasia. However, studies with acute injury have indicated that SPEM disappears after resolution of injury. No studies have addressed whether SPEM may contribute to the healing of gastric ulcers. We now report that SPEM represents a major reparative lineage responsible for wound healing after gastric ulcer injury.

Acetic acid ulcers were induced in young (2-3 mo) and aged (18-24 mo) C57BL/6 mice to determine the quality of ulcer repair with advancing age. Yellow chameleon 3.0 mice were used to generate yellow fluorescent protein-expressing organoids for transplantation. Yellow fluorescent protein-positive gastric organoids were transplanted into the submucosa and lumen of the stomach immediately after ulcer induction. Gastric tissue was collected and analyzed to determine the engraftment of organoid-derived cells within the regenerating epithelium. Wound healing in young mice coincided with the emergence of SPEM within the ulcerated region, a response that was absent in the aged stomach. Although aged mice showed less metaplasia surrounding the ulcerated tissue, organoid-transplanted aged mice showed regenerated gastric glands containing organoid-derived cells. Organoid transplantation in the aged mice led to the emergence of SPEM and gastric regeneration. Thus the healing of gastric ulcers in the aged stomach is promoted by the transplantation of gastric organoids.


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