Fight Aging! Newsletter, May 23rd 2016

May 23rd 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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  • An Interview with the Advocates of the Major Mouse Testing Program Team
  • A Book-Length Interview with Aubrey de Grey
  • A Few Recent Studies of Exercise, Fitness, and Risk of Age-Related Disease
  • Recent Studies of Advanced Glycation End-Products in Aging and Age-Related Disease
  • Media Attention for the Dog Aging Project and Other Trials of Drugs to Modestly Slow the Progression of Aging
  • Latest Headlines from Fight Aging!
    • Heart Rate Variability and Pacemaker Cell Deterioration in Aging
    • Major Mouse Testing Program Hosts an AMA at /r/futurology Today
    • A Review of DNA Damage, DNA Repair, and Aging
    • Interactions of Stem Cells and Immune Cells in Bone Healing
    • Pluripotency Factor Oct4 in Atherosclerosis and Aging
    • Correlating Genetic Variations with a More Youthful Appearance
    • More Tissue Engineering and Cell Therapy aimed at Regeneration of the Thymus
    • An Interview with a Skeptical Cryonics Supporter
    • Using Neural Networks on Blood Samples to Develop Biomarkers of Aging
    • Announcing Success in the MitoSENS Project Crowdfunded at in 2015


By way of following on from today's AMA over at /r/futurology, I recently had the chance to ask a few questions of the Major Mouse Testing Program (MMTP) volunteers, a mix of scientists and advocates who aim to do their part to speed up progress towards effective treatments for the causes of aging. The group formed six months ago or so, and are presently seeking funds for their first mouse studies through crowdfunding with the organization. The initial focus is on senolytic treatments capable of removing senescent cells from old tissues. I encourage you all to take a look at the details of their research proposal.

Growth in the number of dysfunctional, senescent cells is a contributing cause of degenerative aging, involved in the progression and pathology of all of the common age-related diseases. A growing body of evidence supports the outright removal approach as a way to minimize or eliminate this portion of the aging process. Unfortunately there is - as ever in the aging research field - a paucity of funding and always the need for more and better animal data in order to pull in other players with deep pockets. At this stage in the progression from laboratory to clinic, prior to the involvement of any large institutions or companies, all such efforts are important work. I'm pleased to have been able to contribute to this Major Mouse Testing Program fundraiser, and hope to see great things from this group in the future.

How did the Major Mouse Testing Program come about? How did you meet and what made you decide to undertake this particular project?

Elena: I have been collaborating with the International Longevity Alliance (ILA) for about 3 years. It is an international non-for-profit organization with the head office in Paris, our goal is to support innovative biomedical technologies to address aging. At the beginning, the core team had a lot of discussions with other pro-longevity organizations and with the scientific community to identify the bottlenecks that impede the development of the technologies to slow down, postpone and reverse age-related damage to health. And we learned that one of the barriers was the deficiency in robust animal trials for a long list of promising interventions. Then one of the Founding Board Members, Edouard Debonneuil, came in with the idea that the ILA could start its own fundraising project to support this kind of research. This is how MMTP was started.

Steve: I learned about the MMTP project via the International Longevity Alliance. They had a number of projects ranging from lobbying, advocacy to research, for me the research appealed as I wanted to get my hands dirty and get as close to the frontline as possible. MMTP is a mixture of advocacy and actual research so for me it was a good combination. The research is focused on speeding up progress in rejuvenation medicine so I felt it was important to get involved with this kind of project.

Paul: I learned about the MMTP project from Steve. He had just started working on the project, We knew each other quite well and had a good rapport, and he thought I'd be a good fit for the group. I wasn't initially keen to join the group, I didn't appreciate the work that animal researchers do, like a lot of people I guess I didn't appreciate why animal data is so important for developing new drugs and therapies. The more I learned about the project, the more I realised how vital the work was! My skillset seemed to fit the needs of the group so I decided to commit to the group.

The world would be a better place if everyone pitched in to move research forward. Why don't they? What are the challenges in doing this?

Elena: You would be surprised but there is a lot of studies in sociology that answer this question. As I am going to make my PhD in this field, I read a lot and I combine my own experience in longevity promotion with scientific evidence. So far, we know, that if you ask a person to choose a desirable lifespan, he or she will only add about 10 years to the mean life expectancy in any given country. But if you ask, if people would like to live longer while also remaining youthful and healthy, at least 30% will consent to live much longer or even indefinitely. Many people show more interest after being provided with the data from animal studies - which look fantastic today, with mice lifespan extended twofold.

Another important thing to keep in mind is that the perception of the innovation depends very much on its end use. People are keener to support a new and even experimental treatment for a severe disease, but often refuse to accept it in case it is used for life extension. Which basically means, that before promoting life extension technologies, we have to explain that aging is a root cause of severe age-related diseases, that aging itself is very similar to a disease, even if we don't call it so. If people can see how deteriorating aging processes are for their health, they will understand that it is only right to develop the means to protect people from its consequences. Cancer and diabetes are two of the most horrible consequences of aging, and I have not yet met someone who would say no to the development of a cure against cancer or diabetes. This is how powerful the admission of a serious problem can be.

Last but not least, we should not avoid talking about the prejudices and concerns that people have towards personal and social implications of longevity technologies. It is only reasonable that they want to make informed decisions. In our case, to be properly informed means to have some information outside the field of medicine. So we should share evidence-based data and expert foresight in demography, economy, ethics, ecology, law and other sciences on request, as in our case this is what can significantly influence public perception - and will also influence adherence to longevity therapies in the future. So, to get more supporters we seem to have a lot of educating to do.

Paul: Yes it would be truly amazing if more folk who declared an interest in this kind of research, actually played an active role in ensuring that it manifests itself as something people can go to a clinic and receive, rather than just daydreaming about it! But people are inclined to be either overly optimistic, or the complete opposite. Some don't believe this will ever amount to anything, so they see no value in joining the fight, and that is what this is. The other extreme, believe that it will happen whether they do anything or not, so why bother? They just sit around complaining about the lack of progress, while looking at exponential technology graphs, occasionally muttering "Are we there yet?" So the main challenge is to make people realise that this will not happen, if it is not made to happen. And if folks want this soon, it is in their best interests to pitch in and help get the job done.

You've been gearing up for your first fundraiser for a few months now; now that you're launched, what are the details?

Steve: We launched our fundraising campaign on with an ideal goal of 60,000 in order to initiate a robust scientific study. We will scale the experiment based on the funds we raise so no matter what, we will be making progress.

Elena: It is important to mention, that if we raise a little more, we will be able to do even more tests and so improve our data on health changes in our mice.

Once you have the funds in hand and are embarked on making mice live longer, what is next for the Major Mouse team?

Steve: Given the expertise of our researcher, we are very interested in moving into stem cell therapy for longevity. This could be very exciting as we plan to potentially combine senolytics with stem cell therapy. Imagine, first we remove the bad cells from the body, second - we stimulate the regeneration and replenish lost stem cells. This is one reason why our current study not only focuses on lifespan but our secondary goal is to closely examine the effect of senolytics on resident stem cell populations, this information will guide how we approach combining the two therapies.

Where do you see this field of rejuvenation research going over the next few years?

Steve: Stem cells are certainly shaping up to be a big player, CRISPR and gene therapy likewise. Senolytics has attracted a great deal of interest of late too though we need to robustly test this to ensure it is a viable path to longevity. There are a number of "camps" in the research community, the bulk seem to favour tinkering with the metabolism far downstream of the problems, another is the engineering strategy of SENS and the third is the hotly debated telomerase camp.

I think the most important thing at this point is to get the research underway, start answering the unanswered questions and work out what the best approaches are. Personally I see little value in messing with metabolism far downstream but which of the other two camps is right could be some of column A and some of column B. I am not married to either idea which is why we will test these things robustly and find out what works. It would be very poor science indeed if we made a conclusion and then cherry picked our results to support them, no we will research thoroughly and we will go where the data leads!

Elena: If anyone is expecting a universal pill against aging in the next 10 years, I don't believe this is going to happen. If you look at animal data, combine what they are treated with, then you can imagine, what a complex of anti-aging interventions is today. So far the approach to slow down and reverse aging includes drugs, senolytics, vaccines, cell therapies, gene therapies, organ regeneration in situ and of course lifestyle measures. In future, we will learn to combine several types of interventions in one procedure, and maybe we will wear a rechargeable bracelet able to inject a mix of longevity drugs directly into our bodies on demand, maybe several times a month. To repair a damaged organ we will have to undergo an injection of stem cells into that organ, which would supplant some of the more invasive interventions. By the way, this is what is already happening: an ongoing study in Melbourne, Australia, shows amazing results in joint repair in situ, on humans, using stem cell therapy.

Paul: Now that's a question! Things are moving so fast, every week there seem to be announcements, news about CRISPR and stem cells. These are two of the fastest moving areas of research. Those two and Senolytics, this is another rapidly accelerating area of research. Senolytics should help clear the senescent cells, and that will set the stage for recovery or rejuvenation. This is where things like stem cells come in. I know we would like to take our research into combination therapies, either combinations of the same therapies, involving multiple senolytics for example, or combinations of complementary therapies such as Senolytics and stem cells.

Funding is, obviously, ever the battle in the sciences, and especially aging. How can we change this for the better?

Elena: There are several ways for a scientific group to get funded. There is already settled state funding for the research - in this case, our goal is to make a state research institution more interested in investigating aging and longevity. There is an additional source - the grants. This is what most of gerontologists try to obtain, but this form of support has its own limitations: the paperwork can take too much time, there are some inconvenient regulations of spendings timeline, we hear many groups complaining about that.

Crowdfunding is much more attractive in this regards. We don't ask for excessive amount of papers, only a decent experiment protocol and a reasonable estimate, making clear the amount of such expenditures as the substances to test, the mice and their housing, and everything necessary to obtain the data on health changes. The contract between the ILA and the research institution guarantees the observation of the study design and volume. Apart from that, we let the scientific groups do their work without unnecessary distraction. Luckily, the cost of such experiments is from 60 to 100 thousand, so it can be acquired by crowdfunding. And while it is not so easy to influence state funds allocation, in MMTP we let general public influence the progress in biomedical sciences directly.

Paul: I think we need to educate interested parties at all levels, about the need to get this work done. About the potential, not only in terms of human lives and suffering that can be saved, but the enormous cost savings that could be potentially had too, by investing in preventative and rejuvenation therapies. Health providing organisations worldwide are creaking under the financial burden of established medicine, a model that offers increasing periods of decrepitude, in exchange for ever increasing amounts of money. This faustian bargain offers a very poor return on investment and simply cannot continue much longer. So advocacy and education are two of our biggest weapons going forward. We also need to foster a change in governmental policies worldwide! The ILA has already made a start, by approaching bodies like the World Health Organization (WHO), which themselves see a need for change. By the way, WHO recently held a Consultation on Global Strategy and Action Plan on Ageing and Health, where the need for more research on aging and longevity was discussed.

About the Team Members

Steve: Project lead for MMTP and a longevity advocate, whose energy and devotion is inspiring the team.

Elena: Project coordinator and fundraiser, Elena is involved in project management and community outreach to donors.

Paul: Social media manager and writer, Paul is an important part of our promotion team.


Here I'll point out a long discussion with Aubrey de Grey of the SENS Research Foundation that is packaged and sold as a book. This is a most interesting, and I think worthwhile, way for an author or journalist to approach the long-form interview process. Like many other new approaches this wouldn't have been financially viable a few decades ago, and is in and of itself a small example of the sort of freedom, choice, and innovation that can occur when costs fall and barriers to entry crumble. At the present time, we can hope that the same things that have already happened to the publishing industry will also come to pass for the edifice of medical research and development: an explosion of greater participation, experimentation, and creation. These two areas of human endeavor couldn't be more different in their details, but in both cases the costs of participation are falling dramatically.

Aubrey de Grey needs little introduction for the long-time readers here. Something more than fifteen years ago he took it upon himself, as an outsider to the field at the time, to alternately kick and persuade the aging research community into working towards the treatment of aging. When he surveyed the field, he saw plenty of evidence to show that aging is caused by a small variety of forms of cell and tissue damage. Yet that evidence was largely ignored in the formulation of research strategy, while scientific discussion the treatment of aging in public was a threat to career and funding, and the vast majority of aging research was nothing more than a process of gathering data. Fast forward to today, however, and this situation has been turned around. Arguments among scientists are now over how exactly aging should be treated in order to prevent disease and extend healthy life, and researchers can speak in public and publish their thoughts on that goal without any fear of losing their ability to raise funding or advance their careers.

This was achieved through considerable effort by a network of advocates within and beyond the research community, and few would argue that de Grey was anything other than one of the most important of these figures. He now leads the scientific and funding efforts of the SENS Research Foundation, an organization that, along with its parent non-profit the Methuselah Foundation, has accomplished a great deal in moving the vision of rejuvenation therapies closer to reality. Clearing senescent cells as a way to treat aging, for example, was dismissed by many in the research community a decade ago despite the strong evidence for its role in age-related degeneration. Today, however, therapies to clear senescent cells from old tissues have been demonstrated to improve health and extend life in rodent studies, the research non-profit Major Mouse Testing Program is crowdfunding further studies, and two startup companies, Oisin Biotechnologies and UNITY Biotechnology, are working on bringing these treatments to the clinic. The world is changing, and we shouldn't lose sight of those who worked hard to make this the case.

Advancing Conversations: Aubrey de Grey - Advocate For An Indefinite Human Lifespan

Advancing Conversations is a line of interview books documenting conversations with artists, authors, philosophers, economists, scientists, and activists whose works are aimed at the future and at progress. The biogerontologist Aubrey de Grey, as the world's pre-eminent longevity advocate, is nothing if not future oriented. De Grey is the founder of the SENS Research Foundation, an organization developing medical interventions to repair the damage the body does to itself over time. Stated more directly, Aubrey de Grey and his organization aim to defeat aging.

Douglas Lain: I thought I'd start our conversation with a joke from Louis CK. Louis says that when you're forty and you go to the doctor, they don't try to fix anything anymore. Once you get over forty they don't try to fix you, they just say "Yeah, that starts to happen." Is this really a general attitude that people have, that there is any truth to this joke?

Aubrey de Grey: Yes. There is an enormous amount of truth in it. And I think we need to distinguish here a little bit between the medical progression - doctors and other people in the medical world - as against the rest of the world. The medical progression have the enormous problem, which we need to sympathize with, that they have a certain range of tools to work with, to help people to be healthier and to restore people to health, but those tools are very limited in their efficacy. In particular they're extremely limited with regard to what they can do for people who are getting old. Ultimately, your average doctor just has to work with what they have, and a lot of that involves management of expectations. That's really all the Louis CK is saying there. Right?

Of course, that doesn't say anything about what might happen in the future. What might be possible in terms of maintenance or restoration of youthful good health with medicines that haven't yet been developed. But, that is not what doctors are supposed to be interested in. Doctors are all about doing their best with the tools that are already available.

Now contrast that with the situation that the general public has. The general public are not providing care, they are the recipient of medical care. And they are the people who should be thinking about the potential improvement in that medical care that might arise from further advances, from progress in the laboratory. It's kind of beholden on the public and therefore policy makers and opinion formers and so on ... to actually drive this, to actually deliver the funding and general resources that are required to allow people like SENS Research Foundation to move forward and create therapies that don't yet exist. Once those therapies do exist, of course they enter the universe of tools that your doctor can actually prescribe, can actually administer. But until that time, it's not the problem of the doctors. It's not their fault.


Today I'll point out a few recent studies on exercise and age-related disease in human populations. Animal studies show that regular exercise improves health and extends healthspan, the period of life free from age-related conditions. Human studies, which use statistical methods on large sets of population data, tend to show correlations only, but these correlations match what is seen in animal studies. It is not unreasonable to believe based on the evidence that exercise is good for you over the long term, and that maintaining fitness as you age reduces the risk of suffering all of the common age-related diseases - that this is causation, not just correlation. In an age of rapid progress in biotechnology, postponing aspects of the inevitable decline of old age, even for just few years, increases the odds of being around and in good shape to benefit from the rejuvenation therapies that are envisaged, in development, but yet to be realized.

In the long run, yes, only progress in medical science can save us from aging to death. As we grow older and ever more damaged, the span of life remaining is increasingly determined by the capabilities of the medical community and how rapidly those capabilities are improving. So in a sense we'll all need to be rescued by that progress - you can't exercise your way to agelessness. But why sabotage yourself and reduce your odds living to benefit from greatly improved medicine when that much of your fate at least is absolutely under your control? Being sedentary and unfit has a cost, both additional lifetime medical expenditure and lost years of life expectancy. You can always choose not to pay that cost, to be healthier.

Being fit may slow lung function decline as we age

"While everyone's lung function declines with age, the actual trajectory of this decline varies among individuals. What is less known is, beyond smoking, what factors affect this rate of decline. Even though the majority of people will not develop lung disease in their lifetime, declining lung function is known to increase overall morbidity and mortality even in the absence of overt pulmonary disease." Researchers analyzed data from the CARDIA (Coronary Risk Development in Young Adults) Study, which began in 1985-86 with 5,115 healthy black and white men and women, aged 18-30. The study has measured participant's cardiopulmonary fitness periodically over 20 years using a graded treadmill test. At the beginning of the study and at each follow-up assessment, pulmonary function (PF) was also assessed by measuring forced expiratory volume in one second (FEV1) and forced vital capacity (FVC). After adjusting for age, smoking, body mass index and change in BMI, the association between fitness and lung function remained statistically significant.

Researchers found that participants in the top quartile of baseline fitness experienced the least annual decline in PF. Participants with the greatest decline in fitness experienced the greatest decline in FEV1 and PF over 20 years. Participants with sustained or improved fitness experienced the least decline in PF over 20 years.

Study: Regular exercise at any age might stave off Alzheimer's

Recent research suggests that exercise might provide some measure of protection from Alzheimer's disease and other dementias. Thirty men and women ages 59-69 were put through treadmill fitness assessments and ultrasounds of the heart. Then they received brain scans to look for blood flow to certain areas of the brain. "We set out to characterize the relationship between heart function, fitness, and cerebral blood flow, which no other study had explored to date. In other words, if you're in good physical shape, does that improve blood flow to critical areas of the brain? And does that improved blood flow provide some form of protection from dementia?"

The results showed blood flow to critical areas of the brain - and so the supply of oxygen and vital nutrients - was higher in those who were more physically fit. "Can we prove irrefutably that increased fitness will prevent Alzheimer's disease? Not at this point. But this is an important first step towards demonstrating that being physically active improves blood flow to the brain and confers some protection from dementia, and conversely that people who live sedentary lifestyles, especially those who are genetically predisposed to Alzheimer's, might be more susceptible." Since people who exercise frequently often have reduced arterial stiffness, researchers postulate that regular physical activity - regardless of age - maintains the integrity of the "pipes" that carry blood to the brain. "In the mid-late 20th century, much of the research into dementias like Alzheimer's focused on vascular contributions to disease, but the discovery of amyloid plaques and tangles took prevailing research in a different direction. Research like this heralds a return to the exploration of the ways the vascular system contributes to the disease process."

Physical Activity Associated with Lower Risk for Many Cancers

Higher levels of leisure-time physical activity were associated with lower risks for 13 types of cancers, according to a new study. Physical inactivity is common, with an estimated 51 percent of people in the United States and 31 percent of people worldwide not meeting recommended physical activity levels. Researchers pooled data from 12 U.S. and European cohorts (groups of study participants) with self-reported physical activity (1987-2004). They analyzed associations of physical activity with the incidence of 26 kinds of cancer. The study included 1.4 million participants and 186,932 cancers were identified during a median of 11 years of follow-up. The authors report that higher levels of physical activity compared to lower levels were associated with lower risks of 13 of 26 cancers. Most of the associations remained regardless of body size or smoking history, according to the article. Overall, a higher level of physical activity was associated with a 7 percent lower risk of total cancer.


Today I'll link to a few unrelated studies of advanced glycation end-products (AGEs) and their role in aging and the pathology of specific age-related diseases. AGEs are both generated in the body as a side-effect of metabolic operation, but can also be found in the diet. There are numerous different classes of AGE, some more common than others. As a general rule the common AGEs are easily broken down and removed in healthy individuals, while the rare ones are persistent and in some cases cannot be broken down at all by our evolved molecular toolkit. The common AGEs play more of a role in metabolic disease: the dysregulated diabetic metabolism suffers from high levels of circulating AGEs, for example. These AGEs interact with the receptor for advanced glycation end-products, RAGE, to promote chronic inflammation and other bad behavior on the part of cells. As regular readers will know, high levels of inflammation contribute to the progression of damage and disease in aging, and this is one of the ways in which metabolic diseases, such as the varieties of diabetes, shorten life span and raise the risk of suffering age-related conditions.

Long-lasting persistent AGEs are perhaps more dangerous, however. For one they are far less well studied. The predominant form of persistent AGE in humans is glucosepane, and a quick PubMed search will show you that next to no-one is publishing papers on the subject in comparison to other forms of AGE. Glucosepane forms an ever-increasing number of cross-links between macromolecules in the extracellular matrix, and this cross-linking that degrade its structural properties - particularly elasticity in skin and blood vessels. Wrinkled skin we can live with, but blood vessel stiffening produces hypertension, structural failure of tiny vessels in the brain, detrimental remodeling of heart and blood vessel structures, cardiovascular disease, and death. Given all of this it is nothing short of amazing that it remains a struggle to find funding to advance the development of glucosepane cross-link breaker drugs. A single effective drug candidate could largely remove this sizable contribution to the aging process. As a topic this has been discussed in some depth in past posts, so I'll skip that story for the present. Just note that glucosepane isn't a fact of life written in stone; it would take very little investment today to produce drug candidates a few years from now. On that topic, this first paper focuses on AGEs in type 1 diabetes, not the age-related variety, but is unusual for actually including glucosepane in its analysis:

Skin collagen advanced glycation endproducts (AGEs) and the long-term progression of sub-clinical cardiovascular disease in type 1 diabetes

We recently reported strong associations between eight skin collagen AGEs and two solubility markers from skin biopsies and the long-term progression of microvascular disease in in diabetes, despite adjustment for mean glycemia. Herein we investigated the hypothesis that some of these AGEs correlate with long-term subclinical cardiovascular disease (CVD) measurements, i.e. coronary artery calcium score (CAC), change of carotid intima-media thickness (IMT), and cardiac MRI outcomes.

Correlations showed furosine (early glycation) was associated with future mean CAC. Glucosepane and pentosidine crosslinks, methylglyoxal hydroimidazolones (MG-H1) and pepsin solubility (inversely) correlated with IMT change. Left ventricular (LV) mass correlated with MG-H1, and inversely with pepsin solubility, while the ratio LV mass/end diastolic volume correlated with furosine and MG-H1, and highly with carboxymethyl-lysine (CML). In multivariate analysis only furosine was associated with CAC. In contrast IMT was inversely associated with lower collagen pepsin solubility and positively with glucosepane.

In type 1 diabetes, multiple AGEs are associated with IMT progression implying a likely participatory role of glycation and AGE mediated crosslinking on matrix accumulation in coronary arteries. This may also apply to functional cardiac MRI outcomes, especially left ventricular mass. In contrast, early glycation measured by furosine, but not AGEs, was associated with CAC score, implying hyperglycemia as a risk factor in calcium deposition perhaps via processes independent of glycation.

Biological Effects Induced by Specific Advanced Glycation End Products in the Reconstructed Skin Model of Aging

The aging human skin is characterized by decreased elasticity and accumulation of insoluble collagen and impaired wound healing. These changes are worsened in sun-exposed skin in which proinflammatory changes further help remodel the collagen-rich matrix. Two components are expected to participate in the latter process. The first involves a chemical process in which advanced glycation end products (AGEs) are produced from glucose and oxoaldehydes, thereby inflicting damage to the extracellular matrix, which includes protein crosslinking, insolubilization, and loss of elasticity. The second involves interactions between the modified AGE-rich dermal matrix and dermal cells leading to cell activation via AGE receptors (RAGE) and other receptors, eventually resulting in growth factor and cytokine release that profoundly remodel the extracellular matrix. Many of these changes have been observed in two-dimensional models in which cells are grown onto modified matrix. For several years now, our interest has been to evaluate the role of the aging extracellular matrix in three-dimensional models, that is, the reconstructed skin model in which fibroblasts are embedded in a three-dimensional collagen matrix and establish cross-talk with keratinocytes grown on the dermal matrix. Using such system, we were able to demonstrate that the glycated matrix mimicked a phenotype that shared many similarities with the aging skin. In particular, we showed that when AGE-rich glycated matrix formed by the reaction of D-ribose with bovine collagen was used, an aging-like phenotype developed.

Advanced Glycation End Products: Association with the Pathogenesis of Diseases and the Current Therapeutic Advances

Advanced glycation end products (AGE) have been imparted in the development and worsening of complications of diabetes. They are also involved in atherosclerosis, normal aging process, arthritis, cancer and progression of age-related neurodegenerative diseases like Alzheimer's disease. Endogenously, they formed by nonenzymatic glycation by aldoses/ketoses to form intermediates precursor that were slowly converted into AGE. A positive correlation was observed with the level of AGEs formation and progression of the diseases. Exogenously, they formed in foods when they were cooked at very high temperature.

AGEs can interact with the cell surface receptors of AGE (RAGE) to release cytokines, free radicals as well as directly modify the extracellular matrix and action of hormones. Hence, the mechanism of AGE association with pathogenesis of diseases can be ascribed mainly to the generated cytokines and free radicals. Second type of receptors such as AGE receptor-1, 2 and 3 were more specific and involved in their detoxification and clearance. Therapeutic agents were used to inhibit AGEs formation, traps the reactive carbonyl intermediate precursors, interfering with Amadori's products, cross-link breaker and low molecular weight inhibitors of RAGE had been described as well. Despite the several therapeutic agents described so far, none of them have proved to be recommended for clinical use. Furthermore, no methods or standard units were accepted universally to measure AGEs are existing. This review discusses AGEs formation, association with diseases and therapeutic agents to alleviate them.

Advanced Glycation End-Products and Their Receptors: Related Pathologies, Recent Therapeutic Strategies, and a Potential Model for Future Neurodegeneration Studies

Advanced glycation end products (AGEs) are the result of a nonenzymatic reaction between sugars and proteins, lipids, or nucleic acids. AGEs are both consumed and endogenously formed; their accumulation is accelerated under hyperglycemic and oxidative stress conditions, and they are associated with the onset and complication of many diseases, such as cardiovascular diseases, diabetes, and Alzheimer's disease. AGEs exert their deleterious effects by either accumulating in the circulation and tissues or by receptor-mediated signal transduction. Several receptors bind AGEs: some are specific and contribute to clearance of AGEs, whereas others, like the RAGE receptor, are nonspecific, associated with inflammation and oxidative stress, and considered to be mediators of the aforementioned AGE-related diseases. Although several anti-AGE compounds have been studied, understanding the underlying mechanisms of RAGE and targeting it as a therapeutic strategy is becoming increasingly desirable. For achieving these goals efficiently and expeditiously, the C. elegans model has been suggested. This model is already used for studying several human diseases and, by expressing RAGE, could also be used to study RAGE-related pathways and pathologies to facilitate the development of novel therapeutic strategies.

Cellular Mechanisms and Consequences of Glycation in Atherosclerosis and Obesity

Post-translational modification of proteins imparts diversity to protein functions. The process of glycation represents a complex set of pathways that mediates advanced glycation endproduct (AGE) formation, detoxification, intracellular disposition, extracellular release, and induction of signal transduction. These processes modulate the response to hyperglycemia, obesity, aging, inflammation, and renal failure, in which AGE formation and accumulation is facilitated. It has been shown that endogenous anti-AGE protective mechanisms are thwarted in chronic disease, thereby amplifying accumulation and detrimental cellular actions of these species. Atop these considerations, receptor for advanced glycation endproducts (RAGE)-mediated pathways downregulate expression and activity of the key anti-AGE detoxification enzyme, glyoxalase-1 (GLO1), thereby setting in motion an interminable feed-forward loop in which AGE-mediated cellular perturbation is not readily extinguished. In this review, we consider recent work in the field highlighting roles for glycation in obesity and atherosclerosis and discuss emerging strategies to block the adverse consequences of AGEs.

Relationship between advanced glycation end-product accumulation and low skeletal muscle mass in Japanese men and women.

The present study aimed to investigate the relationship between advanced glycation end-product accumulation and skeletal muscle mass among middle-aged and older Japanese men and women. A total of 132 participants enrolled in this cross-sectional study. Skin autofluorescence was assessed as a measure of advanced glycation-end products. Participants were divided into two groups (low skeletal muscle index and normal skeletal muscle index) using the Asian Working Group for Sarcopenia's skeletal muscle index criteria for diagnosing sarcopenia.

Participants consisted of 70 men (mean age 57 ± 10 years) and 62 women (mean age 60 ± 11 years). There were 31 and 101 participants in the low and normal skeletal muscle index groups, respectively. Skin autofluorescence was significantly higher in the low skeletal muscle index group compared with the normal skeletal muscle index group. Skin autofluorescence was a significant independent factor associated with low skeletal muscle index based on multivariate logistic regression analysis.


The Dog Aging Project launched last year, and is lavished with attention in this long press article. The initiative is a combined advocacy and research program intended to trial in pet dogs the small range of drug candidates - such as rapamycin - that have good data in mice to support both safety and the ability to modestly slow aging. In addition to the scientific side of things, this is a way to pull in more interest for the development of treatments for aging, and to gather greater support for moving to human studies. In that the goals of the Dog Aging Project are much the same as the human trial of metformin as a treatment to slow aging that is presently in the works. The bottom line is that we - the research and advocacy community - still have a long way to go when it comes to persuading the public, large funding institutions, and regulators that living longer through medical science is possible, plausible, and desirable.

Given the subject, the article here is narrowly focused on one particular view of aging and how to treat it. The scope is (a) traditional drug discovery and development, (b) slightly slowing the progression of aging by altering the operation of cellular metabolism, and (c) the prospect of a long, expensive slog to very marginal gains at some point in the decades ahead. This is a vision of the future in which humans gain a couple of years of additional healthy life sometime around 2030 because they can take a drug derived from or of a similar class to rapamycin. So on the one hand I think it is great that we now see more lengthy articles from the journalistic community that sensibly discuss both the treatment of aging and specific initiatives in aging research. It is also great that researchers are creating these innovative ways to both accomplish the science and attract more attention to the field. But at the same time, this particular approach of drug development and metabolic tinkering is an expensive and slow road to nowhere special. If it were the only path ahead, then fine, but it isn't. There is an entirely separate approach to treating aging based on targeted repair of cellular and molecular damage that could, if funded well, produce far greater gains in healthy life span for the same investment in money and time, as well achieving rejuvenation in the old.

You don't have to look far to see striking comparisons. Billions have been spent on trying to make drugs to slow aging out of sirtuins for example, and that collection of initiatives is an exemplar of the metabolic tinkering approach, hyped in its day. Yet the only concrete result has been to gain knowledge of a small slice of metabolism and its response to calorie restriction - no gain in health life or method to achieve that end has emerged. Meanwhile, or a tiny fraction of that sum, and in half the span of years, researchers taking the damage repair approach of clearing senescent cells in old tissues have already demonstrated robust benefits to health and life span in rodent studies. The pace of progress, the cost of progress, and the potential gains are night and day when comparing these two strategies. The type of longevity research that is carried out over the next few years matters greatly - our lives depend on the outcome.

Dogs Test Drug Aimed at Humans' Biggest Killer: Age

Ever since last summer, when Lynn Gemmell's dog, Bela, was inducted into the trial of a drug that has been shown to significantly lengthen the lives of laboratory mice, she has been the object of intense scrutiny among dog park regulars. The trial represents a new frontier in testing a proposition for improving human health: Rather than only seeking treatments for the individual maladies that come with age, we might do better to target the biology that underlies aging itself. While the diseases that now kill most people in developed nations - heart disease, stroke, Alzheimer's, diabetes, cancer - have different immediate causes, age is the major risk factor for all of them. That means that even treatment breakthroughs in these areas, no matter how vital to individuals, would yield on average four or five more years of life, epidemiologists say, and some of them likely shadowed by illness. A drug that slows aging, the logic goes, might instead serve to delay the onset of several major diseases at once.

But scientists who champion the study of aging's basic biology - they call it "geroscience" - say their field has received short shrift from the biomedical establishment. And it was not lost on researchers that exposing dog lovers to the idea that aging could be delayed might generate popular support in addition to new data. "Many of us in the biology of aging field feel like it is underfunded relative to the potential impact on human health this could have," said Dr. Matt Kaeberlein, who helped pay for the study with funds he received from the university for turning down a competing job offer. "If the average pet owner sees there's a way to significantly delay aging in their pet, maybe it will begin to impact policy decisions."

"I would resist the idea that we should shift funds away from cancer and diabetes and Alzheimer's, where there are clear drug targets, and say, 'We're going to work on this hypothesis,' " NIH Director Dr. Francis Collins said. "If you had a lot of money for geroscience right now, it's not clear what you would do with it that would be scientifically credible." Researchers in the field, in turn, say they might have more to show for themselves if they could better explain to Congress and the public why basic research on aging could be useful. "People understand 'my relative died of a heart attack, so I'm going to give money to that,' " said Dr. James L. Kirkland, a Mayo Clinic researcher. "It's harder to grasp 'my relative was older, that predisposes them to have a heart attack, so I should give money to research on aging.'"

Some companies have embraced the quest for drugs that delay aging. Google created Calico (for California Life Company) in 2013 with the goal of defeating aging. A start-up called UNITY has said it will develop drugs based on new research on aging mice suggesting that purging certain cells can extend a healthy life span. And a group of academic researchers is trying to persuade the FDA to recognize aging as a disease for which a drug can be marketed, which they hope will draw more interest from pharmaceutical firms. The agency recently greenlighted its proposed trial of a widely used diabetes drug, metformin, to see if it can delay the onset of other age-related diseases in older adults who have received a diagnosis of at least one, as one study suggests it might. But the group has yet to secure funding. One reason, the researchers say, is that the notion that aging is immutable is so deeply entrenched. "When I go out and try to raise money for this, the first thing people will say to me is, 'Eh, we're all getting older,' " said Steven Austad, a researcher at the University of Alabama.



Researchers here report on the details of pacemaker cell decline in aging. These cells drive the heartbeat, but as is the case for all tissues, they and their environment become damaged and dysfunctional in later life. Signaling mechanisms attempt to compensate, but that compensation is imperfect, and itself subject to the effects of damage:

Healthy heart beating intervals (BIs) are not strictly constant, but rather exhibit beat-to-beat variations, imparting complexity to the heart rhythm. Beating Interval Variability (BIV) reduction is a predictor of heart diseases and an increased mortality rate. Although the average basal BI remains constant with advancing age, the basal BIV is found to be reduced. In contrast to the preservation of the average basal BI, the average intrinsic BI, that is, in the absence of autonomic neural input, is found to be prolonged with advanced age. Whether and how the intrinsic BIV is altered in advanced age and the identities of mechanisms that underlie the changes in the BI-BIV relationship that accompany advancing age have not been well characterized.

Two main mechanisms regulate the average BI and BIV: (i) stimulation of extrinsic autonomic receptors on pacemaker cells (i.e. β-adrenergic receptors or cholinergic receptors) within the sinoatrial node (SAN) controlled by the balance between sympathetic and parasympathetic neural impulses to the heart and (ii) constitutive signaling intrinsic to pacemaker cell via Ca2+-calmodulin adenylyl cyclase (AC) types 1 and 8, which, in the absence of autonomic receptor stimulation, drives many of the same cell mechanisms that are modulated by autonomic receptor stimulation. Both neural input to pacemaker cells and mechanisms intrinsic to pacemaker cells deteriorate with advancing age.

We hypothesized that age-associated changes in average BI and BIV result from the alteration in both intrinsic and neural input signaling. We analyzed BI dynamics in mice of varying ages: (i) in vivo, when the autonomic input to the sinoatrial node is intact; (ii) during autonomic denervation in vivo; and (iii) ex vivo, in the intact isolated SAN tissue (i.e. in which the autonomic neural input is absent). BIV was quantified and although the average basal BI did not significantly change with age under intrinsic conditions in vivo and in the intact isolated pacemaker tissue, the average BI was prolonged in advanced age. In vivo basal BIV indices were found to be reduced with age, but this reduction diminished in the intrinsic state. However, in pacemaker tissue BIV indices increased in advanced age vs. adults. In the isolated pacemaker tissue, the sensitivity of the average BI and BIV in response to autonomic receptor stimulation or activation of mechanisms intrinsic to pacemaker cells by broad-spectrum phosphodiesterase inhibition declined in advanced age. Thus, changes in mechanisms intrinsic to pacemaker cells increase the average BIs and BIV in the mice of advanced age. Autonomic neural input to pacemaker tissue compensates for failure of molecular intrinsic mechanisms to preserve average BI. But this compensation reduces the BIV due to both the imbalance of autonomic neural input to the pacemaker cells and altered pacemaker cell responses to neural input.


The researchers and advocates of the Major Mouse Testing Program will be answering your questions in an /r/futurology AMA ("Ask Me Anything") event today. The organization is presently raising funds via crowdfunding in order to run the first in a set of animal life span studies of senolytic drugs as a means to reduce the number of senescent cells in old tissues. The presence of such cells is one of the causes of aging, and a range of initiatives aimed at treatments are presently in the early stages of development. This is a still a very poorly funded area of research in comparison to its potential, however, which is why our continuing support is absolutely necessary if there is to be significant progress in the next few years:

The Major Mouse Testing Program (MMTP) is an ambitious project of the International Longevity Alliance (ILA), featuring an international team of scientists and advocates testing therapies against aging decline. This experiment is is lead by world class stem cell researcher Dr. Alexandra Stolzing and was inspired by our scientific advisor and colleague Dr. Aubrey de Grey.

The Major Mouse Testing Program is seeking to speed up scientific progress in the field of regenerative medicine and biogerontology. After ILA experts conducted an analysis of delays preventing the development of life extension technologies, it was shown that a serious problem was the lack of robust animal data for the potential of different compounds to promote health and extend maximum lifespan. Without this data promising interventions cannot enter clinical trials and become available to the general public. The MMTP is currently running a crowdfunding campaign to raise funds to address this issue.

For the first experiment we are testing a new class of drugs known as senolytics, these drugs have been shown to help seek out and destroy toxic senescent cells that accumulate with age and improve various aspects of health. We wish to see if senolytics can increase maximum lifespan in addition to healthspan. We have big plans for the future with combination testing of senolytics, stem cells and more to help speed up scientific progress. So go ahead and ask us anything!


Mutational damage to nuclear DNA increases with age, and this is one of the reasons as to why cancer is predominantly an age-related disease. The more damage there is, the more likely that some of that damage causes a cell to run wild as the seed of a cancer. Beyond this, there is some debate over whether or not nuclear DNA damage produces a significant contribution to aging by dysregulation of cellular behavior, though the mainstream consensus at this point - in advance of any definite study proving the point - is that it probably does. To a large degree this is based on the observation that any breakdown of the extremely efficient DNA repair mechanisms present in our cells produces a range of conditions, many of which appear superficially similar to aging. The point is subtle, however: if aging is damage, there are many ways to generate cell and tissue damage in a living organism that have no particular relevance to aging, even though they also result in disability and death.

Mammalian cells evolve a delicate system, the DNA damage response (DDR) pathway, to monitor genomic integrity and to prevent damage. DNA carries the inheritable genetic information for all living organisms. However, DNA receives endogenous and exogenous insults every minute and the lesions (approximately 10^4-10^5 per cell per day) are extremely deleterious to cells. These lesions, if not correctly repaired, will interrupt genome replication and transcription and cause wide-scale chromosomal aberrations that trigger malignant transformation or cell death. Therefore, effective sensing and repair systems are developed during evolution to eliminate the DNA lesions and to maintain genome integrity. Dysregulation of DDR and repair is closely associated with human diseases such as cancers, cardiovascular disease, neurodegenerative disorders and aging.

Aging is defined as a progressive decline of body function and a decrease of physiological response to stress that ultimately results in death. Because the insufficiency of repair will cause the accumulation of DNA damage which leads to cell death or functional defect, it is reasonable to hypothesize that DDR and repair is closely associated with aging. Indeed, mice defective in DNA repair exhibit features of premature aging. Human genetic diseases with DNA repair defects such as Huchinson-Gilford Progeria all show premature aging. However, not all DNA damage and repair cause aging. Defects in mismatch repair (MMR) may result in cancer formation but not directly correlate with aging. Interestingly, an accumulation of DNA damage or defect in DNA repair also promotes cellular senescence and apoptosis. This raises the question whether senescence induced by physiological or pathological alterations may be involved in aging.

Many previous studies addressing the senescence mechanism were done in single cells, especially in fibroblasts. An obvious question is how cellular senescence caused by deficient DNA repair finally affects the aging of a living organism. We propose three potential mechanisms to explain the systemic effect. First, senescence depletes the supplemental pool of stem cells or progenitor cells that leads to the continuous decline of tissue homeostasis and accelerates organ aging. Secondly, senescence causes tissue degeneration. As evidenced in human diseases, defects in DNA repair induce senescence and degeneration of nervous and endocrine/exocrine tissues. Dysfunction of the nervous system would decrease the activity of innervated tissues and dysfunction of the endocrine/exocrine system would disturb hormone homeostasis and nutrient balance which ultimately causes organ aging. Thirdly, senescence induces chronic inflammation. One well-known characteristic of senescent cells is the production of pro-inflammatory and matrix-degrading molecules, known as the senescence-associated secretory phenotype (SASP). Higher serum levels of pro-inflammatory factors such as interleukin-6 and tumor necrosis factor are found in aged mice. A similar observation is also confirmed in aged individuals. Chronic inflammation triggered by these pro-inflammatory factors changes the immune response and vascular system and finally disrupts the physiological function of many tissues to promote the aging process.


This open access review paper looks over what is known of the role of the immune system in bone regeneration. A variety of immune cells play important roles in tissue regeneration, but these activities are not yet fully cataloged and understood, and are different in different tissues. Since the immune system declines with age, along with the stem cell populations that provide signals and a supply of new cells for tissue maintenance, it is likely that this is one of the causes of failing regeneration in older individuals.

Bone fractures are among the most common orthopedic problems that require medical intervention, particularly in the elderly. Almost half of fractures are related to osteoporosis, especially in individuals over the age of 55. Bone injury leads to the production of pro-inflammatory cytokines and chemokines and to systemic recruitment of macrophage precursors to the injury site. Bone healing is a complex process and there appears to be a deficiency in our understanding of the interactions between macrophages and mesenchymal stem cells (MSCs) in bone healing, especially in the elderly population. Specifically, aging may alter these interactions and thereby play an important role in the elderly patient's ability for regeneration of musculoskeletal tissues.

As such, it is important to understand the different macrophage populations that play a role in bone repair. Though they exist within a spectrum, macrophages can be broadly described as uncommitted M0, pro-inflammatory M1, and anti-inflammatory M2 populations. In actuality, both in humans and mice, there probably exists a spectrum of polarization phenotypes, with a general preponderance of pro- versus anti-inflammatory properties. With these multiple phenotypes, macrophages play several roles within the bone-healing process, depending on their polarization status and environmental cues.

Although it is apparent that macrophages have altered activities with age, it is unclear as to what these specific changes entail and the mechanisms that drive such changes in musculoskeletal tissues. Several studies point to intrinsic factors that alter macrophage polarization, function, and survival. It was found that aged muscle had higher levels of M2a polarized macrophages, muscle fibrosis, and collagen accumulation. The increased frequency of M2a macrophages and fibrosis was attributable to the aging of myeloid lineage cells, as demonstrated by rescue of aged muscle with infusion of young bone marrow cells. In addition to intrinsic changes of aging, macrophages are modulated by their aging microenvironment and a poorly described number of external factors. When challenging young macrophages with aged serum, studies found reduced macrophage secretion of TNFα and increased basal levels of IL-6. In a study comparing phagocytosis by young and aged peritoneal macrophages and bone marrow-derived macrophages, it was demonstrated that older peritoneal macrophages have significantly impaired phagocytosis compared with younger macrophages.

Aging is also associated with elevated levels of secreted inflammatory cytokines beyond the previously described functional and environmental changes. Much of the literature describes aged macrophage hypersensitivity and increased responsiveness to inflammatory signals. These findings suggest that aged macrophages remain in a pre-activated resting state that enhances their response to exposure of pro-inflammatory stimuli. However, with increased production of reactive oxygen species, aged macrophages are susceptible to oxidative damage. Although there is increased responsiveness to pro-inflammatory signals, aged macrophages also have impaired function with reduced phagocytic activity, reduced nitrite burst capacity, and reduced autophagy.

Given current knowledge, it is apparent that aging-associated changes in the macrophage population are normal events but can also be potential sources for pathological states. With aging, the proliferative and functional abilities of macrophages and MSCs are impaired because of a combination of intrinsic and environmental factors. As proper bone healing requires an inflammatory phase, the increased survival of anti-inflammatory M2 macrophages and reduced secretion of pro-inflammatory factors with age may jeopardize timely bone regeneration. At the same time, aging negatively impacts MSC proliferation and differentiation, further impeding the bone-healing process. It would appear that, taken together, both macrophages and MSCs, cells critical for regeneration of musculoskeletal tissues, are adversely affected by aging. This scenario provides new opportunities for modulation of cellular events in order to optimize the healing of mesenchymally derived tissues, including bone.


Oct4 is one of the factors used in reprogramming recipes that convert ordinary somatic cells into induced pluripotent stem cells, similar to embryonic stem cells and capable of generating any tissue type given the right environment and further programming. Given this, it is not entirely unexpected for Oct4 to show up in mechanisms relevant to aging and regeneration, as is the case here. Researchers have found Oct4 to have a protective role in the development of atherosclerosis, stabilizing the plaques that form in blood vessels over the course of that condition. As a target for therapy this leaves a lot to be desired - it is very far down the line of disease progression, and stable plaques still grow and narrow blood vessels, producing high blood pressure, remodeling of the vascular system, and other aspects of cardiovascular disease. It would be far better to note this research as interesting and focus instead on better ways to remove plaques and prevent their existence in the first place.

The gene, Oct4, plays a key role in the development of all living organisms, but scientists have, until now, thought it was permanently inactivated after embryonic development. Some controversial studies have suggested it might have another function later in life, but a new study is the first to provide conclusive evidence of that. The gene plays a critical protective role during the formation of atherosclerotic plaques inside blood vessels. The rupturing of these plaques is the underlying cause of many heart attacks and strokes. The researchers found that Oct4 controls the movement of smooth muscle cells into protective fibrous "caps" inside the plaques - caps that make the plaques less likely to rupture. The researchers also have provided evidence that the gene promotes many changes in gene expression that are beneficial in stabilizing the plaques. This is exciting, because studies suggest that it may be possible to develop drugs or other therapeutic agents that target the Oct4 pathway as a means to reduce the incidence of heart attacks or stroke. "Our findings have major implications regarding possible novel therapeutic approaches for promoting stabilization of atherosclerotic plaques." One surprising finding: when the researchers blocked the effect of Oct4 in mice, they thought the atherosclerotic plaques might become smaller, because of the reduced number of smooth muscle cells inside. Instead, the plaques grew larger, less stable and more dangerous, stuffed with lipids, dead cells and other damaging components.

Researchers believe the gene could also prove critical to the field of regenerative medicine, which investigates the growth and replacement of tissues and organs. The researchers believe that Oct4 and its family of target genes are activated in other somatic cells - the non-reproductive cells in the body - and play a key role in the cells' ability to repair damage and heal wounds. Studies to test this are under way. Researchers suspect that at least some of the detrimental effects of aging, including the increased possibility of a plaque rupture, stem from a decrease in the body's ability to reactivate Oct4. "Finding a way to reactivate this pathway may have profound implications for health and aging. We think this is just the tip of the iceberg for controlling plasticity of somatic cells, and this could impact many human diseases and the field of regenerative medicine."


Given a robust algorithm for assessing how youthful someone appears to be, and there are a few of those floating around the research community in various stages of development, it comes possible to look for correlations between a youthful appearance and various genetic variations. It isn't clear that this will lead to any practical outcome, but that is true of most fundamental research at the time it is undertaken. Possibly the most interesting aspect of the study noted here is that the correlation they found is present in multiple populations, which is a fairly rare occurrence in research into genetics and longevity.

Looking young for one's age has been a desire since time immemorial. This desire is attributable to the belief that appearance reflects health and fecundity. Indeed, perceived age predicts survival and associates with molecular markers of aging such as telomere length. Understanding the underlying molecular biology of perceived age is vital for identifying new aging therapies among other purposes, but studies are lacking thus far. As a first attempt, we performed genome-wide association studies (GWASs) of perceived facial age and wrinkling estimated from digital facial images by analyzing over eight million single-nucleotide polymorphism (SNPs) in 2,693 elderly Dutch Europeans from the Rotterdam Study. The strongest genetic associations with perceived facial age were found for multiple SNPs in the MC1R gene. This effect was enhanced for a compound heterozygosity marker constructed from four pre-selected functional MC1R SNPs, which was replicated in 599 Dutch Europeans from the Leiden Longevity Study and in 1,173 Europeans of the TwinsUK Study.

Individuals carrying the homozygote MC1R risk haplotype looked on average up to 2 years older than non-carriers. This association was independent of age, sex, skin color, and sun damage (wrinkling, pigmented spots) and persisted through different sun-exposure levels. Hence, a role for MC1R in youthful looks independent of its known melanin synthesis function is suggested. Our study uncovers the first genetic evidence explaining why some people look older for their age and provides new leads for further investigating the biological basis of how old or young people look.


A number of different research groups are working on ways to restore function of the thymus in old individuals, with methods ranging from the introduction of cells with youthful characteristics to the engineering of thymus tissue for transplantation. Promising results have been produced in mice. The thymus is where the immune cells known as T cells mature, and it atrophies fairly early in adult life, reducing the supply of new immune cells to a trickle. That the supply of new cells is so small across most of the life span is one of the factors contributing to the age-related decline of the immune system, and so opening the floodgates to a much larger supply should help to diminish and reverse some of the characteristic failures of an old immune system. Dysfunction of the immune response is a considerable portion of age-related frailty, and it isn't just a matter of failure to deal with invading pathogens. The immune system is also responsible for destroying damaged and potentially threatening cells, such as senescent cells and cancerous cells, and failing that task has equally serious consequences.

The thymus is mainly composed of two types of epithelial cells, medullary thymic epithelial cells and cortex thymic epithelial cells (mTECs and cTECs). The tissue structure and mechanism for T cell development are complicated, with generation of the thymus regulated by complex molecular and cellular interactions of the thymic microenvironment during embryogenesis. Since the development of organ regeneration techniques became available, complete in vitro regeneration of the thymus has been attempted. Steric induction systems are thought to be optimal for tissue regeneration, but three-dimensional (3-D) induction of TECs from induced pluripotent stem cells (iPSCs) has not yet been reported.

Here, we demonstrate the induction of functional TECs from iPSCs by a 3-D spheroid culture system with recruitment of robust numbers of T cells into the peripheral blood. Purified iPSC-derived TECs showed a sufficient expression level of FoxN1 comparable to TECs, and phenotypic analysis revealed that iPSC-derived TECs were expressing K5. Moreover, transplants of cell aggregations into recipient mice were not rejected and there was normal support of T cell development. Functional analysis revealed that T cells showed immune tolerance to both donor and recipient major histocompatibility complexes and could reject an allogeneic third party's skin graft without tumorigenesis. Taken together, these findings raised the possibility of using iPSC-derived TECs induced by 3-D spheroid culture in future regenerative therapy for patients with immunodeficiency.


There is a contingent of cryonics supporters who want more iron-clad evidence beyond that which already exists to demonstrate that the process of vitrification of tissue does work to preserve the fine structure of the brain, and thus the data of the mind. Everyone has a different threshold of comfort for proof, and some people have the luxury of time when it comes to watching the evidence accumulate over the years. There will always be those who will be uncomfortable with all uncertainty and wish to wait until the first preserved individual is revived, for example, but that is distant in time and technology; many decades, or possibly longer. Decisions on whether to sign up and whether to be preserved must be made before that point arrives for most of us.

There is also a contingent of cryonics supporters who see the ultimate destination for a preserved individual as scanning in order to run a mind in emulation in software. The original tissue would be discarded, and some folk are just fine with that. This is not appealing to me, and I see the primary purpose of preservation as being to offer the chance of restoration of the original - a copy of you is not you. Identity is not just a pattern, but also bound up in the particular matter that encodes that pattern. Restoration of vitrified brain tissue to a living, repaired status in a new body will probably be a more challenging task than scanning and emulation for the technology of the late 21st century, even though reversible vitrification of organs other than the brain is fairly close to realization as a practical technology for use in the organ transplant industry. Still, it is the only option if you, yourself, the original individual, wish a chance at a renewed life in the future.

Though no frozen humans have yet been revived, cryonics has been an industry for over fifty years. In that time, focus has shifted slightly. Lately, the emphasis has been more on brain emulation: mental maintenance as opposed to physical resurrection. The body and the self have been, in a sense, decoupled. Michael Cerullo, a neuroimaging specialist, moonlights as a cryonics pioneer. He spends a lot of time working with the Brain Preservation Foundation, an organization devoted to pushing cryonics toward the mainstream or, barring that, the mainstream towards cryonics. Because he's a doctor, Cerullo thinks of the freezing procedure as fundamentally medical in nature. More specifically, he and the BPF consider it an issue of brain health, which is why they awarded scientist Robert McIntyre a prize in February for his pioneering work with Aldehyde Stabilized Cryopreservation. McIntyre's technique allowed him to preserve a rabbit's connectome for, in theory, thousands of years. Cerullo says this is the sort of procedure he hopes will someday happen in hospitals.

What makes Cerullo a particularly compelling advocate for cryonics is that he's not a true believer - not exactly. He's an associate member of Alcor, the most recognizable name in the field, but he hasn't signed up to be preserved: evidence is lacking that current technology actually works. He's a man who wants proof and, more specifically, he's a man who wants proof that his identity can be preserved. He's open to experimentation with machine-neuron interfaces and emulation, but if he comes back, he wants to come back as himself. And that's the rub. We can't know if self-identity can be preserved until the technology starts working. Cerullo gives it twenty years, but points out that current dead bodies are stored as donated organs. If they still contain selves, we'll need to seriously reconsider our relationships with the frozen and the passed on.

If the brain turns off, are we the same people when it turns back on? That's the challenging question. Right away there are two schools of thought. A lot of the cryonics people want to be brought back biologically. They're hoping for a technique that they can be thawed out and continue in the same brain and same body. The challenge with that, though, is that a lot of the procedures, like the Aldehyde Cryopreservation, are not reversible. The first step is infusing the brain with glutaraldehyde, which is about the deadliest substance known. So you're never going to be able to revive that. What you're hoping is that, since you've got all the information there, with improvements in large-scale scanning techniques, you could get all the information uploaded. Let's say you do something like this new procedure, where there's no hope of biological revival. Then you upload the brain. There are still a couple of options: there's destructive and nondestructive uploading. One possibility would be that you could noninvasively scan the brain and get all the information. More likely, it would be destructive uploading, where you slice the brain in billions and billions of little nanometer thick slices, and map the whole connectome. Let's say you do that. Then, you emulate it in a computer in fifty, a hundred years, when the technology is there.

Does identity continue? Ultimately, we don't know the answer. No one has the full answer. A lot of people, though, assume that, you know, 'Okay, well this is just a simulation or a copy, and so of course it's not you.' I think that's the default answer. That seems to be the safe answer, because it doesn't really challenge a lot of things. But, what I think is more interesting, though, is that either way you answer that question - whether you say yes, the person is the same, or no, it's just a copy - either way there are a lot more implications than people realize. Either way, consciousness is a lot more complicated than we think. I don't think there's any easy answer. Either answer you take leads to paradoxes and just bizarre consequences that we really don't have great answers to. A lot of the scientists that I talk to are very gung-ho: 'Yes, this preserves the pattern, the information, and that's all we are.' I have a lot of sympathy for that view, but I think there are still a lot of deep questions that you really need to think about. But, I think that's the strongest answer, because the more we learn about the brain, and the more neuroscience advances, there really doesn't seem to be anything left out. The brain is the neurons and the information, and if that pattern's still there, then the person is still there.


The authors of the open access paper linked here are training neural networks on large numbers of blood samples in an effort to produce biomarkers of aging. This is an interesting approach, primarily because it should in theory answer the question of whether a given data set - such as the data from blood tests - has any useful correlation with age. Biomarkers of biological age, how damaged an individual happens to be, are a necessary development in the field of aging research. At present the only reliable way to see how well a possible rejuvenation therapy works is to wait and see, which is slow and expensive in mice and out of the question in humans. What is needed is a quick measurement that accurately reflects biological age and thus remaining life expectancy. Given that, many more potential approaches to treating aging could be assessed and compared for a given level of funding and time, as the need to wait and see could be eliminated.

One of the major impediments in human aging research is the absence of a comprehensive and actionable set of biomarkers that may be targeted and measured to track the effectiveness of therapeutic interventions. In this study, we designed a modular ensemble of 21 deep neural networks (DNNs) of varying depth, structure and optimization to predict human chronological age using a basic blood test. To train the DNNs, we used over 60,000 samples from common blood biochemistry and cell count tests from routine health exams performed by a single laboratory and linked to chronological age and sex. To make this deep network ensemble available to the public, we placed our system online (at, allowing any patient with blood test data to predict their age and sex.

The best performing DNN in the ensemble demonstrated 6.07 years mean absolute error in predicting chronological age within a 10 year frame, while the entire ensemble achieved 5.55 years mean absolute error. The analysis of relative feature importance within the DNNs helped deduce the most important features that may shed light on the contribution of these systems to the aging process, ranked in the following order: metabolic, liver, renal system and respiratory function. The five markers related to these functions were previously associated with aging and used to predict human biological age. Another interesting finding was the extraordinarily high importance of albumin, which primarily controls the oncotic pressure of blood. Albumin declines during aging and is associated with sarcopenia. The second marker by relative importance is glucose, which is directly linked to metabolic health. Cardiovascular diseases associated with diabetes mellitus are major causes of death within the general population. Current and future directions of this work include adding other sources of features including transcriptomic and metabolomics markers from blood, urine, individual organ biopsies and even imaging data as well as testing the system using data from patients with accelerated aging syndromes, multiple diseases and performing gender-specific analysis.


I'm very pleased to report that that the SENS Research Foundation project on mitochondrial allotopic expression (MitoSENS) that was crowdfunded at this time last year has achieved success. The two target mitochondrial genes have been moved to the cell nucleus, and suitably altered so that the proteins produced return to the mitochondria. This means that cells so treated are immune to age-related damage to those two genes in the mitochondrial genome: they will still construct and make normal use of the proteins encoded in those genes as though nothing happened. Given that mitochondrial DNA damage is an important contribution to the aging process, progress on this front is very welcome.

The crowdfunded work was the final sprint at the end of a years-long project conducted with minimal funding, and it is great to see success. Congratulations are due to the researchers involved. There are thirteen mitochondrial proteins in total that are thought to be all that is needed to move into the nucleus. Allotopic expression of one other mitochondrial gene is solidly complete, and is the basis for the therapies under development at Gensight. Another two genes are somewhere in the middle of the process in the SENS Research Foundation network of researchers. This leaves a further eight genes to go. As ever, this is work that is in search of much greater funding: the researchers are always ready to go, and the more that we can do to help deliver that funding, the sooner we'll see rejuvenation therapies in the clinic.

Note that you may need to click the updates tab on the fundraiser page in order for the updates to load:

Hi everyone, it's been an amazing few months. In short, we have been tremendously successful in our efforts to rescue a mutation in the mitochondrial genome! Essentially we've shown that we can relocate both ATP6 and ATP8 to the nucleus and target the proteins to the mitochondria. We can show that the proteins incorporate into the correct protein complex (the ATPase) and that they improve function resulting in more ATP production. Finally, we show that the rescued cells can survive and grow under conditions which require mitochondrial energy production while the mutant cells all die.

We have finished writing up our results and submitted them for review and publication. It may take a while for our results to be published (the peer review process can be lengthy) but as soon as it is I'll post an update here so you can see the full paper. We have also started the project that you helped us get to our stretch goal on. We have made all the combinations of mitochondrial targeting sequences with ATP6 that we proposed and are now working on testing them. I'll let you know when we know more. Thank you so much for your support!


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