Fight Aging! Newsletter, July 11th 2016

July 11th 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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  • Crowdfunding Progress Towards a Universal Therapy for All Cancers: an Interview with SENS Research Foundation Scientist Haroldo Silva
  • Fundraising Poster: Help the SENS Research Foundation Speed Progress Towards a Universal Therapy Effective for All Cancers
  • An Educational Article on the Business of Selling Nicotinamide Riboside
  • Telomere Dynamics in Mice are Not the Same as in Human Tissues
  • On Cellular Reprogramming and Cellular Rejuvenation
  • Latest Headlines from Fight Aging!
    • Attempting to Improve the Effectiveness of Retinal Cell Therapies
    • The Cross-Organelle Response in Yeast Aging
    • A View on Targeting Inflammaging and Senescent Cell Behavior in Therapies
    • Deeper Investigations of the Relationship Between Amyloid-β and Tau Aggregates in Alzheimer's Disease
    • Loss of β1-integrin and Fibronectin Implicated in Muscle Stem Cell Decline
    • Longer Lives are Healthier Lives for Centenarians
    • A Reminder that Some Mitochondrial Genomes are Better than Others
    • Evidence to Demonstrate that Cartilage Tissue Does Not Renew
    • A Map of Gene Expression Changes with Aging in Human Muscle
    • Arguing for the Effects of Senescent Cells to Extend into the Immune System


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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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


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

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

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

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


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

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

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

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

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

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

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

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

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


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

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

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

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

Human Specific Regulation of the Telomerase Reverse Transcriptase Gene

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

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

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


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

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

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

Stem cells for all ages, yet hostage to aging

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

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

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



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

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

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

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


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

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

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

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

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

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


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

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

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

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


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

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

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

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


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

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

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


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

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

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

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

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


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

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

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

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


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

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

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


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

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

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

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

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


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

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

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

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


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