Fight Aging! Newsletter, January 12th 2015

January 12th 2015

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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  • Explore the Whale Genome
  • Aubrey de Grey Presenting at the DGAB Scientific Symposium on Cryonics
  • The Scientific Institution is Biased Against Shortcuts to the Production of Practical Technology
  • Rejuvenation Biotechnology Update for January 2015
  • Another Complication in Mitochondrial Dynamics is that Cells Can Transfer Mitochondria
  • Latest Headlines from Fight Aging!
    • A Measure of Declining Cancer Mortality Rates
    • Considering Sarcopenia
    • A Review of What is Known of MicroRNAs in Aging
    • Are Lysosomes Influencing Longevity Through Mechanisms Other than Garbage Collection?
    • A Historical Correlation Between Solar Activity at Birth and Consequent Life Expectancy
    • Stem Cell Depletion Does Not Accelerate Muscle Loss in Aging
    • Measures of Function are Maintained to a Greater Degree Over Time in Fit People
    • A Less Dysregulated Immune System is Associated With Better Cognitive Function in Aging
    • More Work on Engineering New Intestinal Tissue
    • Senescent Cells and Detrimental Remodeling of Aged Lungs


The comparative biology of aging is a field that attempts to use differences between species to better understand the genetic and metabolic roots of longevity. Why do some neighboring species of a similar size, such as mice and naked mole-rats, have such radically different life spans, wherein the mole-rats can live nine times as long? Why are humans very long-lived in comparison to other primates? How is it that individuals in some whale species can live for two centuries or more with a thousand times the cell count of a human and yet not have a thousand times the cancer incidence? On the one hand this is a potentially effective way to seek out the few important parts of a very complicated system, mammalian biology, that is poorly understood in depth at this time. It is a short-cut through the vast unknown. On the other hand, the promise at the end of the day is not just knowledge, but the possibility that perhaps therapies or other beneficial alterations to human biology could be produced as a result of these investigations.

It is hard to say whether it is plausible to hope for cross-species porting of useful features of biochemistry, even between mammals. The devil is in the details, and the details are going to vary widely on a case by case basis. It is very possible that researchers will in the next couple of years uncover a beneficial feature in whales that is clearly and evidently useful, but linked to particulars of their biochemistry in ways that make it absolutely impossible to recreate in humans. The investigations of naked mole-rats are much further along in comparison to of those of whales and are turning up some items that sound plausible to attempt as human therapies and other items that sound near impossible to safely recreate in humans at our presently level of technology. Equally the same job might be a walk in the park for the biotechnology of the 2030s: at this point far too little is known to do more than speculate.

Step one in all of this is to sequence the genome of the species in question - it's hard to get too far into the details without that. You might recall a recent publication on the bowhead whale genome from one of the two teams working separately on that project. Here is an article on the work of the other team, who have put up an online searchable database for those interested in exploring the genome:

Could a 200-year-old whale offer clues to help humans live longer?

Joao Pedro de Magalhaes and his team at the University of Liverpool sequenced the genome of the bowhead whale, the longest living mammal on earth. The team wanted to understand why they live so long and don't succumb to some of the same illnesses as humans do earlier in life. "One of the big mysteries of biology is understanding species differences including species differences in aging. For example, mice age 20 to 30 times faster than human beings and we don't know why ... Even primates which are closely related to us age considerably faster than human beings. There has to be some genetic basis to why humans age slower than chimpanzees for instance which are very genetically very similar to us. Likewise, there has to be some genetic basis as to why bowhead whales live so long and appear protected from diseases."

With a 1,000 times more cells than a human, the whale should have a much higher probability of cell death and disease. It doesn't. In their findings the team found as many as 80 candidate genes that may help protect the whale from cancer or contribute to it being the longest living mammal on earth. The team found that the whales have genes related to DNA repair, as well as those regulating how cells proliferate, that differ from those found in humans.

There is a huge industry searching for that elixir which could help humans live longer. Some research has gone into finding what is called longevity genes that could lead to new drug therapies while other research promotes such things as exercise and healthy eating to extend your life. Two groups which funded most of the whale research - the Life Extension Foundation and the Methuselah Foundation - are seeking that magic potion. Life Extension focuses on such things as hormonal and nutritional supplements to fight aging while Methuselah is heavily invested in tissue engineering and regenerative medicine "to create a world where 90 year olds can be as health as 50 year olds, by 2030."

Methuselah's co-founder and CEO Dave Gobel said it invested in the whale research as part of its "hypothesis that the best way to find out how to become longevity outliers is to study those who already are genetic outliers within mammalian species" and then find "what genetic complexes, pathways seem most common among these outliers and to explore what they do, how they act, and what if any advantages can be derived from them to apply in humans."

The Bowhead Whale Genome Resource

The mechanisms for the longevity and resistance to aging-related diseases of bowhead whales are unknown, but it is clear these animals must possess aging prevention mechanisms. In particular in context of cancer, bowhead whales must have anti-tumour mechanisms, because given their large size and longevity, their cells must have a massively lower chance of developing into cancer when compared to human cells. As such, we sequenced the genome of the bowhead whale to identify longevity assurance mechanisms.

A high-coverage genome assembly, and corresponding annotation, of the bowhead whale is made available to the scientific community to encourage research using data from this exceptionally long-lived species. Overall, this project aims to provide a key resource for studying the bowhead whale and its exceptional longevity and resistance to diseases. By identifying novel maintenance and repair mechanisms we will learn what is the secret for living longer, healthier lives and may be able apply this knowledge to improve human health and preserve human life.

As it is turning out the study of comparative biology over the next decade or so will probably not produce much in the way of practical applications in treating aging, but rather be of relevance to advances in (a) cancer treatment, through what is learned from naked mole-rats and possibly from whales, and (b) regenerative medicine, through investigations of proficient regenerators such as salamanders. Those items are where the money is flowing. That said, this research should lead to faster progress in the scientific goal of fully mapping the process of aging and its interaction with metabolism at the detail level, but as outlined elsewhere at Fight Aging! this is not the road to human rejuvenation. At best, given the field as it stands at present, altering the operation of our metabolism can only aim at modestly slowing the accumulation of cellular and molecular damage, not repairing it or reversing it, and even this will be a vast and complicated undertaking. If we want rejuvenation, we must instead aim at repair of the metabolism we have as the primary objective, and fortunately significant progress towards this goal does not require much more knowledge than we have already.


Late last year the German Society for Applied Biostasis (DGAB) held a scientific symposium on cryonics. A number of researchers from the aging research community attended, as there is some overlap between people interested enough in radical life extension to have become members of the aging research community and people interested enough in cryonics to help advance that work. It is similar to another overlap with the field of artificial general intelligence research. If you move in these circles you'll keep bumping into some of the same people regardless of the topic of the present conference.

Why is this the case? Well, there was a coming together of many disparate futurists in the 1990s and a years-long blossoming in the exchange and synthesis of ideas relating to the rapid advance of computing, medicine, and materials science. This happened as a natural result of the accelerating growth in English-language internet usage at the time, and in particular due to a newly enhanced ability to easily organize ad-hoc communities with similar interests but whose members are widely separated geographically. If you trace the people who were present for those online discussions you'll find that a modest but significant number of them have since forged their careers from what they want to see for the future of humanity: radical life extension, cryonics, molecular nanotechnology, artificial general intelligence, and so forth. There was a period of comparative unity and consensus back then, when fewer people were online and it was all still fairly new, followed by a diaspora of ideas and efforts into diverse but conceptually linked fields of technological development, of making the future real.

This is why there are people who work on the molecular biology of aging found at cryonics conferences, why there are people who fund both general AI and aging research and consider both part of a greater whole, and it is also the explanation for many other similar connections in a still growing web of relationships that started with enthusiastic online discussions of futurist goals that took place a couple of decades ago. The futurism - the transhumanism - of the 1990s is the everyday scientific groundwork of today, and those young futurists are often one and the same individuals as the older team leaders now performing that work.

In any case, here is Aubrey de Grey of the SENS Research Foundation presenting on the topic of rejuvenation biotechnology to the DGAB, many of whom are supporters. If you are up for cryonics as an option, then you should certainly be in favor of extending healthy life through other engineering applications of medical science. If you are already familiar with SENS as a strategy for the development of therapies to reverse aging, then you might want to skip ahead to about 25 minutes in to get an update on ongoing research programs: what is being done, and where things stand at present.

If you have an interest in the science of cryonics and cryopreservation, then you'll find a range of other presentations from the symposium available online:

  • Possible Mechanisms of the Cryoprotective Effect of Xenon
  • Functional genomics of cryoprotectant toxicity
  • History of cryonics
  • Definitions of Death
  • Age related degeneration
  • Protocol for Vitrification of Bulky Biological Objects
  • New cryonics technologies
  • [1/2] How to sustain an organization for over a century
  • [2/2] How to sustain an organization for over a century


Technology is the application of scientific knowledge. The scientific culture and scientific process as it is practiced today embodies a strong bias against any sort of shortcut towards the production of technology, however. If it seems plausible at a lesser level of understanding of a system that you could achieve some beneficial application, then the peer pressure in the scientific community is always to hold off and work instead towards a full understanding. This situation is not uncommon in medicine: many discoveries are serendipitous, but to try to turn demonstrated positive results in the laboratory into positive results in the clinic will be opposed at every turn until the underlying mechanisms can be fully explained.

The bias against action and towards understanding as the primary goal is baked into every level of the research establishment and surrounding institutions. The scientific method has researchers moving eternally towards greater understanding. It has nothing to say about what you do with that understanding, however. Application to produce technology is where you step from the Platonic ideal and into the messy real work of engineering: the art of creating meaningful solutions in the absence of full understanding. This boundary between knowledge and technology produces all sorts of cultural friction, and I think it is fair to say that scientists who depart to be engineers are not treated as well as they might be by their former peers. There is little disapproval in the world quite like that of pure scientists directed towards one of their own who steps away to start a technology business.

At root there are very good reasons for this bias: the scientific method is required for progress, yet it is constantly under attack from opportunists and fallible human nature: wishful thinking, the desire to find progress where there is none, the desire for short-term gain over long-term gain, and so forth. If shortcuts are not treated as heresy, then there will be all too many research programs led astray, and development predicated on false results, and in the worst cases outright fraud. This happens even with the scientific culture of disapproval, but far less so than it otherwise might.

While the core of the scientific method is centuries old, to some degree this strong bias against early attempts at practical application is a phenomenon of modern times. In the institution of medical research everything that moves beyond early stage exploration must be explicable to the standards of the day, but matters were not always so rigorous. There any number of grandfathered treatments available today that are not sufficiently well understood at the level of molecular biology to get into clinical trials if they were discovered today. Regulation as it stands today in the US states that you shall only treat named conditions, and you shall present a full understanding of how you are doing it. Since everything else is actually outright forbidden, you end up with a situation in which all funding and effort - even back down the chain to supposedly unconnected free-ranging fundamental research - is focused on the molecular biology of late stage disease and the proximate causes thereof. For most researchers that's the only work with a future if you want to contribute to something that might actually end up approved for clinical use.

So these influential edifices of thought, and all the funding that is influenced by them, say that any approach in research that specifically aims to circumvent our lack of knowledge in some areas is simply Not The Done Thing. Yet there are many lines of research in which it is clearly plausible that great benefits could be derived by doing just this, and - as currently constructed - the walls that the scientific institution is forced to erect for its own defense exclude all of this good, solid work that might lead to better therapies. As one example you might look at leukocyte/granulocyte transfer therapies for cancer. These came to prominence on the basis of very promising results in animal studies, but have not seen significantly funding or much work on human studies precisely because researchers cannot yet present a full accounting of how these treatments work. Without that, you won't see much movement.

In this context we of course come to the Strategies for Engineered Negligible Senescence (SENS). This is not just a proposal for the shortest path to the best results when treating aging, a research plan to create rejuvenation in the old and prevent all age-related frailty and disease, it is also a critique of the scientific community and its way of doing business. The present system is broken by virtue of the fact that its members have gone too far in building defenses against failure modes in the scientific method. They now systematically marginalize useful endeavors aimed at the production of meaningful results in absence of complete knowledge of the biological systems involved. Application of partial knowledge can be good engineering, and is viable, necessary, and needed in medicine, where every delay costs lives. The past shows that the engineering approach can be perfectly workable, as many drugs in use today were brought into use through exactly this sort of methodology, and their full mechanisms are in fact still not understood.

Still, the mainstream of the aging research community will continue to spend billions on efforts that have no greater expectation of practical utility than the sirtuin research of the past decade. They are working towards a full understanding of the overlap of metabolism and aging as a primary objective. This in and of itself is a fine thing if knowledge is the desired end result, but I object to its presentation as a sensible path toward therapies to extend healthy life to any significant degree in the near future. This is just not plausible for the drug development approach to altering metabolism: the best that might be done here in the next couple of decades is to gently slow the progress of aging. Researchers involved tend to think that adding five years of healthy life by 2030 is an ambitious goal. If that five years is all that happens, and when it does it certainly won't be five years for those people already old when treatments arrive, then what a waste of opportunity that would be.

No, we want to see work on rejuvenation, on ways to reverse aging by repairing its causes - work after the SENS model that has a clear plan to produce results in absence of a full understanding of metabolism throughout aging. What is needed is a comprehensive list of damage that distinguishes old tissues from young tissues. This exists, and given this list there is no great need to fully understand how the damage interacts and progresses in intricate detail: researchers just need to periodically repair it. In this environment drawing more researchers to work on SENS repair biotechnologies is a bootstrapping process of attention and funding and results, just like the disruption of any industry by new technologies and new approaches. Things like clearance of senescent cells seem like one of the areas of research that will eventually get grudging attention by virtue of the fact that it will work far more effectively than anything the mainstream is producing with their drugs and their messing with the operation of metabolism in the late stages of disease. If you are trying to make a damaged engine work slightly better when damaged, rather than trying to address the damage itself, why would you expect good results?

The replacement of the present mainstream culture of aging research by SENS-like research focused on periodic repair of the causes of aging to achieve rejuvenation will proceed gradually and through the demonstration of effectiveness. There is a lot of of replacing to be done, however. It's a long road yet, and conservative institutions will continue to support work that does nothing but add knowledge of the fine details of metabolism long after rejuvenation research is much more of a going concern, I'd imagine. Groups like Google's Calico venture do not fund SENS because they are run by exemplars of the current institutions of medical science, who have worked their entire careers in the world of full knowledge as a requirement and where the primary strategy is a struggle to alter metabolism in the late stages of age-related disease, people who live and breath the drug pipeline and FDA dictates. Why should it be any surprise that what they are going to do is simply a continuation of existing programs of aging research? Calico will fund SENS at the same time that other institutions of the mainstream are doing so as a matter of course, which is to say when the disruption has come full circle and when people talk about aging research they usually mean the SENS approach of repair of primary causes.


The Methuselah Foundation and SENS Research Foundation are two of the more important organizations involved in changing the face of aging research from a field of investigation to a field of intervention, speeding progress towards the effective treatment of aging and production of actual, working rejuvenation therapies. Over the past year the staff at these two foundations have collaborated on a series of biotechnology-focused newsletters for supporters, each issue detailing recent research relevant to the goal of repairing and reversing the causes of degenerative aging. I tend to mention them when they turn up in my in-box for those not on the list, and here is the latest. This issue focuses on (a) heterochronic parabiosis, in which the circulatory systems of a young and old individual are linked in order to identify important changes in circulating signal proteins, and (b) indirect evidence for the benefits of targeted clearance of senescent cells from aging tissue, among other items:

Rejuvenation Biotechnology Update, January 2015

We have been following GDF-11 research and are pleased to bring you these two new reports. In the first study, researchers showed that exposing older mice to GDF-11 either through parabiosis, or by administering injections of recombinant GDF-11, was able to induce remodeling of the blood vessels in their brains, inciting the growth of new neurons. Most excitingly, this had a functional impact on older mice. With advanced age, the mice had lost much of their sense of smell, but parabiosis completely restored it to youthful function. In the second study, the research group showed that, again, exposing older mice to GDF-11 - either through parabiosis or injection of recombinant GDF-11 - was able to reverse age-related impairments in the function of their skeletal muscles. The genomes of the muscle cells in aged mice treated with GDF-11 showed greater integrity, their muscle structure and function improved, and they could perform better in tests of strength and endurance.

At this point, GDF-11 appears to be able to exert "rejuvenative" effects on the heart muscle, skeletal muscle, and brains of old mice who have suffered declines in those areas. It is possible that it may have effects on other body systems as well; further research will be needed to test this. It seems unlikely that parabiosis itself could be brought into the clinic for human use, given all the youthful blood (and related ethical concerns that raises). There may also be significant potential roadblocks for recombinant GDF-11 for human clinical use. For example administration of GDF-11 itself would require unmanageably large quantities of the protein. However, it could be used as the basis of a modified version or a drug that targets the same metabolic processes as GDF-11 itself.

On the other hand, there do exist examples of protein drugs in clinical use in large quantities, such as recombinant insulin for diabetics. To illustrate the order of magnitude of recombinant protein production currently in clinical use, researchers estimate that by 2025, there could be a need of approximately 16,000 kg/year of recombinant insulin for diabetics. So it also seems possible that recombinant GDF-11 could be used clinically, but it might be very challenging and expensive. Interestingly, GDF-11 has no effect on young mice at the doses tested. In the skeletal muscle study, the researchers treated both young and old mice with an identical regimen of GDF-11 injections, and it did not change young mouse muscle stem cell number, DNA integrity, or function. In the older mice, the dose of GDF-11 given was meant to recreate the physiological levels of GDF-11 in young mice (which decline with age). So, while restoring GDF-11 to "youthful" levels in older animals appears to rejuvenate several of their tissues - for example, restoring their muscle strength and endurance to "youthful" levels - it does not, for instance, make young mice abnormally strong for their age. Whether GDF-11 at higher doses would have greater effects is not yet known.

A major concern among rejuvenation biotechnology researchers is the accumulation of "senescent" cells in the body with age. Senescent cells are cells that have accumulated DNA damage, lost the ability to divide, and may create areas prone to the development of cancer within tissues where they reside. These "tissue microenvironments" (the biochemical environment in an extremely small area of tissue) near senescent cells may become more prone to the development of cancers because of secretion of molecules such as growth and inflammatory factors and enzymes that break down the supporting tissue around the senescent cells. Senescent cells accumulate in all tissues with age. A reason for attempting to eliminate senescent cells is the possibility that this hormonal and biochemical milieu in aged tissue microenvironments, in addition to the cells themselves, may contribute to some of the problems in aging, such as the development of cancer.

In this study, researchers exposed rats to chemical toxins that induce liver cancer. They next transplanted the rats with healthy liver cells from other, younger rats; the donor rats were genetically matched to the recipients to avoid problems with immune rejection of the transplanted cells. They performed the transplant by simply infusing the cells into the portal veins of the recipient rats. The transplanted cells then took up residence in the recipient rats' livers. One year later, 50% of the control rats that had not received transplanted liver cells had developed liver cancer. However, there was zero liver cancer observed in the group of rats that had received the liver cell transplant. The researchers also observed that after one year, the control group of rats had lots of senescent liver cells (induced by the cancer-causing protocol), but the transplant recipients had fewer senescent liver cells.

Although it was a small sample size (8 rats in the treatment group), it was remarkable that the researchers were able to change the incidence of development of liver cancer from 50% in the control group to 0% in the treatment group. We cannot help but wonder: if more time had passed, would liver cancer have developed in the treatment group? On the other hand, a 1-year follow-up is a relatively long time for rats. Although it is an impressive result, some things about this study are still unclear. The authors claimed that senescent cells in the livers of transplant recipient rats were removed, but it's not clear whether this truly happened. Senescent cell numbers may simply have been "diluted" by the influx of donor liver cells. There is no clear mechanism by which the senescent cells could have been removed, since the transplanted cells were liver cells, not the "natural killer cells" that carry out the body's own, limited ability to clear senescent cells from tissues.

Although the senescent cells may not have been cleared as the authors claimed, this study still provides evidence that via a relatively simple protocol (infusing healthy liver cells), the tissue microenvironment can be changed and malignancies can be kept at bay. We may eventually be able to apply this strategy to human tissues to create tissue microenvironments where cancers do not thrive.

To add to the caveats above, as I said at the time, I'd like to see this cell transplant study repeated in old rats with natural levels of cellular senescence before giving it too much more attention. Based on another study of liver cell senescence and cell transplantation it is vaguely possible that these cell populations can to some degree reverse their senescent status given the right environmental cues. It is perhaps worthy of note that liver tissue is naturally more regenerative than other tissues in mammals, capable of regrowing lost portions of the organ if necessary. But this is all quite speculative, and while there is a lot more that might be done here to iron out uncertainties and fill in the gaps, none of that is terribly relevant to the more direct path of building targeted cell clearance mechanisms and trying them out. The results of that experiment would be far more useful.


Mitochondria are the powerplants of the cell, more or less. There is a herd of mitochondria in every cell, dividing like bacteria as necessary to keep up their own numbers. Their most important - but by no means only - activity is the generation of adenosine triphosphate (ATP) molecules used as chemical energy stores to power cellular processes. Mitochondria have their own DNA separate from that in the cell nucleus, and it encodes a few vital pieces of protein machinery used in the process of generating ATP. Unfortunately this DNA often becomes damaged in ways that evade cellular quality control mechanisms and lead to a takeover of the cell by malfunctioning mitochondria. The details of this takeover are still under investigation: researchers never see it happening, only the before and after state, which suggests that it is fairly rapid at least. Cells in this dysfunctional state are thought to contribute to a range of age-related conditions by exporting a flood of reactive molecules and damaged proteins into surrounding tissues.

One of the challenges in studying the progression of mitochondrial damage is that mitochondrial dynamics are highly complex. Mitochondria are like bacteria in that they multiply by division, copying their DNA and assembling new ATP-creation machinery in the process. Equally they are also like other cell components in that various complicated processes monitor them and destroy them when they show signs of wear. Further, they can also fuse together, and any two individual mitochondria can contain more than one copy of the mitochondrial genome and differing amounts of molecular machinery. To make matters even more entertaining individual mitochondria promiscuously swap components of that molecular machinery between one another. So you can probably see that it is not exactly straightforward to track the process by which a few thousand of these entities in one cell move rapidly from a state in which one mitochondrion has damaged DNA to that same DNA damage being present in all of the mitochondria. There are dozens of distinct mechanisms at work, few of which are fully understood at this time, and all of which have their own particular constraints and reactions to circumstances.

As is the case for many areas in aging, however, researchers could skip over all of this complexity and bypass full understanding in order to sprint down a more direct path towards treatments. The SENS approach to work on rejuvenation treatments, for example, picks out provision of proteins encoded in mitochondrial DNA as the key point. Provided that those proteins are supplied, it doesn't matter what happens to the mitochondrial DNA, as the necessary machinery is still there. The mitochondria will continue to function correctly rather than malfunction. On that basis there are a number of ways to go: deliver replacement mitochondrial genomes while clearing out existing genomes, put copies of mitochondrial genes into the cell nucleus (plus solve the thorny problem of how to transport the proteins produced back into the mitochondria), deliver RNA that will manufacture proteins at the mitochondria, and so forth. None of these methods requires a full understanding of how mitochondrial damage progresses in order to be effective, but as is usually the case in these matters none of them are well funded in comparison to efforts to generate the full understanding of mitochondrial dynamics. Science as practiced is very much biased towards the generation of understanding first and foremost, which sometimes leaves practical paths towards treatments lost and languishing.

In any case, back to the complexity of mitochondrial dynamics: there is yet another level to all of this that has come under investigation in recent years, which is that cells can under some circumstances exchange components such as mitochondria. Stem cells have been shown to donate mitochondria to other cells in tissues where they are needed due to dysfunction, for example. Here researchers investigate another case in which this happens, making use of some of the more recent advances in the tools of biotechnology:

Wandering mitochondrial DNA hint at new ways to fight disease

Researchers discovered that when mitochondrial DNA was removed from mouse models of breast cancer and melanoma, after about a month or so, this DNA was naturally replaced by the surrounding healthy tissue. This allowed the cancer to form tumours and continue spreading around the body, because mitochondrial DNA is responsible for encoding key proteins that are used in the process of converting the energy from our food into the chemical energy that we use to fuel our brain and muscle function.

"Initially we thought the cells had learned to grow without needing mitochondrial DNA. But when we presented the research at a conference, a well-known scientist asked if we had tested the growing cells to see if they contained mitochondrial DNA. We hadn't. Our findings overturn the dogma that genes of higher organisms are usually constrained within cells except during reproduction. It may be that mitochondrial gene transfer between different cells is actually quite a common biological occurrence."

Defective mitochondrial DNA is known to cause around 200 diseases, characterised by the way they affect a person's hearing, eyesight, brain and muscle function, and is being investigated for a whole lot more. The researchers suggest that perhaps synthetic mitochondrial DNA could be custom-designed to replace the defective genes and stop tumours and other diseases from developing. "This appears to be a basic physiological mechanism in the body that no one has seen before because they lacked the exploratory tools. Whether this new phenomenon is important in tumour formation is still unclear, but we are interested in pursuing the research to see if the transfer occurs more widely in the body. Preliminary evidence indicates it may be a common occurrence in the brain."

Mitochondrial Genome Acquisition Restores Respiratory Function and Tumorigenic Potential of Cancer Cells without Mitochondrial DNA

We report that tumor cells without mitochondrial DNA (mtDNA) show delayed tumor growth, and that tumor formation is associated with acquisition of mtDNA from host cells. This leads to partial recovery of mitochondrial function in cells derived from primary tumors grown from cells without mtDNA and a shorter lag in tumor growth. Cell lines from circulating tumor cells showed further recovery of mitochondrial respiration and an intermediate lag to tumor growth, while cells from lung metastases exhibited full restoration of respiratory function and no lag in tumor growth. Stepwise assembly of mitochondrial respiratory (super)complexes was correlated with acquisition of respiratory function.

Our findings indicate horizontal transfer of mtDNA from host cells in the tumor microenvironment to tumor cells with compromised respiratory function to re-establish respiration and tumor-initiating efficacy. These results suggest pathophysiological processes for overcoming mtDNA damage and support the notion of high plasticity of malignant cells.


Monday, January 5, 2015

A combination of advances in medicine and a decline in smoking are reducing the mortality rates due to cancer. The effect of smoking is large because so many people do it and it is an effective road to the development of lung cancer. It is worth noting that the decrease in cancer mortality rates is in a time when the demographic profile of the population is shifting to include a larger number of older people with a greater risk of suffering cancer, as well as a concurrent rise in the number of overweight and obese individuals, a condition that is also associated with increased risk of suffering many cancers:

The American Cancer Society's annual cancer statistics report finds that a 22% drop in cancer mortality over two decades led to the avoidance of more than 1.5 million cancer deaths that would have occurred if peak rates had persisted. Largely driven by rapid increases in lung cancer deaths among men as a consequence of the tobacco epidemic, the overall cancer death rate rose during most of the 20th century, peaking in 1991. The subsequent, steady decline in the cancer death rate is the result of fewer Americans smoking, as well as advances in cancer prevention, early detection, and treatment.

During the most recent five years for which data are available (2007-2011), the average annual decline in cancer death rates was slightly larger among men (1.8%) than women (1.4%). These declines are driven by continued decreases in death rates for the four major cancer sites: lung, breast, prostate, and colon. Lung cancer death rates declined 36% between 1990 and 2011 among males and 11% between 2002 and 2011 among females due to reduced tobacco use. Death rates for breast cancer (among women) are down more than one-third (35%) from peak rates, while prostate and colorectal cancer death rates are each down by nearly half (47%).

The most common causes of cancer death are lung, prostate, and colorectal cancer in men and lung, breast, and colorectal cancer in women. These four cancers account for almost one-half of all cancer deaths, with more than one-quarter (27%) of all cancer deaths due to lung cancer.

Monday, January 5, 2015

A post on age-related loss of muscle mass and strength can be found at the Science of Aging blog of the Buck Institute for Research on Aging:

Sarcopenia comes from the Greek words sacra, "flesh", and penia, "poverty". More specifically, sarcopenia is the gradual loss of muscle mass and strength with age. It's not a disease, not a condition, and not a syndrome, but rather an unfortunate consequence of the natural aging process. Not to be confused with cachexia (accelerated muscle loss secondary to a disease such as cancer), sarcopenia is slow, progressive, and unnervingly unsuspecting. The 0.5-1% loss of muscle mass each year is deceptive, and unlike many of the consequences of aging, sarcopenia actually starts when we are quite young, generally around the age of 30. The loss of muscle mass and strength has profound consequences on day-to-day living.

Sarcopenia alters muscle structure and function in many different ways. First and foremost with sarcopenia comes muscle atrophy. Muscle atrophy is the shrinking of individual muscle cells, called muscle fibers. So while you do not lose a substantial number of muscle fibers, the smaller diameter muscle fibers result in reduced strength and mass. Interestingly, not all muscle undergoes atrophy equally. Muscle fibers can be separated based on size, contraction properties, and metabolic abilities, into different "fiber types". With sarcopenia, the larger more powerful muscle fibers preferentially undergo atrophy and contribute to the loss in overall strength. However, the loss of muscle size is not the only factor that contributes to a loss in muscle strength. A change in muscle quality also occurs with sarcopenia. Healthy muscle is just that, muscle. However, with sarcopenia, muscle becomes increasingly infiltrated with alternative cells types such as fibroblasts (cells that contribute to tissue structure) or adipocytes (fat cells).

How and whether these two physiological processes, loss in muscle size and loss in muscle quality, interact is not entirely known. One theory involves the muscle satellite cells or muscle stem cells. Normally, when muscle fibers are damaged muscle precursor cells that hang out next to the muscle fibers and wait to be called into action replace them. With aging however these muscle stem cells can become dysfunctional and instead of muscle replacing muscle, pesky fibroblast or adipocytes either show up or may be produced by the muscle stem cells (the jury is still out). A number of labs (Campisi Lab, Rando Lab, Blau lab, Conboy lab) in the Bay Area are studying how muscle stem cells function normally and in disease.

Tuesday, January 6, 2015

MicroRNA (miRNA) molecules play a complex and quite indirect role in the process of producing proteins from genetic blueprints, their activities adjusting the amount of protein produced for a range of genes. Since protein levels change in aging, we should expect to also see changes in miRNAs also. The system reacts to the cellular and molecular damage that causes aging, and this is another part of the reaction:

Human ageing is a complex and integrated gradual deterioration of cellular processes. There are nine major hallmarks of ageing, that include changes in DNA repair and DNA damage response, telomere shortening, changes in control over the expression and regulation of genes brought about by epigenetic and mRNA processing changes, loss of protein homeostasis, altered nutrient signaling, mitochondrial dysfunction, stem cell exhaustion, premature cellular senescence and altered intracellular communication.

MicroRNAs are estimated to regulate as many as 60% of all human mRNAs, which represent practically all cellular and molecular functions. MiRNAs are known to be key players in the regulation of transcripts involved in processes as diverse as embryonic development, differentiation, cellular proliferation, apoptosis, metabolism and adaptation to environmental stress. Given the involvement of miRNA regulation in multiple cellular processes, it is unsurprising that this process plays a part in complex, multifactorial and environmentally-influenced cellular processes such as human disease and cellular and organismal ageing.

In this review, I will outline each of the features of ageing, together with examples of specific miRNAs that have been demonstrated to be involved in each one. This will demonstrate the interconnected nature of the regulation of transcripts involved in human ageing, and the role of miRNAs in this process. Definition of the factors involved in degeneration of organismal, tissue and cellular homeostasis may provide biomarkers for healthy ageing and increase understanding of the processes that underpin the ageing process itself.

Tuesday, January 6, 2015

Lysosomes within cells recycle cellular waste and damaged cellular structures, ingesting them and then breaking them down with a range of enzymes. Over time, however, lysosomes in long-lived cells such as those of the central nervous system become bloated with a buildup of comparatively rare waste products that they cannot recycle and their functional activity declines. This certainly has a serious impact on the ability of an older cell to function, but is this only because of the growing level of unrecycled garbage in the cell? Researchers here uncover another way in which lysosomes are influencing longevity in a lower animal, and it will be interesting to see if comparable mechanisms also operate in mammals:

Lysosomes are crucial cellular organelles for human health that function in digestion and recycling of extracellular and intracellular macromolecules. We describe a signaling role for lysosomes that affects aging. In the worm Caenorhabditis elegans, the lysosomal acid lipase LIPL-4 triggered nuclear translocalization of a lysosomal lipid chaperone LBP-8, which promoted longevity by activating the nuclear hormone receptors NHR-49 and NHR-80.

We used high-throughput metabolomic analysis to identify several lipids in which abundance was increased in worms constitutively overexpressing LIPL-4. Among them, oleoylethanolamide directly bound to LBP-8 and NHR-80 proteins, activated transcription of target genes of NHR-49 and NHR-80, and promoted longevity in C. elegans. These findings reveal a lysosome-to-nucleus signaling pathway that promotes longevity and suggest a function of lysosomes as signaling organelles in metazoans.

Wednesday, January 7, 2015

It has been suggested that greater levels of solar radiation may reduce life expectancy by raising the likelihood of damage during embryonic and later development, and researchers have in the past mined historical data in search of correlations. At this point discussion of possible mechanisms is still quite speculative, however. Here is another example of this line of research:

Ultraviolet radiation (UVR) can suppress essential molecular and cellular mechanisms during early development in living organisms and variations in solar activity during early development may thus influence their health and reproduction. Although the ultimate consequences of UVR on aquatic organisms in early life are well known, similar studies on terrestrial vertebrates, including humans, have remained limited.

Using data on temporal variation in sunspot numbers and individual-based demographic data (N = 8662 births) from Norway between 1676 and 1878, while controlling for maternal effects, socioeconomic status, cohort and ecology, we show that solar activity (total solar irradiance) at birth decreased the probability of survival to adulthood for both men and women. On average, the lifespans of individuals born in a solar maximum period were 5.2 years shorter than those born in a solar minimum period. In addition, fertility and lifetime reproductive success (LRS) were reduced among low-status women born in years with high solar activity. The proximate explanation for the relationship between solar activity and infant mortality may be an effect of folate degradation during pregnancy caused by UVR. Our results suggest that solar activity at birth may have consequences for human lifetime performance both within and between generations.

Wednesday, January 7, 2015

Researchers aiming to produce a mouse model of accelerated sarcopenia, the characteristic loss of muscle mass and strength that occurs with aging, instead found that depleting muscle stem cell populations had no effect on this condition. This implies that the loss of stem cell activity in muscle tissue associated with aging may not be all that important in the development of sarcopenia after all:

Sarcopenia affects millions of aging adults. Age-related loss of muscle mass and strength not only robs elderly people of the ability to perform even the most basic tasks of daily living, but also significantly increases their risk of suffering devastating injuries and even death from sudden falls and other accidents. The literature on aging research, particularly muscle aging, postulates a strong correlation between the loss and/or dysfunction of muscle stem cells and sarcopenia, the scientific term for the age-related loss of skeletal muscle mass and strength. Currently entire research programs are focused on developing muscle stem cell therapy to delay, prevent or even reverse sarcopenia.

[Researchers] developed an animal model that allowed them to deplete young adult muscle of stem cells to a level sufficient to impair muscle regeneration throughout the life of a mouse. They expected the mouse to be a model of premature muscle aging. "To our surprise, the mice aged normally; life-long depletion of skeletal muscle stem cells did not accelerate nor exacerbate sarcopenia. Our negative results show a clear distinction between therapeutic strategies that may effectively treat degenerative myopathies, such as dystrophies and cachexia, versus sarcopenia. While degenerative conditions are expected to benefit from a stem cell-based therapy, this does not appear to be a viable approach for treating age-associated muscle wasting. Hopefully, our work will help to refocus aging muscle research on new therapeutic targets to effectively maintain muscle function and prevent frailty in the elderly."

Thursday, January 8, 2015

Here is a study that gives some idea of the degree to which the majority of people who do not maintain a good level of fitness are harming themselves over the years:

The study of amateur older cyclists found that many had levels of physiological function that would place them at a much younger age compared to the general population. The study recruited 84 male and 41 female cycling enthusiasts aged 55 to 79 to explore how the ageing process affects the human body, and whether specific physiological markers can be used to determine your age. Men and women had to be able to cycle 100 km in under 6.5 hours and 60 km in 5.5 hours, respectively, to be included in the study. Smokers, heavy drinkers and those with high blood pressure or other health conditions were excluded from the study.

The results of the study showed that in these individuals, the effects of ageing were far from obvious. Indeed, people of different ages could have similar levels of function such as muscle strength, lung power and exercise capacity. The maximum rate of oxygen consumption showed the closest association with age, but even this marker could not identify with any degree of accuracy the age of any given individual, which would be the requirement for any useful biomarker of ageing.

"An essential part of our study was deciding which volunteers should be selected to explore the effects of ageing. The main problem facing health research is that in modern societies the majority of the population is inactive. A sedentary lifestyle causes physiological problems at any age. Hence the confusion as to how much the decline in bodily functions is due to the natural ageing process and how much is due to the combined effects of ageing and inactivity. In many models of ageing lifespan is the primary measure, but in human beings this is arguably less important than the consequences of deterioration in health."

Thursday, January 8, 2015

The adaptive immune system declines with age for reasons that are partially structural. The slow rate of production of new immune cells in adults and the pace of turnover results in an effective cap on the number of these cells present at any one time. Immune cells are devoted to remembering threats as they occur, but some otherwise largely innocuous and widespread pathogens like cytomegalovirus cannot be effectively cleared from the body. Ever more memory T cells are devoted to that particular topic over the years, and this leaves ever less space for naive T cells capable of destroying invading pathogens. So to a first approximation the more memory cells you have in old age the worse off you are.

Here is a correlation between that measure of immune system dysregulation and age-related declines in cognitive function. We can speculate that linking mechanisms might include the chronic inflammation that accompanies age-related immune system dsyfunction or a decline in aspects of the supporting role played by portions of the immune system that are specific to brain tissue:

Immunosenescence and cognitive decline are common markers of the aging process. The current view is that the immune system plays a modulatory role in brain function, including in cognitive abilities and neurogenesis, which supports the notion that throughout life the brain is not "immune privileged" but rather "enjoys the privilege" of immune-dependent maintenance. Taking into consideration the heterogeneity observed in aging processes and the recently described link between lymphocytes and cognition, we herein explored the possibility of an association between alterations in lymphocytic populations and cognitive performance. In a cohort of cognitively healthy adults (n = 114), previously characterized by diverse neurocognitive/psychological performance patterns, detailed peripheral blood immunophenotyping of both the innate and adaptive immune systems was performed by flow cytometry.

Better cognitive performance was associated with lower numbers of effector memory CD4+ T cells and higher numbers of naive CD8+ T cells and B cells. Furthermore, effector memory CD4+ T cells were found to be predictors of general and executive function and memory, even when factors known to influence cognitive performance in older individuals (e.g., age, sex, education, and mood) were taken into account. This is the first study in humans associating specific phenotypes of the immune system with distinct cognitive performance in healthy aging.

Friday, January 9, 2015

A number of research groups are working towards growing intestinal tissue, but this area of the field of tissue engineering is still at the exploratory stage, with no-one much past the level of creating small sections of usefully structured tissue. Getting the structure right is one of the challenging parts of tissue engineering; every organ is different and requires the development of its own particular recipe and methodology.

Tissue-engineered small intestine (TESI) grows from stem cells contained in the intestine and offers a promising treatment for short bowel syndrome (SBS), a major cause of intestinal failure. TESI may one day offer a therapeutic alternative to the current standard treatment, which is intestinal transplantation, and could potentially solve its largest challenges - donor shortage and the need for lifelong immunosuppression. Scientists had previously shown that TESI could be generated from human small intestine donor tissue implanted into immunocompromised mice. However, in those initial studies - published in 2011 - only basic components of the intestine were identified. For clinical relevance, it remained necessary to more fully investigate intact components of function such as the ability to form a healthy barrier while still absorbing nutrition or specific mechanisms of electrolyte exchange.

The new study determined that mouse TESI is highly similar to the TESI derived from human cells, and that both contain important building blocks such as the stem and progenitor cells that will continue to regenerate the intestine as a living tissue replacement. And these cells are found within the engineered tissue in specific locations and in close proximity to other specialized cells that are known to be necessary in healthy human intestine for a fully functioning organ. "We have shown that we can grow tissue-engineered small intestine that is more complex than other stem cell or progenitor cell models that are currently used to study intestinal regeneration and disease, and proven it to be fully functional as it develops from human cells. Demonstrating the functional capacity of this tissue-engineered intestine is a necessary milestone on our path toward one day helping patients with intestinal failure."

Friday, January 9, 2015

Senescent cells accumulate with age. Transition into a senescent state is, at least initially, a defense against cancer in which cells that are damaged or likely to become damaged due to a dysregulated tissue environment permanently suppress their ability to divide. Many destroy themselves or are destroyed by the immune system, but all too many of them linger on intact. In old skin a large portion of tissue is made up of senescent cells, for example. Cellular senescence as a cancer defense is likely an adaptation of a tool used to shape tissue growth during embryonic development, which might explain why senescent cells secrete a range of molecules that cause harm to surrounding extracellular matrix structures and negatively impact the behavior of nearby cells.

The more senescent cells you have the more their presence degrades the function of tissues and organs. Eventually a large enough number of senescent cells and their secreted signals tip over from being protective against cancer due to removing the ability for damaged cells to replicate to a state of promoting cancer by creating inflammation and other harms in tissue. The best solution to all of this is periodic clearance of senescent cells via some form of targeted cell killing technology, such as those under development in the cancer research community. That approach, like most related to repairing the causes of aging, receives comparatively little attention and funding, however. Here is another of the many examples of the damage done to a particular organ by growing numbers of senescent cells:

Age-associated decline in organ function governs life span. We determined the effect of aging on lung function and cellular/molecular changes of 8- to 32-month old mice. Proteomic analysis of lung matrix indicated significant compositional changes with advanced age consistent with a profibrotic environment that leads to a significant increase in dynamic compliance and airway resistance. The excess of matrix proteins deposition was associated modestly with the activation of myofibroblasts and transforming growth factor-beta signaling pathway. More importantly, detection of senescent cells in the lungs increased with age and these cells contributed toward the excess extracellular matrix deposition observed in our aged mouse model and in elderly human samples.

Mechanistic target of rapamycin (mTOR)/AKT activity was enhanced in aged mouse lungs compared with those from younger mice associated with the increased expression of the histone variant protein, MH2A, a marker for aging and potentially for senescence. Introduction in the mouse diet of rapamycin, significantly blocked the mTOR activity and limited the activation of myofibroblasts but did not result in a reduction in lung collagen deposition unless it was associated with prevention of cellular senescence. Together these data indicate that cellular senescence significantly contributes to the extracellular matrix changes associated with aging in a mTOR 1-dependent mechanism.


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