Fight Aging! Newsletter, May 27th 2013

May 27th 2013

The Fight Aging! Newsletter is a weekly email containing news, opinions, and happenings for people interested in aging science and engineered longevity: making use of diet, lifestyle choices, technology, and proven medical advances to live healthy, longer lives. This newsletter is published under the Creative Commons Attribution 3.0 license. In short, this means that you are encouraged to republish and rewrite it in any way you see fit, the only requirements being that you provide attribution and a link to Fight Aging!

To subscribe or unsubscribe to the Fight Aging! Newsletter, please visit the newsletter site:


  • Mitochondrially Targeted Antioxidant SS-31 Reverses Some Measures of Aging in Muscle
  • Costly Publicity Makes Little Sense When Research is Cheap
  • Radioactivity as a Viable Kill Mechanism in Targeted Therapies
  • Reactive Oxygen Species are a Complex Topic
  • Discussion
  • Latest Headlines from Fight Aging!
    • Early Mortality Rates Predict Late Mortality Rates
    • Decellularization May Enable Use of More Donor Organs
    • Arguing for the Role of Nuclear DNA Damage in Aging
    • The Unfolded Protein Response in Mitochondria
    • How Senescent Cells Can Promote Cancer Formation
    • A Better Understanding of Oligomers in Alzheimer's Disease
    • Macrophages Essential to Salamander Regeneration
    • A Look at First Generation Targeted Cancer Therapies
    • A Review of Research Suggesting Retirement is Bad For Health
    • Halting the Progression of Osteoarthritis in Mice


Antioxidants of the sort you can buy at the store and consume are pretty much useless: the evidence shows us that they do nothing for health, and may even work to block some beneficial mechanisms. Targeting antioxidant compounds to the mitochondria in our cells is a whole different story, however. Mitochondria are swarming bacteria-like entities that produce the chemical energy stores used to power cellular processes. This involves chemical reactions that necessarily generate reactive oxygen species (ROS) as a byproduct, and these tend to react with and damage protein machinery in the cell. The machinery that gets damaged the most is that inside the mitochondria, of course, right at ground zero for ROS production. There are some natural antioxidants present in mitochondria, but adding more appears to make a substantial difference to the proportion of ROS that are soaked up versus let loose to cause harm.

If mitochondria were only trivially relevant to health and longevity, this wouldn't be a terribly interesting topic, and I wouldn't be talking about it. The evidence strongly favors mitochondrial damage as an important contribution to degenerative aging, however. Most damage in cells is repaired pretty quickly, and mitochondria are regularly destroyed and replaced by a process of division - again, like bacteria. Some rare forms of mitochondrial damage persist, however, eluding quality control mechanisms and spreading through the mitochondrial population in a cell. This causes cells to fall into a malfunctioning state in which they export massive quantities of ROS out into surrounding tissue and the body at large. As you age ever more of your cells suffer this fate.

In recent years a number of research groups have been working on ways to deliver antioxidants to the mitochondria, some of which are more relevant to future therapies than others. For example gene therapy to boost levels of natural mitochondrial antioxidants like catalase are unlikely to arrive in the clinic any time soon, but they serve to demonstrate significance by extending healthy life in mice. A Russian research group has been working with plastinquinone compounds that can be ingested and then localize to the mitochondria, and have shown numerous benefits to result in animal studies of theSkQ series of drug candidates.

US-based researchers have been working on a different set of mitochondrially targeted antioxidant compounds, with a focus on burn treatment. However, they recently published a paper claiming reversal of some age-related changes in muscle tissue in mice using their drug candidate SS-31. Note that this is injected, unlike SkQ compounds:

Mitochondrial targeted peptide rapidly improves mitochondrial energetics and skeletal muscle performance in aged mice

Mitochondrial dysfunction plays a key pathogenic role in aging skeletal muscle resulting in significant healthcare costs in the developed world. However, there is no pharmacologic treatment to rapidly reverse mitochondrial deficits in the elderly. Here we demonstrate that a single treatment with the mitochondrial targeted peptide SS-31 restores in vivo mitochondrial energetics to young levels in aged mice after only one hour.

Young (5 month old) and old (27 month old) mice were injected intraperitoneally with either saline or 3 mg/kg of SS-31. Skeletal muscle mitochondrial energetics were measured in vivo one hour after injection using a unique combination of optical and 31 P magnetic resonance spectroscopy. Age related declines in resting and maximal mitochondrial ATP production, coupling of oxidative phosphorylation (P/O), and cell energy state (PCr/ATP) were rapidly reversed after SS-31 treatment, while SS-31 had no observable effect on young muscle.

These effects of SS-31 on mitochondrial energetics in aged muscle were also associated with a more reduced glutathione redox status and lower mitochondrial [ROS] emission. Skeletal muscle of aged mice was more fatigue resistant in situ one hour after SS-31 treatment and eight days of SS-31 treatment led to increased whole animal endurance capacity. These data demonstrate that SS-31 represents a new strategy for reversing age-related deficits in skeletal muscle with potential for translation into human use.

So what is SS-31? If look at the publication history for these authors you'll find a burn-treatment focused open access paper that goes into a little more detail and a 2008 review paper that covers the pharmacology of the SS compounds:

The SS peptides, so called because they were designed by Hazel H. Sezto and Peter W. Schiler, are small cell-permeable peptides of less than ten amino acid residues that specifically target to inner mitochondrial membrane and possess mitoprotective properties. There have been a series of SS peptides synthesized and characterized, but for our study, we decided to use SS-31 peptide (H-D-Arg-Dimethyl Tyr-Lys-Phe-NH2) for its well-documented efficacy.

Studies with isolated mitochondrial preparations and cell cultures show that these SS peptides can scavenge ROS, reduce mitochondrial ROS production, and inhibit mitochondrial permeability transition. They are very potent in preventing apoptosis and necrosis induced by oxidative stress or inhibition of the mitochondrial electron transport chain. These peptides have demonstrated excellent efficacy in animal models of ischemia-reperfusion, neurodegeneration, and renal fibrosis, and they are remarkably free of toxicity.

Given the existence of a range of different types of mitochondrial antioxidant and research groups working on them, it seems that we should expect to see therapies emerge into the clinic over the next decade. As ever the regulatory regime will ensure that they are only approved for use in treatment of specific named diseases and injuries such as burns, however. It's still impossible to obtain approval for a therapy to treat aging in otherwise healthy individuals in the US, as the FDA doesn't recognize degenerative aging as a disease. The greatest use of these compounds will therefore occur via medical tourism and in a growing black market for easily synthesized compounds of this sort.

In fact, any dedicated and sufficiently knowledgeable individual could already set up a home chemistry lab, download the relevant papers and synthesize SkQ or SS compounds. That we don't see this happening is, I think, more of a measure of the present immaturity of the global medical tourism market than anything else. It lacks an ecosystem of marketplaces and review organizations that would allow chemists to safely participate in and profit from regulatory arbitrage of the sort that is ubiquitous in recreational chemistry.


Broad public understanding and support is a necessary part of scaling rejuvenation research programs like SENS into a scientific community the size of the cancer or Alzheimer's establishments. At a small scale, even up to millions of dollars, research funds can be obtained whether or not the man in the street knows or cares about what is happening in the laboratory. Philanthropists can be convinced, foundations approached, and so forth: all that is needed there are scientific credentials and a talent for opening doors and making connections.

Once you start talking about sourcing hundreds of millions of dollars, however, the goal must be something that most people know of and approve. That level of resources requires scores of funding organizations and laboratories, an ecosystem of hundreds of researchers willing to join in, an eager next generation being taught in graduate programs, and the persuasion of thousands of people who make funding and research allocation decisions. None of that can credibly happen for a research program that lacks support in the public eye. Unpopular or unknown research takes place, certainly, but awareness must accompany growth.

Numerous different approaches can be taken in raising awareness for a particular branch of scientific research. One method of bootstrapping focuses first on raising research funds from philanthropists in the absence of public support - which is challenging, but you have to start somewhere - and then publicizing ongoing research programs through the normal channels. A subset of the overlapping journal and media industries deals with research publicity, for example, and that is one way to talk to the public. Another approach is the years-long drudgery of advocacy: knocking on doors, giving talks, going to conferences, making connections, and writing on the topic. These two are largely the approach taken by the SENS Research Foundation and Methuselah Foundation, and are effectively a trade of time for money.

There are more expensive methods of publicity, such as making infomercial-length programs and putting them in front of television audiences, for example. Production costs will set you back $50,000 for a few-minute piece and $250,000 for a 30 minute slot, if done by professionals who know the business. Per-showing cost for a single channel can be thousands of dollars. If someone gives you this sort of coverage for free - such as by deciding to make a film about your efforts - then obviously you don't look the gift horse in the mouth, but for most initiatives the filmmakers don't come knocking until there is already so much attention that their efforts are largely moot.

There is a good reason as to why research charities don't tend to go in for this sort of thing, even aside from considering whether or not a cost-benefit argument could be made for creating video publicity materials - something that is hard to do for intangibles like public attention. The good reason is that most research is cheap. Consider that Jason Hope's $500,000 donation to the SENS Research Foundation made back at the end of 2010 continues to keep two labs working on the foundation of AGE-breaker therapies. For the $250,000 cost of a profession publicity video for public consumption you could set up a modest lab and hire two smart industry biotechnologists for a year - or get twice those resources working in an established academic lab, where remuneration is nowhere near as grand and economies of scale are somewhat better.

Thus it isn't hard to make the choice between expensive publicity and getting research done, given that progress in research is (a) the point of the exercise, and (b) generates its own opportunities for low-cost publicity as results roll in. If we were still in a 1970s-like situation regarding the cost of biotechnology then perhaps one could field an argument for greater expenditures on publicity, because without large-scale funding there would be no meaningful progress, and public support is necessary for that end goal. Things are different today, however - and just as well. Capable, low cost biotechnology makes meaningful progress in medicine much more likely to occur, as it enables smaller, less wealthy, and more numerous groups to contribute to advancing the state of the art.


A range of methods to target specific types of cell in the body are presently under development: immune cells, nanoparticles, viruses, and bacteria can all be used to deliver payloads to specific cells, provided that a suitable sensor mechanism can be established for the target in question. One of the benefits of this approach is that almost all existing methods used to destroy cells can be adapted for this new world of precision therapies. Tiny amounts of proven chemotherapy compounds can be loaded into nanoparticles and remain effective in destroying the cancer cells they are delivered to, but the severe side effects of standard chemotherapy are almost entirely eliminated. Chemotherapy in its present incarnation is a very unpleasant exercise, and targeting is a great leap forward in the application of chemical attacks on cancer.

Radiation is also used as a cancer treatment. As for chemotherapy, the present state of the art in available treatments involves a range of techniques that aim to to hurt the cancer more than the rest of the patient. It's still a pretty unpleasant exercise - not something that anyone would choose to undergo unless it were the least worst available option. Like chemotherapy compounds, radioactive compounds can also be cut down to amounts as small as individual atoms and loaded up onto nanoparticles or other delivery systems. For example, last month researchers reported on the use of a type of bacteria that only infects cancer cells as a carrier for radioactive materials that destroy those infected cells.

Tiny amounts of highly radioactive compounds are like tiny amounts of poison - they don't cause much harm at all outside the target cells, and this is the key to building therapies that have minimal side-effects. Here is another recent example of targeted therapy development using radioactive materials, but with nanoparticles as the delivery agent this time:

Researchers Develop Radioactive Nanoparticles that Target Cancer Cells

Cancers of all types become most deadly when they metastasize and spread tumors throughout the body. Once cancer has reached this stage, it becomes very difficult for doctors to locate and treat the numerous tumors that can develop. Now, researchers at the University of Missouri have found a way to create radioactive nanoparticles that target lymphoma tumor cells wherever they may be in the body.

In an effort to find a way to locate and kill secondary tumors [researchers] have successfully created nanoparticles made of a radioactive form of the element lutetium. The MU scientists then covered the lutetium nanoparticles with gold shells and attached targeting agents. [Previous research] has already proven the effectiveness of similar targeting agents in mice and dogs suffering from tumors. In that research, the targeting agents were attached to single radioactive atoms that were introduced into the bodies of animals with cancer. The targeting agents were able to seek out the tumors existing within the animals, which were then revealed through radio-imaging of those animals.

In their current research, the MU scientists have shown the targeting agents can deliver the new radioactive lutetium nanoparticles to lymphoma tumor cells without attaching to and damaging healthy cells in the process. "This is an important step toward developing therapies for lymphoma and other advanced-stage cancers. The ability to deliver multiple radioactive atoms to individual cancer cells should greatly increase our ability to selectively kill these cells."

Twenty years from now cancer will be comparatively well controlled: the trend is towards highly effective therapies, thousands of researchers are involved in building them, and a lot of money is flowing into this work. Cancer doesn't worry me anywhere near as much as common causes of sudden death in the elderly such as heart failure and stroke. If, against the odds, you find yourself nailed by cancer in the 2030s - and I think that this is an unlikely outcome for anyone in a wealthier region of the world - then even the worst case scenarios still allow you plenty of time to wrap up matters and arrange your own cryopreservation. Heart failure and stroke arrive with no such warning, and the only way to reliably deal with all of the causes of functional degeneration in the heart and brain is to implement SENS rejuvenation biotechnologies. Despite tremendous progress in recent years the SENS program remains in a comparatively early stage of funding and support within the research community - it is tiny in comparison to the cancer research community, and funding is the greatest obstacle to faster progress.


It wouldn't be too far wrong to regard ourselves as ambulatory chemical processing plants: biology is very complicated and highly organized chemistry, a collection of reactions and products. The operation of our metabolism is as much based on processing oxygen as it is on processing food. Thus you don't don't have to wander all that far into the scientific literature on the biology of aging to find mention of reactive oxygen species (ROS), the mechanisms of oxidative stress, and the various oxidative theories of aging, such as the mitochondrial free radical theory of aging. All sorts of reactive molecules containing oxygen can be found in our biology at any given time, an inevitable byproduct of being an oxygen-processing species.

Cells and their components are intricate assemblies of protein machinery, but all it takes to disrupt a component is for it to react with a passing ROS molecule. It'll quickly be replaced by a cell's repair mechanisms, but in the meanwhile it is broken. Oxidative stress refers to the level of ongoing damage caused by ROS; ambient levels of ROS can rise due to environmental circumstances such as heat or radiation exposure, but we're more interested in what happens during aging. Older theories of aging based on oxidative damage suggest that aging is caused by an accumulation of this damage, and indeed levels of oxidative stress rise with aging, but the relationship isn't that simple.

Evolutionary selection is very ready to use any tool to hand. An individual's biology is a set of interconnected systems that share component molecules, and which are tied together into feedback loops and signal exchanges. Just like every other molecule in our biology reactive oxygen species were long ago co-opted into all sorts of vital mechanisms. This means that it is far from straightforward to talk about ROS and aging, as there are many different roles in metabolism for what at first sight seems to be nothing but a damaging, toxic class of molecule, and these roles are affected by rising levels of ROS in different ways. The specific location in cells and the body and the present circumstances all matter when it comes to what happens when ROS levels increase.

For example, it has been shown that some of the benefits of exercise are based on slightly increased levels of ROS as a signal. Increased use of muscle results in a higher output of ROS from the mitochondrial power plants working away in muscle cells, and cells react to this change with greater housekeeping efforts - an outcome known as hormesis. If tissues and bloodstream are bathed in antioxidants that soak up those ROS, then these benefits of exercise can be blocked. Thus general use of antioxidants in a normal metabolism may potentially do more harm than good.

Similarly, it seems fairly clear at this point, based on work in mice, that targeting antioxidants specifically to mitochondria is a beneficial strategy, and this presumably works by soaking up ROS at source before they can cause harm. How does this impact exercise and its effects on health? As yet unknown. Further, a range of life-extending genetic alterations in nematode worms work by globally increasing or globally reducing ROS output from mitochondria, with either outcome resulting in longer-lived worms. Increased ROS works through hormesis, by increasing repair activities, while reduced ROS output directly reduces damage, or at least that is the present consensus.

Mitochondria are important in aging - that much is worth taking away as a lesson here. I view much of the research into ROS and mitochondria as little more than a confirmation that it is vital to develop the range of envisaged biotechnologies that enable mitochondrial repair and replacement. The mitochondrial free radical theory of aging suggests that aging is in large part caused by the way in which mitochondria damage themselves with their own ROS output. It is that damage that is the important thing, not the ROS, but mitochondrial damage has such a great impact on aging and longevity that even modest changes in either (a) the pace at which they damage themselves or (b) the likelihood of damaged mitochondria being replaced by cellular maintenance mechanisms, both of which are influenced by rates of ROS production, have a measurable effect on longevity in shorter-lived species.

But back to complexity resulting from the uses that ROS are put to in our biology. Here are a couple of papers that illustrate a few more of the ways in which nothing is simple:

Rejuvenation of Adult Stem Cells: Is Age-Associated Dysfunction Epigenetic?

The dysfunctional changes of aging are generally believed to be irreversible due to the accumulation of molecular and cellular damage within an organism's somatic cells and tissues. However, the importance of potentially reversible cell signaling and epigenetic changes in causing dysfunction has not been thoroughly investigated. Striking evidence that increased oxidative stress associated with hematopoietic stem cells (HSCs) from aging mice causes dysfunction has been reported. Forced expression of SIRT3, which activates the reactive oxygen species (ROS) scavenger superoxide dismutase 2 (SOD2) [to] reduce oxidative stress, functionally rejuvenates mouse HSCs.

These data, combined with numerous other reports, suggest that ROS act as a signal transducer to play a critical regulatory role in HSCs and at least in some other stem cells. It is likely that ectopic expression of SIRT3 restores homeostasis in gene expression networks sensitive to oxidative stress. This result was surprising because age-associated damage from impaired DNA repair had been thought to be irreversible in old HSCs. These data are consistent with a hypothesis that potentially reversible processes, such as aberrant signaling and epigenetic drift, are relevant to cellular aging. If true, rejuvenation of at least some aged cells may be simpler than generally appreciated.

Endothelium, heal thyself

[The endothelium] cooperates with leukocytes to create openings to provide the infection-fighting cells ready access to their targets. By and large, these ensuing "micro-wounds" are short-lived; as soon as the cells have crossed the endothelium, these pores and gaps quickly heal, restoring the system's efficient barrier function. In cases when these gaps fail to close - and leakage occurs - the results can be devastating, leading to dramatic pathologies including sepsis and acute lung injury.

[Researchers] set up experimental models that mimicked acute, intense inflammation. Using dynamic time-lapse and high-resolution confocal microscopy, the investigators could see the process by which leukocytes were breaching the endothelial cell. In the course of a 10-minute span, they observed that a single endothelial cell tolerated the passage of at least seven leukocytes directly through its body, and that within this brief period, the gaps closed, leaving no sign of the pores.

This response [is] fundamentally dependent on proteins (i.e. NADPH oxidases) that can generate reactive oxygen species (ROS), specifically hydrogen peroxide. ROS are widely implicated in causing cellular, tissue and organ damage when present at excessive levels in the body. But, these findings show that low levels of these molecules - when produced in discrete locations within the cell - are highly protective. "It's tempting to speculate that excess ROS causes vascular breakdown by short-circuiting the recuperative response process and creating 'white noise' that dis-coordinates and disrupts micro-wound healing. It appears that we've got an essential homeostatic self-repair mechanism that is completely dependent on the generation of intracellular ROS, which is opposite to our typical thinking about ROS in cardiovascular health and disease."


The highlights and headlines from the past week follow below. Remember - if you like this newsletter, the chances are that your friends will find it useful too. Forward it on, or post a copy to your favorite online communities. Encourage the people you know to pitch in and make a difference to the future of health and longevity!


Friday, May 24, 2013

In past centuries exposure to infectious disease and malnutrition caused high mortality rates in children. Those who survived did so with a greater burden of various forms of low-level biological damage. Degenerative aging is caused by an accumulation of damage and thus remaining life expectancy is reduced. Researchers here dig up historical demographic data that supports this view, showing that people who survived high childhood mortality went on to live shorter lives on average:

Early environmental influences on later life health and mortality are well recognized in the doubling of life expectancy since 1800. To further define these relationships, we analyzed the associations between early life mortality with both the estimated mortality level at age 40 and the exponential acceleration in mortality rates with age characterized by the Gompertz model.

Using mortality data from 630 cohorts born throughout the 19th and early 20th century in nine European countries, we developed a multilevel model that accounts for cohort and period effects in later life mortality. We show that early life mortality, which is linked to exposure to infection and poor nutrition, predicts both the estimated cohort mortality level at age 40 and the subsequent Gompertz rate of mortality acceleration during aging.

After controlling for effects of country and period, the model accounts for the majority of variance in the Gompertz parameters (about 90% of variation in estimated level of mortality at age 40 and about 78% of variation in Gompertz slope). The gains in cohort survival to older ages are entirely due to large declines in adult mortality level, because the rates of mortality acceleration at older ages became faster.

Friday, May 24, 2013

Decellularization is the process of taking an existing organ and stripping its cells, leaving the intricate skeleton of the extracellular matrix intact. That can then be repopulated by a patient's own cells to recreate a donor organ for transplant, though only a few organs have been successfully rebuilt in this way so far. As a technique this has many advantages over simple transplants: it removes the possibility of immune rejection, makes the use of animal organs practical, and rehabilitates donor organs that would otherwise be unsuitable:

[Perhaps a fifth of the] kidneys from deceased donors are thrown away each year due to damage. A paper [published] earlier this month suggests that they could be put to use as raw material for engineering new kidneys. The study's authors treated discarded human kidneys with a detergent, which cleared the organ of cells and left only the cells' extracellular matrices. The eventual plan is to grow the patients' own cells on the scaffold, producing a kidney that the patients would be less likely to reject than an ordinary transplant. "These kidneys maintain their innate three-dimensional architecture, their basic biochemistry, as well as their vessel network system."

The scientists tested the scaffold for antigens that might cause a patient to reject the organ and found that they had been eliminated along with the cells. When the researchers transplanted the modified kidneys into pigs and connected their vasculature to the pigs' circulatory systems, blood pumped through the kidneys at normal pressure. "With about 100,000 people in the U.S. awaiting kidney transplants, it is devastating when an organ is donated but cannot be used. These discarded organs may represent an ideal platform for investigations aimed at manufacturing kidneys for transplant."

Thursday, May 23, 2013

There is some debate over whether the accumulation of damage to nuclear DNA contributes meaningfully to degenerative aging. It certainly raises the odds of cancer, but are its effects beyond that significant? Here is an open access paper in search of evidence, in which the authors suggest that epigenetic changes in individual cells result from repair of significant forms of damage such double strand breaks. The theory is that a growing disarray in cellular behavior is caused by scattered mutations and epigenetic changes, and this disarray contributes to aging, for example via degrading the ability of stem cells to maintain tissues - but again there are the questions of degree, and whether this sort of thing is significant in comparison to the other causes of aging:

The DNA damage theory of aging postulates that the main cause of the functional decline associated with aging is the accumulation of DNA damage, ensuing cellular alterations and disruption of tissue homeostasis. Stem cells are at high risk of accumulating deleterious DNA lesions because they are so long-lived. Such damage may limit the survival or functionality of the stem cell population and may even initiate or promote carcinogenesis.

The ultra-high resolution of transmission electron microscopy (TEM) offers the intriguing possibility of detecting core components of the DNA repair machinery at the single-molecule level and visualizing their molecular interactions with specific histone modifications. We showed that damage-response proteins [such as] 53BP1 can be found exclusively at heterochromatin-associated DNA double-strand breaks (DSBs).

Using 53BP1-foci as a marker for DSBs, hair follicle stem cells (HFSCs) in mouse epidermis were analyzed for age-related DNA damage response (DDR). We observed increasing amounts of 53BP1-foci during the natural aging process independent of telomere shortening [suggesting] substantial accumulation of DSBs in HFSCs. Electron microscopy [showed] multiple small 53BP1 clusters diffusely distributed throughout the highly compacted heterochromatin of aged HFSCs.

Based on these results we hypothesize that these lesions were not persistently unrepaired DSBs, but may reflect chromatin rearrangements caused by the repair or misrepair of DSBs. Collectively, our findings support the hypothesis that aging might be largely the remit of structural changes to chromatin potentially leading to epigenetically induced transcriptional deregulation.

Thursday, May 23, 2013

The unfolded protein response is a housekeeping mechanism that repairs disarrayed protein machinery in cells or guides those cells to self-destruction if there is too much damage. Like many cellular repair and quality control mechanisms, it appears to be associated with longevity via its effects on mitochondria - but in this case only in early life, which raises a number of as yet unanswered questions:

[Researchers] analyzed mice genomes as a function of longevity and found a group of three genes situated on chromosome number two that, up to this point, had not been suspected of playing any role in aging. But the numbers didn't lie: a 50 percent reduction in the expression of these genes - and therefore a reduction in the proteins they code for - increased mouse life span by about 250 days [in a lineage that normally lives between 400 to 900 days]. Next, the team reproduced the protein variations in a species of nematode, Caenorhabditis elegans. "By reducing the production of these proteins during the worms' growth phase, we significantly increased their longevity." The average life span of a worm manipulated in this way went from 19 to more than 30 days, an increase of 60 percent. The scientists then conducted tests to isolate the common property and determined that the presence of mitochondrial ribosomal proteins (MRPs) is inversely proportional to longevity.

The researchers concluded that a lack of MRP at certain key moments in development created a specific stress reaction known as an "unfolded protein response" within the mitochondria. "The strength of this response was found to be directly proportional to the life span. However, we noted that it was more pronounced if the protein imbalance - the reduction in MRP - occurred at a young age. A similar stimulation in an adult did not affect the worms' longevity." What's more, the effect can be induced without genetically manipulating the worms. "Exposure to certain readily available drugs inhibits ribosomal function and thus causes the desired reaction." In other words, mitochondria are sensitive to certain antibiotics, and the drugs can be used to prolong life.

The process examined in worms exists in mice (and humans for that matter), so it looks like the next step is to explore these specific antibiotics in mice to see whether they also exhibit longevity effects and dependence on age at treatment.

Wednesday, May 22, 2013

Cells that have divided too many times or are damaged become senescent, removing themselves from the cell cycle as a protective measure that reduces the risk of cancer by preventing damaged cells from being active. Senescent cells should be destroyed, either by the immune system or by the mechanisms of programmed cell death, but some evade this fate and their numbers grow with age. These cells exhibit a range of damaging behaviors: promoting senescence in surrounding cells, releasing compounds that harm nearby tissue structure, and so forth. Sadly, and despite their role in cancer suppression, they also serve to increase the risk of cancer:

Senescence is assumed to be a cell-autonomous tumor-suppressor mechanism, because it is accompanied by irreversible cell-cycle arrest occurring mainly in response to irreparable telomeric and non-telomeric DNA damage. This has been especially well demonstrated for fibroblasts, the major cell component of the stroma. Yet fibroblast senescence may contribute to promoting cancer development and evolution, in a non-cell-autonomous, paracrine way, as suggested by the observation that senescent fibroblasts can stimulate growth, the epithelial-mesenchymal transition (EMT), and invasiveness of premalignant and malignant cells. This results from the fact that senescing fibroblasts develop a senescence-associated secretory phenotype (SASP) similar to that of carcinoma-associated fibroblasts, characterized by increased expression and secretion of growth factors, inflammatory cytokines, and matrix metalloproteinases.

We investigated here whether the senescent fibroblast secretome might have an impact on the very first stages of carcinogenesis. We chose the cultured normal primary human epidermal keratinocyte model, because after these cells reach the senescence plateau, cells with transformed and tumorigenic properties systematically and spontaneously emerge from the plateau. In the presence of medium conditioned by autologous senescent dermal fibroblasts, a higher frequency of post-senescence emergence was observed and the post-senescence emergent cells showed enhanced migratory properties and a more marked epithelial-mesenchymal transition. Using pharmacological inhibitors, siRNAs, and blocking antibodies, we demonstrated that the MMP-1 and MMP-2 matrix metalloproteinases, known to participate in late stages of cancer invasion and metastasis, are responsible for this enhancement of early migratory capacity. We present evidence that MMPs act by activating the protease-activated receptor 1 (PAR-1), whose expression is specifically increased in post-senescence emergent keratinocytes.

Developing the means to periodically clear out and destroy senescent cells is a necessary part of any future package of rejuvenation therapies, such as those of the SENS research program. Good progress is being made in targeted cell killing technologies by the cancer research community, and there are a number of possible mechanisms that might be used to distinguish senescent cells from healthy cells, so this type of therapy looks very feasible from a technical perspective.

Wednesday, May 22, 2013

The biochemistry of Alzheimer's disease is complex, and the tools available to researchers only recently up to the task of deciphering it all. Understanding the way in which the condition develops is still an ongoing work in progress:

Amyloid fibrils can form the foundations of huge protein deposits - or plaques - long-seen in the brains of Alzheimer's sufferers, and once believed to be the cause of the disease, before the discovery of "toxic oligomers" [a] decade or so ago. A plaque's size and density renders it insoluble, and consequently unable to move. Whereas the oligomers, which give rise to Alzheimer's disease, are small enough to spread easily around the brain - killing neurons and interacting harmfully with other molecules - but how they were formed was until now a mystery.

The new work [shows] that once a small but critical level of malfunctioning protein "clumps" have formed, a runaway chain reaction is triggered that multiplies exponentially the number of these protein composites, activating new focal points through "nucleation". It is this secondary nucleation process that forges juvenile tendrils, initially consisting of clusters that contain just a few protein molecules. Small and highly diffusible, these are the "toxic oligomers" that careen dangerously around the brain cells, killing neurons and ultimately causing loss of memory and other symptoms of dementia.

"We are essentially using a physical and chemical methods to address a biomolecular problem, mapping out the networks of processes and dominant mechanisms to 'recreate the crime scene' at the molecular root of Alzheimer's disease. With a disease like Alzheimer's, you have to intervene in a highly specific manner to prevent the formation of the toxic agents. Now we've found how the oligomers are created, we know what process we need to turn off."

Tuesday, May 21, 2013

Researchers investigate the ability of lower animals like the salamander to regenerate limbs and organs with the hopes that some of these mechanisms also exist in humans, just turned off at some point in our evolutionary history. Even if this is not the case, it may be that a greater understanding of the mechanisms of salamander regeneration will lead to ways to improve human regenerative capacity.

Salamanders' immune systems are key to their remarkable ability to regrow limbs, and could also underpin their ability to regenerate spinal cords, brain tissue and even parts of their hearts. [Researchers] found that when immune cells known as macrophages were systemically removed, salamanders lost their ability to regenerate a limb and instead formed scar tissue. "Now, we need to find out exactly how these macrophages are contributing to regeneration. Down the road, this could lead to therapies that tweak the human immune system down a more regenerative pathway."

Salamanders deal with injury in a remarkable way. The end result is the complete functional restoration of any tissue, on any part of the body including organs. The regenerated tissue is scar free and almost perfectly replicates the injury site before damage occurred. There are indications that there is the capacity for regeneration in a range of animal species, but it has, in most cases been turned off by evolution. "Some of these regenerative pathways may still be open to us. We may be able to turn up the volume on some of these processes. We need to know exactly what salamanders do and how they do it well, so we can reverse-engineer that into human therapies."

Tuesday, May 21, 2013

Ten years from now targeted therapies that selectively deliver cell-killing mechanisms to cancer cells will be the dominant method of treating cancer. This sort of technology offers the prospect of removing cancer cells even after metastasis, and with few side effects:

Nanomedicine started creating its own footprint in the sands of cancer research back in the mid-1970s when a group of European researchers discovered what would eventually become known as the liposome. These nano-sized, spherical structures form spontaneously when naturally occurring or synthetic lipids are exposed to water. Although they were identified by accident, these same researchers soon realized the potential of liposomes to carry drugs to diseased cells and tissues.

Around the same time, Massachusetts Institute of Technology research engineer Robert Langer also developed nanoparticles as chains of hydrocarbons known as polymers. Decades later, researchers have shown that such targeted nanoparticle therapies can effectively deliver drug cargo to tumors, while sparing the rest of the body's cells from the drug's toxic effects. Indeed, both types of nanoparticles are in clinical development as cancer-drug delivery vehicles, and some liposome-based have even made it to the market. There are now a total of three nanoparticles on the market as cancer therapies, and at least a dozen more are currently making their way through clinical trials.

The liposome platform is limited, however, in that it cannot release the drug into the tumor in a regulated way. The mechanism of drug release from liposomes is not well-understood, and may involve complex processes such as disruption of the liposome membrane or fusion with cellular membranes. In contrast, the polymer-based nanoparticles [allow] researchers to design treatments that release the chosen drug at a predictable rate controlled by diffusion. "While the first generation of drugs using [lipid] nanotechnology were considered pioneering at the time and became successful blockbuster cancer drugs, they were essentially reformulations of older drugs. Now, the next generation [using polymers] is taking nanotechnology to a whole new level with the ability to fundamentally change the efficacy and safety of drugs. The properties of these advanced compounds are well suited to target rapidly proliferating cells such as cancer cells, and several are already in the clinic."

Monday, May 20, 2013

A recent publication by the Institute of Economic Affairs (PDF format) looks at studies that suggest retirement leads to worse long-term health and shorter remaining life expectancy. You'll find the meaningful discussion on how researchers went about trying to identify cause and effect in the PDF rather than the press article quoted below: does the data actually show that retirement causes worsening health versus a tendency for people with worsening health to retire, for example?

A study out of the U.K. suggests that while it may provide an initial sense of relief and well-being, over the long-term, retirement is bad for your health, increasing the likelihood of developing depression and at least one physical illness. The study's author [analyzed] data from a survey of 11 European countries that sampled 7,000 to 9,000 people between the ages of 50 and 70 using two separate methodologies. He found that retirement had a "consistent negative impact" on physical health that worsens as the number of years spent in retirement increase.

[The author] also analyzed past studies on the subject of retirement and health and found that their results were mixed, with some finding a positive impact and others a negative or neutral one. The researcher attributes these varied results largely to a failure to distinguish short-term effects from long-term ones and to take the length of retirement into account. In the short term, retirees may experience a boost to health, he says, but this is outweighed by the negative impacts that manifest over the medium and long term.

[The author] acknowledges that there are many variables in any one individual's retirement that can often have contradictory effects on physical and mental health. Retirement can decrease work-related pressures and stress, for example, but it can also cut retirees off from the social networks they formed at work and lead to greater isolation, which can negatively affect health. By contrast, it can lead to more leisure time, which can result in new non-work-related social contacts or more participation in physical activities that positively affect health and well-being. "Untangling cause and effect in the relationship between retirement and health is very difficult. Whereas the short-term impacts of retirement on health is somewhat uncertain, the longer-term effects are consistently negative and large."

Monday, May 20, 2013

Osteoarthritis is one of the more common age-related conditions, and at the present time little can be done to treat the causes other than to alter lifestyle in ways that usually slow down the progression of the condition. Signs of progress towards effective therapies are on the horizon, however:

[Scientists] have turned their view of osteoarthritis (OA) inside out. Literally. Instead of seeing the painful degenerative disease as a problem primarily of the cartilage that cushions joints, they now have evidence that the bone underneath the cartilage is also a key player and exacerbates the damage. In a proof-of-concept experiment, they found that blocking the action of a critical bone regulation protein in mice halts progression of the disease.

Using mice with ACL (anterior cruciate ligament) tears, which are known to lead to OA of the knee, the researchers found that, as soon as one week after the injury, pockets of subchondral bone had been "chewed" away by cells called osteoclasts. This process activated high levels in the bone of a protein called TGF-beta1, which, in turn, recruited stem cells to the site so that they could create new bone to fill the holes. But the bone building and the bone destruction processes were not coordinated in the mice, and the bone building prevailed, placing further strain on the cartilage cap. It is this extraneous bone formation that [researchers] believe to be at the heart of OA, as confirmed in a computer simulation of the human knee.

With this new hypothesis in hand, complete with a protein suspect, the team tried several methods to block the activity of TGF-beta1. When a TGF-beta1 inhibitor drug was given intravenously, the subchondral bone improved significantly, but the cartilage cap deteriorated further. However, when a different inhibitor of TGF-beta1, an antibody against it, was injected directly into the subchondral bone, the positive effects were seen in the bone without the negative effects on the cartilage. The same result was also seen when TGF-beta1 was genetically disrupted in the bone precursor cells alone.


Post a comment; thoughtful, considered opinions are valued. New comments can be edited for a few minutes following submission. Comments incorporating ad hominem attacks, advertising, and other forms of inappropriate behavior are likely to be deleted.

Note that there is a comment feed for those who like to keep up with conversations.