Fight Aging! Newsletter, November 6th 2017

"Aging is mathematically inevitable - like, seriously inevitable. There's logically, theoretically, mathematically no way out. As you age, most of your cells are ratcheting down and losing function, and they stop growing, as well. But some of your cells are growing like crazy. What we show is that this forms a double bind - a catch-22. If you get rid of those poorly functioning, sluggish cells, then that allows cancer cells to proliferate, and if you get rid of, or slow down, those cancer cells, then that allows sluggish cells to accumulate. So you're stuck between allowing these sluggish cells to accumulate or allowing cancer cells to proliferate, and if you do one you can't do the other. You can't do them both at the same time."

Although human mortality is an undisputed fact of life, the researchers' work presents a mathematical equation that expresses why aging is an "incontrovertible truth and an intrinsic property of being multicellular. People have looked at why aging happens, from the perspective of 'why hasn't natural selection stopped aging yet?' That's the question they ask, and implicitly in that is the idea that such a thing as non-aging is possible, so why haven't we evolved it? We're saying it's not just a question of evolution not doing it; it can't be done by natural selection or by anything else."

"You might be able to slow down aging but you can't stop it. We have a mathematical demonstration of why it's impossible to fix both problems. You can fix one problem but you're stuck with the other one. Things will get worse over time, in one of these two ways or both: Either all of your cells will continue to get more sluggish, or you'll get cancer. And the basic reason is that things break. It doesn't matter how much you try and stop them from breaking, you can't."

Whereas mutation accumulation and antagonistic pleiotropy theory address the role of organismal selection in aging, we ask here whether aging is a fundamental and intrinsic feature of multicellular life. For an organism to avoid aging, it must overcome or mitigate the consequences of heritable changes in somatic cells, the vast majority of which are deleterious, and hence best thought of as "damage." Heritable cellular degradation is a product not just of somatic mutations but also of other changes, such as epigenetic drift and the accumulation of misfolded proteins. In unicellular organisms, competition between cells can weed out deleterious heritable changes, allowing a population to exist indefinitely despite individual degradation. Just as competition between individuals can eliminate deleterious alleles from a unicellular population, competition between cells within a multicellular organism can weed out malfunctioning, slower growing cells within an organism. Therefore, intercellular competition seems to hold the potential for immortality; by continually eliminating damaged cells, a multicellular organism might persist in perpetuity if only selection to do so were somehow strong enough.

Aging in multicellular organisms occurs at both the cellular and intercellular levels. Multicellular organisms, by definition, require a high degree of intercellular cooperation to maintain homeostasis. Often, cellular traits required for producing a viable multicellular phenotype come at a steep cost to individual cells. Conversely, many mutant cells that do not invest in holistic organismal fitness have a selective advantage over cells that do. If intercellular competition occurs, such "cheater" or "defector" cells may proliferate and displace "cooperating" cells, with detrimental consequences for the multicellular organism. Cancer, a leading cause of death in humans at rates that increase with age, is one obvious manifestation of cheater proliferation.

Thus, intercellular competition proves to be a double-edged sword; competition can remove damaged cells, but competition can also allow cheating cells to prosper. Here, we derive a general model of the effect of somatic evolution on aging and examine the behavior of a related model of discrete genotypes in simple numerical cases. Aging is characterized by the dual, but seemingly contradictory, features of loss of cellular vigor and uncontrolled cell growth, and we model the evolution of two corresponding cellular traits. First, we use the term "vigor" to reflect general cellular function or metabolic activity. Second, we use the term "cooperation" to represent investment in traits that are costly to the cell but beneficial for the organism as a whole; one manifestation of loss of cooperation is an increased propensity toward cancer. We show that intercellular competition produces a double bind resulting in inevitably declining organismal vitality with age in multicellular organisms.

Given most organisms' capacity to grow and regenerate, aging does not seem, at first glance, inevitable. Consequently, many have argued that aging is an accident of imperfect selection, where selection fails to purge deleterious, age-related mutations from an otherwise potentially immortal genotype. We have shown that even if selection against aging could be made more powerful, aging would remain an inescapable facet of multicellular life. As our model addresses the role of somatic evolution in aging, it should be seen as complementary, rather than contradictory, to models of aging via evolution by natural selection of multicellular individuals. Our model points to intercellular competition as a key factor in navigating the double bind of cellular degradation and cancer. It suggests that research programs focusing on quantifying the degree of intercellular competition and making comparisons across taxa, among individuals in the same population, among tissues of the same individual, and across developmental time, may be key to understanding the evolution and progress of aging.

Preliminary results from the world's first clinical trials to reverse menopause and its associated negative health effects in women has shown reversal of menopausal symptoms and hormone restoration to fertile levels. Since July 2017, the California-based Inovium trials have been evaluating the link between a new treatment to restore ovarian function discovered in 2015 by partner clinicians in Athens, Greece. Approximately 10 women and their partners have been selected to move forward in the trial, which will further examine their progress as they begin In-Vitro Fertilization and other strategies for late-life pregnancy. Over 100 additional women have received the treatment in 2017, with over 75% of all women proceeding forward positively towards pregnancy.

The clinical results of the California trials have effectively reproduced the success of preclinical trials conducted in Greece in 2015, where Platelet Rich Plasma (PRP) injections were discovered to rejuvenate the ovaries of menopausal women, restore fertility, and pursue pregnancy. Of more than 60 women who received the treatment preclinically, over 75% now have the option of natural pregnancy or in vitro fertilization, including 9 successful pregnancies. Over 75% have also seen overall hormone levels return to youthful levels. No donor is needed - instead, the patient's own genetic material is used to heal the body. The basic process involves the removal of the patient's own blood plasma, enrichment via centrifuge, and re-injection into the ovaries once elements commonly present in youthful blood have emerged.

The fixed primordial follicles pool theory, which monopolized reproductive medicine for more than one hundred years, has been broken by the discovery, successful isolation and establishment of ovarian stem cells. It has brought more hope than ever of increasing the size of primordial follicle pool, improving ovarian function and delaying ovarian senescence. The traditional view holds that stem cell aging contributes to the senility of body and organs. However, in the process of ovarian aging, the main factor leading to the decline of the reproductive function is the aging and degradation of ovarian stem cell nests, rather than the senescence of ovarian germ cells themselves.

Recent studies have found that the immune system and circulatory system are involved in the formation of ovarian germline stem cell niches, as well as regulating the proliferation and differentiation of ovarian germline stem cells through cellular and hormonal signals. Therefore, we can improve ovarian function and delay ovarian aging by improving the immune system and circulatory system, which will provide an updated program for the treatment of premature ovarian failure and infertility.

SRF Adds New Reward Drawings to 2017 Year-End Campaign

We would like to thank everyone who has donated so far to our year-end campaign. In just over two weeks, we have raised 37,803! This is a great start, but we still have a long way to go before reaching the 250,000 goal, and we are counting on you to help us get there. To help encourage you, we have decided to add monthly drawings to our campaign. On November 30th and December 31st, we will be drawing two winners from among all the donors who gave during that month. In each of these monthly drawings, one donor will receive a new long sleeve SENS t-shirt, and the other will receive a polo shirt in their size.

Also, on Giving Tuesday, we will be drawing three winners from among everyone who donates that day to receive exclusive SRF gift packs. Each gift pack will include a long sleeve t-shirt, a polo shirt, an SRF notebook and pen, and a signed copy of Ending Aging. Please mark your calendars - Giving Tuesday is November 28, 2017, and it's a great day to commit your support to helping SRF in our fight to cure age-related disease. So if you are as determined as we are to alleviate the grave human costs and suffering from conditions like cancer, Alzheimer's, atherosclerosis, and other age-related health problems, go to SRF's donate page today. Thank you so much.

CLSI and SRF Meet To Advance Rejuvenation Biotech Industry

In September, California Life Sciences Institute (CLSI) members and supporters, SENS Research Foundation (SRF) major donors, and other leaders from our biotech community met in San Francisco for an evening of insight and networking opportunities. The California Life Sciences Institute (CLSI) supports California's leadership in life sciences innovation through its entrepreneurship, education and career development programs. CLSI's FAST (Fellows All-Star Team) Accelerator provides select entrepreneurs with intensive team review and coaching to perfect their business model, product development plans, and to build a compelling commercialization strategy.

To leverage the opportunities presented at this unique point in the emergence of the rejuvenation biotech industry, CLSI and SRF brought together a selection of recent FAST companies with a rejuvenation biotechnology focus, and SRF translational research projects that will become the rejuvenation biotech companies of tomorrow. The focus of the program was to highlight and share information about and between key players poised to directly impact the direction and growth of these companies and the healthcare industry.

Undoing Aging 2018: Call for Poster Submissions

The 2018 Undoing Aging Conference will include poster sessions on the first two evenings. In addition, a small number of posters will be selected for oral presentation; those selected should also prepare a poster. Poster topics should lie within the scope of the conference: scientific/medical research contributing to the eventual postponement of age-related decline in health, with an emphasis on measures that repair damage rather than slowing its creation. Poster submissions are due on January 15, 2018. To submit your poster, please visit the Abstracts page on the Undoing Aging website.

SRF Summer Scholars Program Update

The 2017 SRF Summer Scholars Program culminated this year with our undergraduate researchers gathering at the Sanford Consortium for Regenerative Medicine to summarize the results of their summer projects. The Summer Scholars and mentors also attended the Meeting on the Mesa Scientific Symposium at the Salk Institute. View the 2018 Summer Scholars information page to learn more about the research opportunities being offered for 2018. Online applications will be available on December 1, 2017 and applications will be accepted until February 5, 2018. Our Summer Scholars Program is made possible by our donors' generous support. Please consider donating today to help support our 2018 student researchers.​

Microorganisms of the phylum Bacterioidetes are prevalent in the human intestinal flora and within this phylum, members of the Bacteroides genera represent approximately one-third of the cultivable microbial flora of the human intestinal microbiome. Periodontal diseases are also associated with increased percentages of specific Bacteroidetes species at periodontal disease sites. Porphyromonas gingivalis is considered to be a primary pathogen for chronic destructive periodontal disease. P. gingivalis has also been implicated in the development of atherosclerosis in experimental animals and P. gingivalis genomic products have been identified in a limited percentage of human atherosclerotic artery samples. In contrast to the atherogenic members of the oral flora, little is known regarding the capacity of intestinal organisms, particularly intestinal Bacteroidetes organisms, to contribute to the development of atherosclerosis.

Serine dipeptide lipids are produced by common oral and intestinal Bacteroidetes bacteria and the serine dipeptide lipids produced by P. gingivalis engage human and mouse Toll-like receptor TLR2. The serine lipids of P. gingivalis are comprised of two classes. One class is termed Lipid 430 and contains a single hydroxyl fatty acid linked to a serine-glycine dipeptide. The other class, termed Lipid 654, contains two fatty acids. Our work has shown that Lipid 654 engages TLR2. We have demonstrated that human blood sera samples contain detectable levels of Lipid 654 and lipid extracts of diseased periodontal tissues also contain Lipid 654. Therefore, accumulation of Lipid 654 in human tissues represents the presence of an exogenous TLR2 ligand produced by organisms of either the oral cavity or intestinal tract. TLR2 has been shown in experimental animal models to be an important innate immune receptor in the development of atherosclerosis.

The first goal of this investigation was to determine whether Lipid 654 is recovered in lipid extracts of common intestinal and oral Bacteroidetes, as well as in lipid extracts of human carotid artery tissue, brain, and blood samples. The median Lipid 430/Lipid 654 ratio was significantly elevated in carotid artery tissue when compared with control artery samples. Our results indicate that deacylation of Lipid 654 to Lipid 430 likely occurs in diseased artery walls due to phospholipase A2 enzyme activity. These results suggest that commensal Bacteriodetes bacteria of the gut and the oral cavity may contribute to the pathogenesis of TLR2-dependent atherosclerosis through serine dipeptide lipid deposition and metabolism in artery walls.

Advanced age is associated with chronic low-grade inflammation, which is usually referred to as inflammaging. Elderly are also known to have an altered gut microbiota composition. However, whether inflammaging is a cause or consequence of an altered gut microbiota composition is not clear. In this study, gut microbiota from young or old conventional mice was transferred to young germ-free (GF) mice. Four weeks after gut microbiota transfer immune cell populations in spleen, Peyer's patches, and mesenteric lymph nodes from conventionalized GF mice were analyzed by flow cytometry. In addition, whole-genome gene expression in the ileum was analyzed by microarray.

Here, we show by transferring aged microbiota to young GF mice that certain bacterial species within the aged microbiota promote inflammaging. This effect was associated with lower levels of Akkermansia and higher levels of TM7 bacteria and Proteobacteria in the aged microbiota after transfer. The aged microbiota promoted inflammation in the small intestine in the GF mice and enhanced leakage of inflammatory bacterial components into the circulation was observed. Moreover, the aged microbiota promoted increased T cell activation in the systemic compartment. In conclusion, these data indicate that the gut microbiota from old mice contributes to inflammaging after transfer to young GF mice.

Werner syndrome (WS) is a segmental progeria. It belongs to a small group of disorders characterized by accelerated aging. WS patients in their 20s and 30s display features similar but not identical to those of normal older individuals. WS is caused by mutations in the WRN gene, a RecQ helicase that protects genome stability by regulating DNA repair pathways and telomeres. Because of its resemblance to normal aging, WS is widely studied in the field of aging, and many consider WS the best example of an accelerated aging syndrome. The recently described hallmarks of aging pathways have been widely considered the key processes affected during aging. Since WS clinical features include many aspects of normal aging, it is not surprising that WRN functions in, or its loss impacts, many of these pathways.

Aging research has enumerated nine hallmarks of aging: genomic instability, telomere attrition, epigenetic alterations, loss of proteostasis, deregulated nutrient sensing, mitochondrial dysfunction, cellular senescence, stem cell exhaustion, and altered intercellular communication. Patients with WS have defects in DNA repair machinery and show genomic instability. WRN, in association with the telomere-protecting shelterin complex, promotes telomere maintenance, and loss of WRN, as seen in vitro and in patients with WS, results in the rapid decline of telomere length. A progressive increase in DNA methylation is considered an aging biomarker, and, consistent with this, patients with WS display increased epigenetic age. Increased DNA damage accumulation, genomic instability, telomere attrition, and histone methylation are contributing factors for cellular senescence and stem cell exhaustion in WS. Although extensive research is required to sort out the molecular functions of WRN in regulating proteostasis, nutrient sensing, and mitochondria, WS is phenotypically associated with a loss in proteostasis and mitochondrial dysfunction.

Thus many of the hallmarks of aging are found in patients with WS and altered as a direct consequence of WRN loss. Although there is strong evidence for a role for WRN in several of the pathways, others show a weak association and need further investigation. Patients with WS display many aging features, but the initiating pathology for most is still not known.

The traditional objections raised against the idea of longer lifespans touch a variety of different topics, but they can all be reduced down to a single, general form: "Rejuvenation biotechnologies would cause a specific problem, so it's best not to go there." Here, we're not going to question whether rejuvenation will cause a certain problem or not; rather, whatever problem we may be talking about, let us assume that it will happen and weigh it against the benefits of the defeat of aging.

To do so, let's keep in mind that aging kills about 100,000 people a day; that is, it accounts for two-thirds of all deaths worldwide. Moreover, it causes an indecent amount of suffering, disability, and debilitation, making the last decades of one's life increasingly miserable. To that, we must add all the problems of an aging society - money and resources spent on pensions and geriatrics with little to no utility, practical and emotional burden on the families of the elderly, too many retired people to be supported by a declining younger population, the lot of them. Let's also not forget that these are virtually everyone's problems. Is the above better than the potential side effects of the defeat of aging and the countermeasures we might thus have to take?

For example, suppose we determined that rejuvenation would cause such an unmanageable population increase that, in order to prevent it, it would be necessary to limit births worldwide, at least until we were able to support a larger population. Is asking all people to become sick and die better than asking those who want children to postpone their parenthood plans?

Another example: imagine that an evil dictator used rejuvenation to prolong his reign of terror by decades. So, on one hand, nobody would suffer and die of aging anymore; on the other hand, people who lived under the dictator would have to endure the dictatorship for longer. Forget for a moment that waiting for a dictator to die of old age isn't the best way to get rid of him; rather, let's reflect on this: would the amount of suffering caused by the dictator to a fraction of the human population be worse than that caused by aging to everyone? Would it be fair to ask the whole world to give up on lifesaving medical technology so that no dictator could ever use it to continue oppressing a minority that could be saved by more effective means anyway?

Let's face it - suffering and death are hardly a solution to anything. Will the rise of rejuvenation biotechnology cause unexpected side effects and challenges? Quite possibly, because it is a disruptive technology, and as such, it has the power to revolutionize our lives. But as for other past disruptive technologies, we'll figure things out as we go.

What if you could experience full health until the very end of your life? Researchers think long-lasting immunity from disease might be possible - if the thymus and the T-cells it produces to fight infection can be brought back to work efficiently. As we age, cells that defend against infection are gradually lost because we stop making them. This is particularly true with T-cells, and the result is often an onslaught of infectious diseases later in life. By rejuvenating the immune system, the researchers are hoping to stop that onslaught.

"T-cells are made in the specialized T-cell factory that sits behind our chest bone, and this is called the thymus. T-cells are critical in orchestrating an immune response. However, by the time we have gone through puberty, the thymus is churning out only one-tenth of the T-cells it made before puberty. What's more, there is evidence that between age 40 and 50, there's another tenfold drop. Down to 1 percent. So, the good news is it's not down to zero. The bad news is you're not producing many T-cells. That's really the earliest manifestation of our aging, the shrinking of the thymus."

However, even if the thymus remained plump and pumped out T-cells at a mad rate, it would be for naught. With age comes the sullying of the lymphatic system, whose job it is to circulate lymph and serve as a highway for T and other immune cells, equipped with vital communication checkpoints. Although T-cells still enter the lymph system in older people, the scant T-cells that are produced can't readily enter the lymph nodes. "Aged lymph nodes aren't able to effectively call in the cells from the outside, so fewer cells arrive. Moreover, when the cells arrive, they don't move inside like they should. Inside the lymph node is a superhighway meshwork, and we have found that this really gets messed up in aging."

So, researchers are formulating a novel plan of attack. "The idea here is that we want to rejuvenate both the thymus and the peripheral lymph organs, so both the factory that makes the cells and sites where the T-cells go to do the real work of defense against infection can once again work together. We feel like we will never get to rejuvenation if we work only on the thymus. If we are successful, we will see an improvement in immune defense and survival. Older adults are still by far the largest population for which infectious diseases still represent a significant risk. Our dream is to bring back the thymus and the T-cells to work the way that they should, particularly if we can fix the lymph nodes. That's not only going to benefit the T-cells but it will benefit the entire immune system. Our lifespan has been extended, but the problem is that for a sizable number of people, they're dealing with chronic diseases the last 15 or 20 years of life, and that is the part I'd like to get rid of. That is the dream of gerontology and the promise of the biology of aging research."

The most visible effects of aging are observed in skin and have been extensively studied for medical and cosmetic purposes. The three skin layers are affected both structurally and functionally. However, aging primary impacts the mechanical integrity of the dermis. At macroscopic scale, the mechanical behavior of aged dermis shows an increased stiffness and a decreased ability to recoil. At lower scales, a complex multi-parameters process eventually results in a decrease of collagen and elastin contents due to an imbalance between matrix proteins synthesis and degradation by matrix metalloproteinases, an increase of collagen cross-linking, a deterioration of proteoglycans and a subsequent loss of water.

Collagens are the main component of the dermis and other connective tissues. Fibril-forming collagens assemble into striated fibrils, the diameter and three-dimensional organization of which are tissue-specific. They form multiprotein networks with other matrix proteins such as the elastin fibers and non-fibrillar matrix (proteoglycans, glycoaminoglycans...) that determine the mechanical behavior of dermis and other collagen-rich tissues. Collagen fibers are usually heterotypic structures. In dermis, they are made of type I, III and V collagens. Type V collagen is a minor component that acts as a regulatory fibril-forming collagen. As such, it plays an important role in the pathogenesis of the classical Ehlers-Danlos (EDS) syndrome. This rare connective tissue disease illustrates the close link between collagen microstructure and tissue mechanics since it is caused by mutations in collagen V genes. EDS patients show a prematurely aged skin, which illustrates the close link between collagen microstructure and skin aging.

The relationship between collagen hierarchical structure and mechanical behavior has been explored using numerical simulations from the molecular scale and constitutive models have been proposed to explain the skin mechanical behavior. Recently, multiphoton microscopy has been used to monitor the reorganization of collagen microstructure during mechanical assays in skin and in various tissues. This allows us to measure simultaneously the microstructural reorganization of the tissue under mechanical stimulation and the mechanical behavior at macroscopic scale, which provides multiscale experimental data not accessible using other techniques.

This study aims at addressing the role of aging on the mechanical multiscale behavior of skin. This issue is addressed in murine skin because of easier availability of matched groups at different ages. We combined traction assays with multiphoton microscopy in ex vivo skin samples from mice aged 15 to 20 months. We compared these data to our previous results obtained in one-month old mice. We studied both wild type (WT) and genetically-modified mice for which collagen V expression in skin has been modulated, inducing modified biomechanical behavior in young mice.

Age-related microstructural changes in the dermis affect collagen fibers as well as the other components of the extracellular matrix. Notably, there is a progressive decrease in collagen, elastin and proteoglycans content, an increase in glycation cross-linking within and between fibers and the matrix proteins become fragmented with little spatial structure. Accordingly, the dermis is thinner, as reported in the literature for human skin and observed in our data for murine skin. The age-related structural changes of the skin have been reported to be largely similar in human and murine skin. Specifically, it has been reported that the collagen content decreases by about 30% between 2 (young) and 22 (old) months in murine skin.

Microstructural data for WT mice showed that the microstructural reorganization upon imposed stretch is the same for young and old mice. This might be surprising considering the many age-related changes in the skin ultrastructure and the quantitative changes of the mechanical parameters. This absence of variation may be explained by the combination of two effects that compensate each other: the increase of cross-linking in old mice impedes the collagen network reorganization, while the decrease of collagen content facilitates this reorganization. The collagen network has a higher level of organization in old mice. This may be attributed to the cumulated effect of skin stretching during lifespan, which is facilitated by the reduced content of collagen and its increased cross-linking. Further, the overall volume of old skin samples decreased upon stretching compared to young mice. This may be explained by the degradation of proteoglycans in old mice, which results in a decreased efficiency to retain water during mechanical stimulation, and therefore a smaller final volume.

In conclusion, our simultaneous observations of the mechanical behavior at macroscopic scale and of the microstructure of dermis are well explained in the framework of our multiscale interpretation of skin mechanics, which seems applicable to both aged and young murine skin. The two main microstructural changes affecting the mechanical properties appear to be the age-induced cross-linking and the degradation of the proteoglycan non-fibrillar matrix, which let the water flow out more easily. All these considerations emphasize the complex role of the microstructure in the mechanical properties. Our findings open the door to future research on human skin to verify whether the above findings obtained in murine skin fully apply to human skin.

In a teak-lined office overlooking the ocean, the biologist Ron Evans introduced me to two specimens: Couch Potato Mouse and Lance Armstrong Mouse. Couch Potato Mouse had been raised to serve as a proxy for the average American. Its daily exercise was limited to an occasional waddle toward a bowl brimming with pellets of laboratory standard "Western Diet," which consists almost entirely of fat and sugar and is said to taste like cookie dough. The mouse was lethargic, lolling in a fresh layer of bedding, rolls of fat visible beneath thinning, greasy-looking fur. Lance Armstrong Mouse had been raised under exactly the same conditions, yet, despite its poor diet and lack of exercise, it was lean and taut, its eyes and coat shiny as it snuffled around its cage. The secret to its healthy appearance and youthful energy, Evans explained, lay in a daily dose of GW501516: a drug that confers the beneficial effects of exercise without the need to move a muscle.

Evans began experimenting with 516, as the drug is commonly known, in 2007. He hoped that it might offer clues about how the genes that control human metabolism are switched on and off, a question that has occupied him for most of his career. When Evans began giving 516 to laboratory mice that regularly used an exercise wheel, he found that, after just four weeks on the drug, they had increased their endurance - how far they could run, and for how long - by as much as seventy-five per cent. Meanwhile, their waistlines ("the cross-sectional area," in scientific parlance) and their body-fat percentage shrank; their insulin resistance came down; and their muscle-composition ratio shifted toward so-called slow-twitch fibres, which tire slowly and burn fat, and which predominate in long-distance runners.

The drug works by mimicking the effect of endurance exercise on one particular gene: PPAR-delta. Like all genes, PPAR-delta issues instructions in the form of chemicals-protein-based signals that tell cells what to be, what to burn for fuel, which waste products to excrete, and so on. By binding itself to the receptor for this gene, 516 reconfigures it in a way that alters the messages the gene sends - boosting the signal to break down and burn fat and simultaneously suppressing instructions related to breaking down and burning sugar.

In dozens of other ways, 516 triggers biochemical changes that take place when people train for a marathon - changes that have substantial health benefits. Evans refers to the compound as "exercise in a pill." But although Evans understands the mechanism behind 516's effects at the most minute level, he doesn't know what molecule triggers that process naturally during exercise. Indeed, one of the most significant challenges facing anyone who wants to develop an exercise pill is that the biological processes unleashed by physical activity are still relatively mysterious. For all the known benefits of a short loop around the park, scientists are, for the most part, incapable of explaining how exercise does what it does.

The compound 516 was developed in the late nineties. GlaxoSmithKline took the drug all the way through Phase II clinical trials in humans, successfully demonstrating that it lowered cholesterol levels without any problematic side effects. But, in 2007, GlaxoSmithKline decided to shelve 516. The company was about to embark on Phase III trials - the large, expensive, double-blind, placebo-controlled trials that are required for F.D.A. approval - when the results of a long-term-toxicity test came in. Mice that had been given large doses of the drug over the course of two years (a lifetime for a lab rodent) developed cancer at a higher rate than their dope-free peers.

The real problem, according to Ron Evans, lies in the term "exercise," which is too general to be useful. "You have to be more granular about it," he told me. He suspects that a mere handful of biochemical pathways will prove to be responsible for the majority of exercise's benefits. Among the current field of exercise-pill competitors, Evans is the closest to the finish line. He has set up a company, Mitobridge, to take an improved version of 516 to market; this summer, it launched Phase I trials in humans.

Scientists have been exploring the potential of stem cell and other cell therapies to regenerate fibrosis-damaged organs including cirrhotic livers. One problem with this strategy is that inflammatory and other disease processes within a damaged organ tend to create an inhospitable environment - or "niche" - for transplanted cells and even for resident stem cells. Prior work has shown, however, that vessel-lining endothelial cells can produce special organ-specific growth factors, known as angiocrine factors, that restore a healthier niche and promote regeneration without provoking scarring. "In the case of liver cirrhosis, blood vessels in the liver are damaged and fail to supply angiocrine factors that promote regeneration. So the idea underlying this endothelial cell therapy is to rejuvenate that vascular niche. Accordingly, the remaining hepatocyte progenitors in the liver can get the proper signals from angiocrine factors they need to suppress fibrosis and regenerate liver tissue."

For the study, the investigators harvested small quantities of endothelial cells from the liver vessels of eight pigs, and multiplied the cells to large quantities in the laboratory. After inducing cirrhosis in each pig's liver, the researchers then treated half of the pigs by infusing the liver-specific endothelial cells into a large vein that runs into the liver, using a small catheter inserted through the skin and guided by ultrasound and live X-ray imaging.

Although the number of pigs in the study wasn't large enough to determine the therapeutic effectiveness of the technique, examination of the pigs' livers three weeks after treatment revealed some striking differences between treated and untreated animals. When the investigators examined samples of cells and tissues taken from the treated pigs' livers under the microscope, they found that the organ appeared much more like the livers of healthy pigs, in contrast to the untreated livers. The researchers now hope to conduct larger trials of the endothelial cell therapy in pigs and, if they are successful, progress to clinical trials in humans. In principle the cell therapy could be used to treat not just cirrhosis but other forms of liver injury as well.

Therapy with mesenchymal stem cells, the so-called progenitor cells of connective tissue, holds great promise for the regeneration of cartilage tissue but how stem cell therapy contributes to the healing of damaged connective tissue has been unclear. Debate has centered on whether the injected cells promote regeneration or stimulate the body's own cells to proliferate. A new strategy has now enabled researchers to solve the question. The problem was that a marker protein was recognized by the immune system of the recipient as a non-self protein, leading to the rejection of the injected stem cells. The scientists were able to overcome this limitation and show that progenitor cells do not participate directly in cartilage regeneration but serve to "animate" the process.

"To date, it has not been possible to show what an injection of stem cells really does in an animal model. The problem is that you have to track the cells with particular proteins that the immune system of the recipient recognizes as non-endogenous and thus potentially harmful. The resulting rejection of the injected cells has prevented the validation of their mode of action." It was thus only possible to track stem cells in immunodeficient animal models that had no reaction to the proteins due to a genetically reduced immune system. Yet these models could not provide any clues about the mode of action of the stem cells in normal animals. "We therefore worked with a 'lifelike' animal model that is immunocompetent but shows no response to our tracker molecule. This enabled us to show that stem cells have a purely modulating action in the treatment of cartilage damage. Our results contribute to our understanding of stem cell therapy, as they show for the first time that therapy stimulates the body's own cells to promote the regeneration of damaged connective tissue, such as cartilage."

The first rigorous clinical test of whether blood plasma donated by healthy young people can help reverse Alzheimer's disease in older adults has found that the treatment produced minimal, if any, benefits. Caregivers for 16 people with mild or moderate Alzheimer's disease reported that their charges performed slightly better at daily tasks after receiving weekly injections of young plasma. But the patients did no better on cognitive tests administered by researchers - a crucial standard for whether the treatment had a significant impact. All the same, the sponsor of the trial - startup company Alkahest - is "encouraged" to run more trials

Nine patients with mild to moderate Alzheimer's got four once-weekly infusions of either saline (as a placebo) or plasma from 18- to 30-year-old male donors. After a 6-week break, the infusions were switched so that the patients who had gotten plasma got saline, and the patients who had gotten saline received plasma. Another nine patients received young plasma only, and no placebo. Two patients dropped out of the trial, one after developing a rash from an infusion and another who had an unrelated stroke.

After receiving young plasma, the 16 remaining patients performed no better on objective cognitive tests given by medical staff. However, on average their scores improved slightly - 4.5 points on a 30-point scale - on a caregiver survey about whether they needed help with daily activities such as making a meal or traveling. The patients' scores also improved modestly on another survey that asks caregivers how well patients can perform simple tasks like getting dressed and shopping. The positive effects reported by the caregivers could merely be a placebo effect: "Patients could feel better because somebody paid attention to them."

Because the treatment seemed safe, Alkahest now wants to launch another trial that will use just the fraction of the blood plasma that contains growth factors, but not coagulation factors and other components that may do more harm than good. In animals, this plasma fraction was more effective at improving cognition in the mice with an Alzheimer's-like condition than whole plasma. Alkahest also wants to test a range of doses and include patients with more severe Alzheimer's.

Many conditions that contribute to cardiovascular diseases (CVDs) are due to narrowing and hardening of the blood vessels through a process known as atherosclerosis, arising due to lipid accumulation which, over time, develops into plaques. Subsequently, these atherosclerotic plaques can lead to ischaemic injury by a number of mechanisms such as complete occlusion of the blood vessel or alternatively, the plaque may become unstable and rupture resulting in thrombosis. This process may be exacerbated by risk factors encompassing genetic aspects, lifestyle choices such as smoking, excessive drinking, physical inactivity and obesity or conditions such as diabetes.

Indeed, in both type 1 and type 2 diabetic patients, a high proportion of mortality is associated with CVD, where defective insulin signalling leads to endothelial dysfunction and accelerated atherosclerosis. The mechanism contributing to this pathology is somewhat unclear; however, it has been suggested that insulin resistance (IR) and hyperglycaemia results in intracellular metabolic changes leading to oxidative stress and chronic low-grade inflammation. Therefore, targeting components that inhibit IR signalling could prove to be an effective therapeutic.

Protein tyrosine phosphatase (PTP)1B (PTP1B) has been identified as the major negative regulator of the IR itself. In mice, whole body PTP1B-/- studies established PTP1B as a major regulator of insulin sensitivity and body mass, via inhibition of insulin and leptin signalling respectively. Our recent data suggested that hepatic-specific deletion of PTP1B, in addition to improving glucose and lipid homoeostasis and increasing insulin sensitivity, was protective against endothelial dysfunction in response to high fat diet (HFD). This was also associated with decreased hepatic inflammation in these mice. Since atherosclerosis is regarded as a chronic low level inflammatory disease, we hypothesized that targeting PTP1B activity using a PTP1B-specific inhibitor trodusquemine, could prove effective in prevention and possibly reversal of atherosclerotic plaque formation.

We demonstrate here, using the LDLR-/- mouse model of atherosclerosis, that pharmacological PTP1B systemic inhibition leads to protection against and reversal of atherosclerosis development, suggesting beneficial effects of PTP1B inhibition for the treatment of CVDs and reduction in CVD risk. We present evidence that, in addition to its improvement in glucose homeostasis and adiposity, PTP1B inhibition results in activation of aortic Akt and AMPKα1, that is independent of the effects on the IR itself. Most importantly, for the first time, we demonstrate that inhibition of PTP1B results in a decrease in circulating serum cholesterol and triglyceride levels and protection against atherosclerotic plaque formation.

Atherosclerosis is now widely regarded as a chronic, low-grade inflammatory condition characterized by an increased pro-inflammatory environment and decreased anti-inflammation, pro-resolutionary signalling. Thus, a vicious cycle ensues and a failure of the tissue to return to homeostasis. Therefore, we investigated the expression of genes important in the inflammatory response including MCP-1, ICAM-1 and VCAM-1. MCP-1 is responsible for recruiting monocytes to the aortic tissue whereas both ICAM-1 and VCAM-1 enable their transmigration. Although there were no changes in the expression of aortic ICAM-1 or VCAM-1, those animals treated with a single injection of trodusquemine exhibited attenuated aortic MCP-1 expression levels. Hence, suggesting less monocyte recruitment and a reduced inflammatory environment which could contribute to the reduction in plaque development.

Picture a bare wire, without its regular plastic coating. It's exposed to the elements and risks being degraded. And, without insulation, it may not conduct electricity as well as a coated wire. Now, imagine this wire is inside your brain. Much like that bare wire, the nerve fibers in the brain lose their protective coating, called myelin, and become extremely vulnerable. This leaves the nerve cells exposed to their environment and reduces their ability to transmit signals quickly, resulting in impaired cognition, sensation, and movement. In disease, the brain seems to activate mechanisms to repair myelin, but cannot complete the process. For years, scientists have been trying to understand why these repair mechanisms are halted, as overcoming this obstacle holds great potential for treating disabling neurological diseases.

The cells needed to repair myelin already exist in the central nervous system. They are adult stem cells that travel to sites of damage, where they mature into myelin-producing cells. However, in many neurological diseases, this process is blocked. This is why the brain is unable to repair damaged myelin. In an effort to understand why the brain can't repair itself, scientists have in the past focused on understanding what happens inside the cell. "We thought it might be important to look instead at the toxic environment outside the cell, where blood proteins accumulate. We found that when fibrinogen (a blood-clotting protein) leaks into the central nervous system, it stops brain cells from producing myelin and, as a result, prevents repair. We realized that targeting the blood protein fibrinogen could open up the possibility for new types of therapies to promote brain repair."

"Repairing myelin by eliminating the toxic effects of blood-brain barrier dysfunction in the brain is a new frontier in disease therapeutics." Researchers can now look for new ways to target fibrinogen as a way to restore regenerative functions in the central nervous system. This could lead to novel therapies to help patients with multiple sclerosis and many other diseases associated with myelin.