Fight Aging!

In the scientific commentary I'll point out today, the authors advocate for the expansion of efforts to target mutations of the cancer suppressor gene TP53, encoding the protein p53, as a path to cancer therapies that might be broadly applicable to many cancer types. As I've noted in the past, the biggest problem with the majority of today's cancer research isn't that it is challenging and expensive, but rather that the therapies resulting from these efforts are only applicable to one or a few of the hundreds of subtypes of cancer. This is no way to defeat cancer; there are too few scientists and too little funding to do things this way, one cancer at a time. What is needed is a shift in high level strategy to focus much more aggressively on paths that will produce technology platforms that can, out of the box, target a wide variety of cancers, or where the cost of adapting the technology to different cancer types is very low.

This strategic focus is the reason for the SENS-advocated approach of blocking telomere lengthening, for example. All cancers must lengthen telomeres in order for continual cellular replication to take place, and there are a limited number of mechanisms by which that can happen. Without telomere lengthening, a cancer will wither away in short order. This is the most cost-effective way to deal with cancer: a small set of targets that can lead to a truly universal cancer therapy, a technology platform that can be easily adapted to each new type of cancer. That research is still in its early stages, and still very much in search of widespread support, however. Closer to the mainstream you'll find things like the use of chimeric antigen receptors in immunotherapy, which is an incremental improvement over most therapies from the past few decades in that it should have a reduced cost to adapt the technology to attack a wide variety of cancer types.

This leads to the research review for today, in which scientists note that TP53 is mutated in half of all cancers, and therefore an attractive target. This is somewhat conditional on the ability to produce an effective therapy from this basis, of course, but it seems a plausible goal at this point in time. The worst outcome would be to find that targeting p53 caused a large fraction of cancers to evolve around that attack, and turn into varieties that did not depend on p53 mutations to survive and grow. This is unfortunately a fairly likely outcome - it has been observed in the field in connection with other cellular mechanisms. It is also what makes a blockade of telomere lengthening, as mentioned above, very attractive: telomere-related mechanisms are so very fundamental to cellular replication that cancer cells should be incapable of evolving new ways around that attack. Regardless, it is always good to see more discussion in the cancer research community that acknowledges the problems in the field, and proposes technical solutions to those problems:

Targeting mutant p53 for cancer therapy

The p53 tumor suppressor protein serves as a major barrier against cancer; consequently, mutations in the TP53 gene, encoding p53, are the most frequent single genetic alteration in human cancer, occurring in about half of all individual cancer cases. Besides abrogating the tumor suppressive effects of the wild type (WT) p53 protein, many of the TP53 mutations endow the mutant p53 protein with new oncogenic gain-of-function activities, which actively promote a variety of features characteristic of aggressive tumors, such as increased migratory and invasive capacities and increased resistance to many types of anti-cancer therapy agents. This realization has led to extensive attempts to restore full p53 functionality in cancer cells, as a novel cancer therapy strategy. However, these attempts have been seriously hampered by the fact that p53 has no known enzymatic activities, and rather operates primarily as a sequence-specific transcription factor. Furthermore, restoring the activity of a defective tumor suppressor protein is vastly more difficult than abrogating the activity of a hyperactive oncoprotein.

Nevertheless, significant advances have been achieved in recent years, and hopes for the introduction of p53-based novel cancer therapies into the clinic are becoming increasingly supported by evidence. In principle, attempts to develop such therapies have taken 3 main approaches: [1] Introduction of WTp53, mainly via viral transduction ("gene therapy"), into tumors that have sustained TP53 mutations; [2] enhancement of the functionality of the endogenous WTp53 in tumors that have retained a non-mutated TP53 gene, mainly be disrupting the interaction of the WTp53 protein with its major negative regulator MDM2; and [3] "correction" of the mutant p53 protein in tumors that have sustained TP53 missense mutations, thereby restoring its ability to perform the tumor suppressive activities of WTp53.

The latter approach, namely the "re-education" of mutant p53, is particularly appealing. First of all, it can simultaneously reinstate WTp53 tumor suppressive activity together with abrogating the gain-of-function oncogenic effects of the mutant p53 protein. Additionally, since cancer cells bearing TP53 missense mutations often accumulate massive amounts of the mutant p53, its conversion into a WT-like state will potentially flood the cancer cell with excessive amounts of tumor suppressive p53, far beyond what one finds in normal cells. This may provide a large therapeutic window and may potentially circumvent the severe limiting toxicity observed with compounds that augment the activity of non-mutated p53 in cancer cells.

Indeed, attempts to "re-educate" mutant p53 in cancer cells have seen substantial progress in the last several years. The most advanced effort has identified a small molecule named PRIMA-1, which can reactivate mutant p53. We have opted for a different approach, based on identification of small peptides that specifically stabilize mutant p53 proteins in a functional state. These peptides can stabilize the WT conformation of mutant p53, and restore its ability to activate canonical WTp53 target genes. Moreover, they promote selective apoptotic death of cancer cells harboring mutant p53, and very effectively reduce, and even completely block, the growth of human cell line-derived mouse xenograft tumors representing several types of highly aggressive cancer. Importantly, all common p53 mutants tested in our study were found to be amenable to functional stabilization by these peptides. Bringing small peptides into the clinic remains challenging, mainly owing to the need to deliver the peptides efficiently into the tumor cells. Nevertheless, their greater specificity, relative to small molecules of the types described above, bears the hope for minimal non-specific toxicity, rendering such approach potentially highly promising in the long run.

Aging kills all of us eventually, given how little today's medical technology can do to intervene in the causes of age-related degeneration, but along the way there is a quite a distribution of outcomes in health and frailty. Some people live longer than others, obviously. But also, some people do comparatively well until close to the end of life, while others suffer considerable pain and disability for a much longer period of time in later life. Some of these differences are the result of poor lifestyle choices, but others result from chance and the interaction of genetic variations with growing levels of biochemical damage. A lot of effort goes into studying these variations in the state of aging, but really, that funding and the time would be better directed towards finding ways to repair the cell and tissue damage that causes aging. Success on that front would make the unmodified progression of aging a historical curio, and produce far longer healthy lives for all.

You might believe that older adults who deal with extensive chronic illnesses or serious diseases would be more likely to be frail and to have a poorer quality of life than healthier older adults. That may be true for some elders - but not for all. Researchers suggest that an undefined coping mechanism of some sort may play a role in how well older adults are able to live despite having burdensome illnesses.

The researchers examined three groups of participants enrolled in the Cardiovascular Health Study, a large research project that examined adults 65-years-old and older from four cities around the country. Researchers assigned people to one of three groups, based on the extent of their disease and their level of vigor or frailty: (1) The expected agers (3,528 people) had higher disease but also higher frailty levels. They spent 47 percent of the remainder of their lives able and healthy. (2) The adapters (882 people) had higher disease levels as well as relatively high vigor (being active and mobile) levels. They spent 55 percent of the reminder of their lives able and healthy. (3) The prematurely frail (885 people) had lower disease levels but higher frailty levels. They spent 37 percent of their remaining lives able and healthy.

The researchers said "adapter" older adults who were more vigorous than expected, based on their disease burden, lived longer lives when compared to those who were more frail than expected based on their disease burden. These "adapters" could have unique characteristics, perhaps some undefined coping mechanism, that should be studied further, suggested the researchers.

Link: http://www.healthinaging.org/news/research-summaries/article:06-21-2016-12-00am-some-older-adults-live-well-despite-advancing-years-and-the-burdens-of-chronic-diseases-compared-to-others-with-similar-levels-of-illness/

This is a fairly interesting take on reducing the impact of heart attacks. It isn't the best approach to the situation, which is to find methods of prevention, but rather a matter of engineering the heart to be more resilient to temporary loss of oxygenated blood flow by spurring the growth of additional blood vessels, over and above those that normally exist.

The reason heart muscle dies in a heart attack is that it becomes starved of oxygen - a heart attack is caused by blockage of an artery supplying the heart. If heart muscle had an alternative blood supply, more muscle would remain intact, and heart function would be preserved. Many researchers have therefore been searching for ways to promote the formation of additional blood vessels in the heart. "We found that a protein called RBPJ serves as the master controller of genes that regulate blood vessel growth in the adult heart. RBPJ acts as a brake on the formation of new blood vessels. Our findings suggest that drugs designed to block RBPJ may promote new blood supplies and improve heart attack outcomes."

"Studies in animals have shown that having more blood vessels in the heart reduces the damage caused by ischemic injuries, but clinical trials of previous therapies haven't succeeded. The likely reason they have failed is that these studies have evaluated single growth factors, but in fact building blood vessels requires the coordinated activity of numerous factors. Our data show that RBPJ controls the production of these factors in response to the demand for oxygen. We used mice that lack RBPJ to show that it plays a novel role in myocardial blood vessel formation (angiogenesis) - it acts as a master controller, repressing the genes needed to create new vessels. What's remarkable is that removing RBPJ in the heart muscle did not cause adverse effects - the heart remained structurally and functionally normal in mice without it, even into old age."

RBPJ is a promising therapeutic target. It's druggable, and our findings suggest that blocking it could benefit patients with cardiovascular disease at risk of a heart attack. It may also be relevant to other diseases. Inhibitors of RBPJ might also be used to treat peripheral artery disease, and activators might be beneficial in cancer by inhibiting tumor angiogenesis."

Link: http://www.eurekalert.org/pub_releases/2016-06/spmd-sbm062716.php

While aging is complex, and so is diet, the recommendations are fairly straightforward: practice calorie restriction and you'll find that most of the other pieces of a sane diet fall into place by themselves, as it is very hard to assemble a calorie restricted diet out of anything other than healthy food. Not that you'd think there is a simple solution from reading around the subject. Diet is a topic in which there ten thousand people eagerly overcomplicate the situation, building mountains from molehills, confusing the issue, and generally making a mess of things. Ignore them all. Still, there is an interesting dichotomy that arises as a result of research on calorie restriction on the one hand and on protein intake and muscle mass in older individuals on the other, and that is the subject of the open access review paper I'll point out today.

The practice of calorie restriction is demonstrated to produce considerable benefits to health, even when undertaken in later life, and that includes benefits to muscle metabolism. The immediate effects of a lowered calorie intake appear to be triggered by protein restriction, and there is a fair amount of research that examines the role of lowered levels of the essential amino acid methionine as the primary trigger. On the other hand, older people do not process dietary protein as well as younger people, a change thought to contribute to the progression of sarcopenia, age-related loss of muscle mass and strength, and there is evidence to suggest that this can be offset to some degree by higher levels of protein. There is some work along these lines that investigates supplementation of the essential amino acid leucine as a possible preventative treatment, based on what is known of how processing of leucine changes with age.

Protein Consumption and the Elderly: What Is the Optimal Level of Intake?

One of the major threats to living independently is the loss of muscle mass, strength, and function that progressively occurs with aging, known as sarcopenia. A loss or reduction in skeletal muscle function often leads to increased morbidity and mortality either directly, or indirectly, via the development of secondary diseases such as cardiovascular disease, diabetes, and obesity.

Traditionally, protein recommendations have been based on studies that estimate the minimum protein intake necessary to maintain nitrogen balance. However, the problem with relying on these results is that they do not measure any physiological endpoints relevant to healthy aging, such as muscle function. In the case of daily protein intake, the estimated average requirement (EAR) for dietary protein is 0.66 g/kg/day and the Food and Nutrition Board recommends a recommended dietary allowance (RDA) of 0.8 g/kg/day for all adults over 18 years of age, including elderly adults over the age of 65. Experts in the field of protein and aging recommend a protein intake between 1.2 and 2.0 g/kg/day or higher for elderly adults. The RDA of 0.8 g/kg/day is well below these recommendations. It is estimated that 38% of adult men and 41% of adult women have dietary protein intakes below the RDA.

Most published results, based on data from either epidemiological or short-term studies, indicate a potential beneficial effect of increasing protein intake in elderly adults. These data demonstrate that elderly adults, compared with younger adults, are less responsive to low doses of amino acid intake. However, this lack of responsiveness in healthy older adults can usually be overcome with higher levels of essential amino acid (EAA) consumption. The mechanism by which dietary protein affects muscle is through the stimulation of muscle protein synthesis and/or suppression of protein breakdown by the absorbed amino acids consumed in the diet. There appears to be an EAA threshold when it comes to stimulating muscle protein synthesis. Ingestion of relatively small amounts of EAA (2.5, 5 or 10 g) appears to increase myofibrillar protein synthesis in a dose-dependent manner. However, a larger dose of EAA (20-40 g) fail to elicit an additional effect on protein synthesis in young and older subjects. Similar results were observed after the ingestion of either 113 or 340 g of lean beef containing 10 or 30 g EAA, respectively. Despite a threefold increase in EAA content, there was no further increase in protein synthesis in either young or older subjects following consumption of 340 g versus 113 g of protein.

The consumption of dietary protein consistent with the upper end of the recommendations (as much as 30%-35% of total caloric intake) may prove to be beneficial, although practical limitations may make this level of dietary protein intake difficult. The consumption of high-quality proteins that are easily digestible and contain a high proportion of EAAs lessens the urgency of consuming diets with an extremely high protein content.

So if you are going to try to optimize, bearing in mind that once past the simple and obvious items optimizing diet is largely a fool's game, does that mean more protein for older individuals or less protein throughout life? It is interesting that both approaches show benefits in various different animal and human studies, though the weight of evidence leans towards calorie restriction at the present time. I'd be inclined to think that the right approach to this question is to keep practicing calorie restriction, adjust the proportion of protein upwards over the years, and support work to find and address the causes of age-related changes in amino acid processing. The SENS vision would expect these changes to be somewhere downstream of the standard list of forms cell and tissue damage that cause aging, following a chain of epigenetic cause and effect, most of which is yet to be mapped.

Ultimately, no lifestyle plan can help you do any more than live just a little longer than you were going to anyway - your life span will still be somewhere in the expected human range. That isn't a big improvement in the grand scheme of things. If lifestyle is all you think about with regard to health, then a great opportunity has been missed. The real determinant of life expectancy and health in old age is progress in medical science, and specifically in the development of rejuvenation biotechnologies that can repair the damage that causes aging. That is the road to very large gains in healthy life span, far beyond those achievable by any available method today.

Researchers have recently investigated one of the numerous mechanisms by which regular exercise acts to improve brain function over the long term. In this case, there is a chain of interactions that leads via cathepsin B to the better known brain-derived neurotrophic factor (BDNF) that then boosts neurogenesis, the creation of new brain cells. Neurogenesis declines in adult life, but is essential to neural plasticity, the ability of the brain to adapt and, to a limited degree, heal itself. Cathepsin B is also involved in lysosomal function, a part of the cellular maintenance systems responsible for clearing out damaged proteins and cell structures. Down that path, if you look back in the Fight Aging! archives, you'll find an interesting study on increased cathepsin B levels in flies, in which improved lysosomal function cleared more unwanted cellular debris as a result.

A protein called cathepsin B, produced and secreted by muscle during exercise, is required for exercise-induced memory improvement and brain cell production in mice. Researchers also showed that levels of cathepsin B are positively correlated with fitness and memory in humans. "This is a super exciting area. Exercise has so many health benefits, yet we know so little about many of these effects at a molecular level. This paper provides a convincing mechanism that involves running-induced increases in a particular protein - cathepsin B - that appears to promote neurogenesis by enhancing expression of a growth factor - BDNF - in the brain. This is a long chain of events, from exercise to muscle to brain to cognition, but the authors do a great job at demonstrating each of the links."

Running has been shown in animals to have a variety of effects on the brain, including enhanced memory function and increased production of new brain cells (neurogenesis). In humans, a correlation between exercise and memory function has also been observed. But how muscle activity might be mechanistically linked to memory has been somewhat of a mystery. To hunt for mucle-produced factors called myokines that might modulate brain function, researchers treated rat muscle cells in culture with the drug AICAR - "an exercise mimetic," meaning it boosts the cells' metabolic activities. Among the proteins upregulated in the treated cells was a secreted factor, small enough to traverse the blood-brain barrier, that had previously been shown to be upregulated in muscle during exercise: cathepsin B.

In mice that exercised for two to four weeks, plasma levels of cathepsin B were significantly increased, and the animals showed improved memory as well as increased neurogenesis in their hippocampi - a brain region involved in learning and memory. Mice that were genetically engineered to lack cathepsin B, on the other hand, did not show these exercise-related effects. The team also showed that cathepsin B treatment of murine adult hippocampal progenitor cells in culture induced the expression of two key nerve growth factors - brain-derived neurotrophic factor (BDNF) and doublecortin - which may explain how the myokine induces neurogenesis. In rhesus monkeys and humans, four months of treadmill training increased blood levels of cathepsin B, the team showed, and this increase was correlated with improved memory recall in the human study participants.

Link: http://www.the-scientist.com/?articles.view/articleNo/46397/title/Exercise-Induced-Muscle-Factor-Promotes-Memory/

Researchers continue to search for better methods of 3-D printing to build tissues, approaches capable of producing the correct structural properties in the resulting product. Cartilage is a challenge in particular, as while it is a comparatively simple tissue type and thus a good place to start, it has proven difficult to recreate the strength and resilience of naturally grown cartilage. So far the most promising line of work has involved recreating the stage of mesenchymal condensation, but this has not yet been widely adopted.

Cartilage is a good tissue to target for scale-up bioprinting because it is made up of only one cell type and has no blood vessels within the tissue. It is also a tissue that cannot repair itself. Once cartilage is damaged, it remains damaged. Previous attempts at growing cartilage began with cells embedded in a hydrogel - a substance composed of polymer chains and about 90 percent water - that is used as a scaffold to grow the tissue. "Hydrogels don't allow cells to grow as normal. The hydrogel confines the cells and doesn't allow them to communicate as they do in native tissues." This leads to tissues that do not have sufficient mechanical integrity. Degradation of the hydrogel also can produce toxic compounds that are detrimental to cell growth.

Researchers have developed a method to produce larger scale tissues without using a scaffold. They create a tiny - from 3 to 5 one hundredths of an inch in diameter - tube made of alginate, an algae extract. They inject cartilage cells into the tube and allow them to grow for about a week and adhere to each other. Because cells do not stick to alginate, they can remove the tube and are left with a strand of cartilage. The cartilage strand substitutes for ink in the 3D printing process. Using a specially designed prototype nozzle that can hold and feed the cartilage strand, the 3D printer lays down rows of cartilage strands in any pattern the researchers choose. After about half an hour, the cartilage patch self-adheres enough to move to a petri dish. The researchers put the patch in nutrient media to allow it to further integrate into a single piece of tissue. Eventually the strands fully attach and fuse together.

The artificial cartilage produced by the team is very similar to native cow cartilage. However, the mechanical properties are inferior to those of natural cartilage, but better than the cartilage that is made using hydrogel scaffolding. Natural cartilage forms with pressure from the joints, and the researchers think that mechanical pressure on the artificial cartilage will improve the mechanical properties.

Link: http://news.psu.edu/story/415808/2016/06/27/research/3d-printing-produces-cartilage-strands-bioink

There are any number of ways to make mice live a little longer by slowing the accumulation of cell and tissue damage that causes age-related degeneration. Processes such as the cellular repair mechanisms of autophagy, for example, influence life span, and anything that causes a little damage so as to provoke greater levels of repair tends to make shorter-lived species like mice live somewhat longer. Since all of the mechanisms of cellular metabolism influence one another directly or indirectly, there are countless ways to increase the level of cellular housekeeping. This is true of any of the other processes thought to influence life span in a similar way, but the value in this approach to aging is an open question. Life spans have evolved to be much more plastic in response to circumstances in short-lived animals; the same methods do not produce the same length of life extension when practiced by long-lived mammals such as we humans. Calorie restriction is perhaps the best example of this point. It can extend life in mice by up to 40% or so, but certainly isn't capable of that feat in our species.

Today I'll point out an open access paper in which the authors provide evidence to show that alkaline water intake at pH 8.5 over the long term very slightly slows aging in mice - it is a tiny effect. This is not a methodology I had heard of, though there are a few papers out there on the intermittent use of alkaline water as a treatment for conditions in which the stomach produces too much acid, as well as exploring the effects of long-term alkaline water intake on rats at pH 11 to 12. A year of water at that alkalinity led to rats that were smaller and less healthy for reasons that remain unclear; the researchers concluded that "long-term exposure to alkaline drinking water seems to have profound systemic effects manifested as significant growth retardation, as a result of mechanisms that require further studies." However, there are other studies suggesting beneficial effects of various sorts, perhaps through a positive impact on levels of oxidative stress or fundamental cell mechanisms relating to growth. There is also, it seems, a thriving snake oil community happy to tell you that drinking alkaline water or eating a more alkaline diet will cure all ills.

It seems a fair wager that life is extended very slightly in mice via long-term alkaline water intake through hormesis. The alkalinity causes a little damage that produces increased cellular maintenance activity for a net benefit. The rats were exposed to greater alkalinity, so these results may well be points on the standard dose-response curve for a damaging substance. Alternatively, since the authors don't seem to have controlled for calorie intake, and alkaline water is claimed by some authors to negatively impact the apparatus of digestion, the result may also be a consequence of mild calorie restriction. There is enough uncertainty to propose other possible mechanisms, but to my eyes this is an excellent example of research that is interesting to pick apart while being no real value to our community.

Alkaline Water and Longevity: A Murine Study

The biological effect of alkaline water consumption is object of controversy. Alkaline and electrolyzed water have been shown to exert a suppressive effect on free radical levels in living organisms, thereby resulting in disease prevention. Various biological effects, such as antidiabetic and antioxidant actions, DNA protecting effects, and growth-stimulation activities, were documented. Although a variety of bioactive functions have been reported, the effect of alkaline water on lifespan and longevity in vivo is still unknown. Animal alkalization has been shown to be well tolerated and to increase tumor response to metronomic chemotherapy as well the quality of life in pets with advanced cancer. Therefore, we performed a study based on survival rate experiments, which play central role in aging research and are generally performed to evaluate whether specific interventions may alter the aging process and lifespan in animal models. The present paper presents a 3-year survival study on a population of 150 mice, and the data were analyzed with accelerated failure time (AFT) model.

The experiment consisted in an initial 15-day acclimatization period. After acclimatization, animals (50, group A) were watered with alkaline water at pH 8.5, obtained by a water ionizer, whereas group B animals (50) were watered with water alkalized at pH 8.5 by a concentrated alkaline solution for 15 days. Group C animals (50), control group, were watered with the local water supply at pH 6-6.5. This period has been identified to gradually accustom the animals treated with alkaline water. At the end of the second period of acclimatization, group A and B animals were watered with alkaline water at pH 9.5, while animals of group C were watered with local tap water. After the first year, the most aggressive individuals were moved to other cages within the same group and an environmental enrichment protocol was employed in order to decrease the hyperactivity. This phenomenon was observed especially in animals of groups A and B.

The results provide an informative and quantitative summary of survival data as a function of watering with alkaline water on long-lived mouse models. Starting from the second year of life, mice watered with alkaline water showed a better survival than control mice. Histological examination of mice kidneys, intestines, hearts, livers, and brains was performed in order to verify the risk of diseases correlated to alkaline watering. No significant differences emerged among the three groups. No significant damage, but aging changes, emerged; organs of alkaline watered animals resulted to be quite superimposable to controls, shedding a further light in the debate on alkaline water consumption in humans.

Using a mouse model of Parkinson's disease, researchers here demonstrate that an enzyme called c-Abl is associated with the accumulation of misfolded and toxic α-synuclein that is involved in the progression of this degenerative condition. They manage to halt the progression of Parkinson's symptoms, which is a promising sign when accompanied by supporting evidence to the degree it is here:

Researchers say they have gleaned two important new clues in the fight against Parkinson's disease: that blocking an c-Abl prevents the disease in specially bred mice, and that a chemical tag on a second protein may signal the disorder's presence and progression. Autopsies have revealed that c-Abl is especially active in the brains of people with Parkinson's disease, a progressive disorder of the nervous system that affects movement. Additionally, studies in mice bred to be prone to the disease found drugs that block c-Abl may prevent or slow it. But, the drugs used in those studies could also have been blocking similar proteins, so it wasn't clear that blocking c-Abl was what benefited the animals by either preventing symptoms or influencing disease progression.

The researchers' new experiments started with mice genetically engineered to develop the disease and knocked out the gene for c-Abl, a move that reduced their disease symptoms. Conversely, genetically dialing up the amount of c-Abl the mice produced worsened symptoms and hastened the disease's progression. Increasing c-Abl production also caused normal mice to develop Parkinson's disease. To learn more about how that happened, the team took a look at how c-Abl interacts with another protein, α-synuclein. It's long been known that clumps of α-synuclein in the brain are a hallmark of Parkinson's. The researchers found that c-Abl adds a molecule called a phosphate group to a specific place on α-synuclein, and that increasing levels of c-Abl drove more α-synuclein clumping along with worsening symptoms. "We plan to look into whether α-synuclein with a phosphate group on the spot c-Abl targets could serve as a measure of Parkinson's disease severity." No such objective, biochemical measurement exists now, which hampers studies of potential therapies for the disease.

Link: http://www.hopkinsmedicine.org/news/media/releases/blocking_key_enzyme_halts_parkinsons_disease_symptoms_in_mice

You might find this interview interesting. It is illustrative of the views of many in the industry, with the primary focus being on continued exploration of the molecular biochemistry of aging in order to identify drug targets and drug candidates in the traditional way, rather than the SENS rejuvenation approach of taking what is already known and implementing repair methodologies for the existing catalog of fundamental cell and tissue damage that causes aging.

Age is the single most important risk factor for major diseases, normally associated with aging. There's been a tremendous progress in understanding molecular biology of characterization and even controlling aging in the labs. Lifespans of model animals were increased up to an order of magnitude in some species and some of the research is being translated into future therapies. Last year researchers conducted clinical trials of rapalogs, their proprietary analogs of probably one of the best known life-extending compounds, rapamycin, in elderly cohorts, and showed a reverse in age-related decline of immune function. In another major development, the FDA approved a clinical protocol for TAME (Targeting Aging with Metformin) study, the first-ever study design aimed to test a therapy against aging endpoints. This year at BIO International Convention we organized a panel of distinguished experts, including a VC (venture capitalist), a biotech, a pharma, and public health representatives. We discussed the business opportunities created by the aging research, and the financial, regulatory and larger policy and public perception issues around the subject.

I believe that the most important challenges researchers face when developing anti-aging drugs are still of a technological nature. We need to understand the biology of aging better first. To do that, we developed a theoretical model, linking gene expression networks stability and aging. That model allows us to identify novel biomarkers, patterns of aging process, as well as targets for therapeutic interventions. Some areas of the research have already produced translatable products. As the nature of the research in the field changes towards practical applications, so do the funding and development requirements. That's why we discussed possible business models, the solutions of the fund-raising and regulatory problems.

Interestingly, there are only a few companies and thinkers are trying to address aging as the core problem. Most are concerned with understanding and treatments of specific diseases. It is hence possible, that the emergent longevity companies will have to tackle the diseases of age, one by one, following existing regulatory paths. Another possibility would be to classify aging as a disease itself and introduce robust and cost-effective clinical trials design to accelerate and focus the development. Should the technological and regulatory issues be resolved, the panel experts agree, the funding would go (and is already going at increasing pace!) right into the sector growth fuel. The business opportunities for a successful product against aging are very clear. The population of the developed world grows, and the burden of the diseases of age puts increasing pressure on public health system. There is, undoubtedly, enormous money to be saved for the both customers and the society, and, hence, to be earned by the longevity solutions providers.

Link: http://www.dddmag.com/article/2016/06/searching-perfect-anti-aging-drug

Is aging a disease? The answer to that question really only matters to the degree that it can be used to bring funding into the better portions of aging research, those focused on treating aging as a medical condition. All age-related disease is caused by aging. If we want longer lives that are less troubled by disability and frailty, then aging itself, its causes, must be the target for therapies, not its results. It is a very real problem that this is still a radical statement for much of the research and funding communities. It is a very real problem that the research community is still fighting regulators to have the treatment of aging acknowledged as a legitimate, permitted goal.

Then, on top of this, as is pointed out in the article below, aging research remains the poor relative within the broader medical research community. Efforts to treat specific age-related diseases receive near all of the attention and funding, and this almost always means tinkering with proximate causes and disease state mechanisms with very little in the way of efforts to address root causes. This is why such work rarely produces more than incremental improvements: keeping a damaged machine running without actually repairing the damage is a very challenging proposition. Researchers focused on the biochemistry of aging, and on ways to address damage and change, receive little funding and attention in comparison to the mainstream focus on specific diseases. This is the case even as years of small-scale philanthropic efforts have managed to both raise the profile of aging research, and push a few lines of research to the point at which meaningful results in the treatment of aging can be demonstrated in animal studies.

Should we treat aging as a disease?

"The fundamental questions of whether aging can and should be classified as a disease are not new, but today they are more pressing than ever for many reasons." Gerontology, the study of old age, spans multiple academic fields from economics to social sciences. Biogerontology specifically focuses on those biological process that contribute to aging, as well as the ultimate effects of aging on our health. Insights from biogerontology studies will contribute to public and private medical research, influencing our societal values, and guide policy makers in their decisions. "The main problems in biogerontology are similar to those in drug discovery for most human diseases, but with fewer resources, less visibility and less of a sense of urgency".

To bring into focus aging as a disease, researchers are looking to the future, and the 2018 release of the WHO-curated ICD-11. The ICD (International Classification of Diseases) is an extensive piece of work used at all levels of healthcare management: from physicians to patient organizations, from insurers to policy makers. Via the assignment of codes to disease, it helps countries to direct and reimburse research efforts. "There is an urgent need to proactively develop actionable codes for age-related muscle wasting, many conditions related to cognitive decline, decline of the metabolic system, loss of regenerative capacity and even skin and hair pathologies."

The fundamental questions of whether aging can and should be classified as a disease are not new, but today they are more pressing than ever for many reasons. Recent technological advances in many areas of technology allow for detailed analyses of the progression of aging and the development of epigenetic, transcriptomic, biochemical and imaging biomarkers. Both animal and human data suggest that effective interventions can be developed to extend longevity and prevent the onset of various age-related diseases. There is a clear business case to be made to healthcare providers, pharmaceutical and insurance companies and, most importantly, policy makers, funding bodies and scientists. Research into aging processes and related diseases to identify specific and actionable markers and targets is scarce.

It isn't just a matter of throwing money at the problem and making regulators acknowledge aging as a legitimate therapeutic target. Funding has to go to the right programs. The bulk of aging research programs can easily absorb decades and billions, but will achieve nothing but additions to the knowledge of human cellular metabolism. New sources of funding have a way of being sidetracked into these programs when they enter the field, and so wind up achieving little of practical use. Their funds go towards expanding the grand map of metabolism, and little else. This was the fate of Larry Ellison's funding, of much of Paul Glenn's funding, of the hundreds of millions in for-profit funding provided to Sirtris Pharmaceuticals and related sirtuin research, and so far looks likely to be the way that Google's Calico venture will ultimately go.

Meaningful progress towards the treatment of aging as a medical condition will not come from traditional approaches to drug development that focus on alter the operation of metabolism to as to modestly slow aging. Yet this is the vast majority of the field in a nutshell. There is overall little funding and attention, and the work that does take place is mostly futile: expensive ways to produce at best minuscule outcomes. Scientists who are working on more useful lines of research that involve repair and reversal of the root causes of aging, such as senescent cell clearance, will eventually win out as their low levels of funding produce results in animal studies and then human trials that are better and more robust than those of the current and future slow-aging drug candidates. But, my, it is a slow and painful process to watch in action. Disruption in the sciences requires philanthropy, and when regulation and the mainstream are determinedly focused on other goals for medicine, it is taking quite some time to get the job done.

This is why it is important for us to help, and why it is possible for people of average means to make a real difference when we act together. We can fund the research that lights the way, that will prove that the best paths forward towards treatments for aging are in fact the best paths, beyond argument. Then the rest of the world will, finally, follow the signs we hold up and take over the rest of the work.

Nicotinamide mononucleotide (NMN) is one of a small number of molecules that might very modestly slow some of the effects of aging, based on a few initial results from animal studies. Recently, news has emerged of a forthcoming small trial in humans to be conducted by the Japanese research community. NMN is a precursor to nicotinamide adenine dinucleotide (NAD), important in mitochondrial function, which is in turn important in the progression of degenerative aging. At this point in time skepticism is the appropriate response, however, given the small amount of data for beneficial effects in animals and the past history of this sort of research, which typically starts with hype and ends with nothing of any use. Drugs to tinker with the operation of metabolism in order to modestly slow aging are in any case a bad use of time and effort when there are potential means of rejuvenation that might be developed instead, based on repair of the cell and tissue damage that causes aging. Thus, all in all, this news is of greatest interest for the insight it provides into changing opinions and support for the goal of treating aging in Japanese society:

Researchers plan to begin a joint clinical study in Japan to test the safety and effectiveness in humans of a compound that is gradually being proved to retard the aging process in animals, scientists have said. If approved, researchers plan to begin giving the compound - nicotinamide mononucleotide (see below) or NMN - to about 10 healthy people to confirm its safety. They will then examine whether NMN can improve functions of the human body. The clinical study is scheduled to begin as early as next month. The planned clinical study will use NMN by treating it as food. If it is found to be safe for humans and has any benefits, NMN will likely be distributed as a product similar to "food with functional claims."

Progress in the study of a substance believed to help slow the aging process may reduce medical and nursing-care expenses, according to specialists. How to prolong people's healthy life span is an important task for Japan's rapidly aging society. The study of the reportedly age-retarding substance may make it possible for elderly people to live their daily lives free of restrictions. Starting next fiscal year, the Japanese government will make full-fledged efforts to promote projects aimed at slowing the aging process, using a large amount of budgetary appropriations for this endeavor. The move is expected to promote research activities in this field of study.

Link: http://www.the-japan-news.com/news/article/0003030620

Laura Deming has worked with the SENS Research Foundation and others on the molecular biology of aging, and a few years back helped organize the Longevity Fund to invest in startups relevant to the treatment of aging as they emerged. Here is a short interview in which she gives her view of the state of the field in fairly general terms:

Solana: It seems like there's significant resistance to the idea that we don't have to die. Why is that?

Deming: That's an awesome question and one that I'm entirely unqualified to answer. I can give you a bit a background, just from spending most of my life talking to a lot of people who think this is a really terrible idea, and trying to understand why they think that. For the longest time, I think people had been promised these amazing snake oil-like cures, "we're going to make you live forever." "This will make you live longer." And so, I think maybe part of the large inability to believe in this space comes from a history of it being impossible to work on. But if you look at the science, it would only have been possible to work on it recently as a point of fact. And then I think another part of it comes from folks having a large inability to believe that it works, and therefore, in their minds, not allowing themselves to hope for the possibility of living a longer time.

Solana: Who's working to extend longevity? Who's best at it right now? Who's poised to be better at it in the near future?

Deming: There are a couple of very high-profile efforts in this space, that have a lot of funding and public attention. One, of course, is Calico, funded in part by Google. And the other is Human Longevity, Inc., from Craig Venter. What I think a lot of people kind of overlook is that there are hundreds of companies doing interesting research in aging, some subset of which may be successful in a clinic, but are in the early stages of development. These are a lot of companies that have a drug that's a lead candidate, they know what they're targeting, they're about a year away from getting it to people, but they're pre-proof of concept. And so, I think that's the interesting area to watch. It's really difficult to say right now what the interesting companies and that cohort will be, but there are a lot of them that have very solid science.

Solana: Where are we going in the next 10 or 20 years with longevity science?

Deming: I think it's an interesting mix of two different tracks. One is the area of using traditional methods of pharmaceuticals to develop drugs for the genes that we know extend life in mice. There are lots of companies working on drugs that do basically that, but could be used for humans and are going into clinical trials soon, or are in clinical trials currently. But I think, in general, biology has a kind of underlying problem in that it's a very complicated science that's thought of in very linear terms in the drug world. So you have this kind of first-generation, very linear approach of using what we have to do what we can. But then you have kind of the second wave of work trying to figure out how biology actually works and how you can actually talk about these very complex systems in ways that are amenable to human intervention. And that's a process that - we don't know how long it will take to get useful, actionable information out of, but - I think that's where you're going to see a lot of the very long-term increases in lifespan.

Solana: Last question: what about rejuvenation?

Deming: I'd say 50% of the stuff we see is just preventative, and 50% is taking an old thing and trying to make it younger. And I think it's much more difficult to do that, but you're going to see at least a couple therapies in that regard coming along.

Link: http://foundersfund.com/2016/06/longevity-inc/

I should preface this short discussion by saying that I'm scarcely cut out to be raising a venture capital fund to target investments in SENS rejuvenation research companies and other useful ventures likely to help produce effective treatments for aging - ways to extend healthy life and defeat age-related disease. To assemble a venture fund requires superb connections to start with, and then successfully running said fund after you've persuaded people to put tens of millions of dollars into your care requires a whole set of other skills and experience that I lack, and in truth have no great interest in acquiring. You might look at the venture capital aptitude test for an only slightly exaggerated way to assess your own suitability for this line of work.

There are venture capitalists out there today raising funds for longevity-related investments in biotechnology and medical development, however. This is a natural consequence of deep pockets like Google and Abbvie becoming involved in the field, as well as the large sums of money being invested in ventures like Human Longevity Inc. Ironically, Human Longevity is actually a well-dressed personalized medicine company, with little to do with the enhanced longevity the principals talk about, but appearance counts for a lot in the calculations being made behind the scenes. Where there are deep pockets, there are potential acquirers for new companies, and so the nascent field of treating aging has become much more attractive as a place to start new companies. Combine that with growing awareness of the state of the science, very much on the verge and ready to deliver new technologies at a steady pace in the years ahead, and it explains the interest new seen in portions of the venture capital community.

If I were going to raise a fund to profit from the first decade of the SENS rejuvenation biotechnology industry, small but soon to grow, it would be under terms that earmarked 10% or so of capital for funding research. Let us say - to simplify greatly - that venture funds have a lifetime of seven to ten years before they dissolve and return gains or losses to the investors. A successful biotechnology company focused on a single class of therapies, starting out with a working technology fresh from the labs, may run five years from start to acquisition, or to going public, though that second option has lost its popularity these days. Either of those endpoints would close out the participation of a fund invested in that company: the fund owners would count their profits at that point. These timelines allow a venture fund with capital earmarked for research to selectively make non-profit donations to fund research groups in the first couple of years of its existence. The idea in doing so is to establish strong relationships with those groups working on technologies that are plausibly quite close to the point at which a demonstration can be made, a drug candidate established, or other suitable point to launch a startup is reached, and then push that research across the finish line. At that point, the fund then invests in the resulting startup.

Venture funds make all of their profits from the very few outstanding successes they invest in. They lose money on more than half of their investments, and manage only a small profit on most of the rest. This is why venture capitalists behave in the way they do: they need to nurture companies that swing for the fences so as to become enormous successes if they do succeed. If you have a great idea for a sustainable business that cannot achieve this goal, and flattens out at merely large and successful, then that business is not the right fit for venture funding. Given this distribution of gains from venture investment, I suspect that a fund could earmark considerably more than 10% of its capital for research and still do very well by the method I outline above. You still have to sell this earmark to the people who will be investing in your fund, however, and they will probably require some convincing as the number grows.

I should emphasize that good venture capitalists provide a lot of aid to their portfolio companies. They are far from being just a source of money. The idea of using a portion of the fund to advance the necessary state of the science so as to create startups to invest in, and becoming very familiar with the research community as this takes place, is really just an acknowledgement that the process of development and creation of wealth doesn't start at the point at which a company is incorporated. That is quite some way down the line from the true starting point. If venture funds can aid and nurture growth companies, they can also reach further back down the development pipeline to aid and nurture research groups.

One of the reasons that this strategy isn't seen in the wild is, I suspect, that it is in fact very hard to gather the right connections and knowledge to pick winners in the laboratory. The present situation for SENS rejuvenation research may be quite uncommon, in that there are (a) numerous lines of work that are not heavily funded, but that should yield a large number of good approaches to therapies if completed, and (b) knowledge and connections in the SENS Research Foundation and the surrounding community sufficient to identify these opportunities. Further, the approach of creating startups by funding research probably doesn't scale very well from the point of view of a fund organization, in that the fund would have to make a comparatively large number of investments in research and seed level rounds in order to generate the opportunity for a smaller number of larger and later round investments. For a fund of tens of millions of dollars, this is not a problem, but this is not a strategy that much larger funds could adopt given the way they are currently staffed and organized. There are only so many hours in the day, and there are only so many opportunities for smaller investments; you can't fit a whale into a fish tank.

Still, this is, I think, something well worth considering as our community moves forward and venture capitalists join our ranks. We have this opportunity, possibly uncommon, to reach back past the point at which companies start, to build hybrids of venture funds and research institutes focused on the most promising biotechnologies of rejuvenation and longevity. It would be a shame to let it go to waste.

Researchers are attempting to understand the biochemistry of limb and organ regeneration, exceptional cancer resistance, and hibernation in a number of species in order to see whether they can form the basis for therapies or enhancements in humans. Here, hibernation is the focus:

Novel adaptations discovered in hibernating animals may reveal ways to mitigate injuries associated with strokes, heart attacks and organ transplants. A person typically takes a long time to recover from cardiac surgery or organ transplant. This is in part because organ tissue is damaged when blood flow ceases or is reduced when a heart stops or an organ is removed. Tissue is also damaged when blood flow is restored and the body's metabolic machinery is not able to safely handle the returning rush of oxygenated blood. Protection of tissues following cardiac arrest or organ transplant has remained an elusive scientific target, despite significant research and promising data.

In 2009, researchers began collaborating to identify how a hibernating Arctic ground squirrel's heart can survive what is akin to repeated cardiac arrests. Unlike other animals, Arctic ground squirrels can lower their metabolism to 2 percent of their normal rate, which allows them to essentially shut down bodily functions they don't need and, importantly, puts their organs in a state of suspended animation. The researchers collected and analyzed proteins associated with heart muscle from cooled, hibernating Arctic ground squirrels in which blood flow had been stopped. They repeated the analyses on heart proteins from active summer Arctic ground squirrels and rats, which don't hibernate.

By comparing the various proteins produced and the metabolic changes within each animal, they identified novel internal adaptive mechanisms by which ground squirrels cope with cold and other stressors and how those mechanisms relate to blood flow problems associated with cardiac surgery. One such mechanism is the ability of hibernators to exclusively use lipids, which include fats, vitamins and hormones, as metabolic fuel instead of burning carbohydrates, as humans do during surgeries. Understanding this unique model of extreme metabolic flexibility may help scientists develop strategies that enable doctors to "switch" the metabolism of a patient who has suffered a stroke, cardiac injury or hypothermia to resemble that of a hibernator and thereby improve survival and recovery. The authors anticipate that the knowledge gained from this study could be applied to organ protection in nonhibernators and ultimately in patients undergoing heart surgery and transplantation, and for victims of cardiac arrest, trauma and hypothermia.

Link: https://www.iab.uaf.edu/news/news_release_by_id.php?release_id=135

Cognitive decline with aging is a patchwork of scores of progressive failures in different systems in the brain, all proceeding at their own pace. The research noted here is a good example of the way in which researchers try to pick apart the whole into comprehensible pieces, a necessary part of the much lengthier process of mapping specific declines to specific damage and change in the brain:

Staying on topic may be more difficult for older adults than it is for younger people because older adults begin to experience a decline in what is known as inhibition - the ability to inhibit other thoughts in order to pursue the storyline. Evidence for inhibition deficits in older adults has appeared in studies that task participants with completing a familiar phrase with an unfamiliar word. For example, when asked to complete out loud the sentence "I take my coffee milk and ..." with the word "pajamas" instead of "sugar," older adults are more likely to first respond with "sugar" than young participants because they have a harder time inhibiting the high-probability word to complete the sentence. Decline in inhibition also can affect visual perception, as is demonstrated by new research. Inhibition is an important part of neural processing throughout the brain, and it plays a significant role in visual perception. For example, evidence suggests that when we look at an object or a scene, our brain unconsciously considers alternative possibilities. These competing alternatives inhibit one another, with the brain effectively weeding out the competition before perceiving what is there. With regard to vision, age-related declines in the efficiency of inhibitory processes have been demonstrated in research involving simple perception tasks, such as the ability to detect symmetry and discriminate between shapes.

In this study, the researchers were interested specifically in what is known as figure-ground perception, in which two areas in a person's visual field share a border. If you imagine a white heart on a black background, for example, the heart is the "figure" - with its definitive shape - and the black background is the "ground," which seems to simply continue behind the figure. In the lab, researchers showed on a screen a series of small, symmetrical white-on-black silhouettes to two different groups: young participants with an average age of about 20 and older participants with an average age of about 66. Participants were asked to determine whether each white "figure" depicted a familiar object, such as an apple, or a novel object - a meaningless shape.

"For a long time my students and I have been investigating how we see the world. Our work has suggested that the brain first detects all the borders in a scene and then for every border, accesses object properties - essentially different interpretations - on both sides. These two interpretations compete by inhibiting each other, and whichever one has more evidence in favor of it is going to exert more inhibition on the other one to win the competition." In the end, younger and older participants both came to the same conclusions about whether the white objects were familiar. However, it took longer overall for older adults to come to that conclusion, especially when images presented more inhibitory competition. The findings support and further evidence that older adults experience age-related deficits in inhibition related to vision.

Link: https://uanews.arizona.edu/story/research-shows-how-visual-perception-slows-age

Rejuvenation Biotechnology 2016 is the latest in a series of conferences hosted by the SENS Research Foundation, focused on bringing together industry and academia to pave the way for the advent of first generation rejuvenation therapies. The first of these therapies are already in clinical development, each narrowly focused on one cause of aging, such as senescent cell clearance at Oisin Biotechnologies and some of the SENS Research Foundation's own drug candidates for breaking down damaging metabolic waste at Human Rejuvenation Technologies. There are numerous other examples I could give, for either work based on the SENS vision of controlling aging through repair of cell and tissue damage, or other initiatives with less ambitious goals. If all goes well, they will be available in clinics outside the US within a few years, and have passed through the regulatory system inside the US at most a decade from now.

Building a whole new field of medicine and getting it into the clinic doesn't just magically occur, however. This is a big deal, and requires allies, advocacy, setting expectations, and either pulling in the heavyweight support of Big Pharma or creating an entirely new network of distribution and validation akin to the medical tourism industry for stem cell therapies. Laying these foundations for the work that lies ahead is one of the goals of the Rejuvenation Biotechnology conferences. You can look back in the Fight Aging! archives to read about the 2014 and 2015 conferences; well attended and well spoken of. You might take a look at this year's program for a sense of how the theme will follow on from prior years. Rejuvenation Biotechnology 2016 is being held at the Buck Institute for Research on Aging just North of the Bay Area, California. It is invitation only, I'm afraid - the wages of success and popularity - so if you feel the need to attend, you should contact the SENS Research Foundation folk and ask. The conference will be streamed live this year, however, so no-one need miss out.

Rejuvenation Biotechnology 2016, August 16-17

World populations are aging, and the social and economic burdens of age-related disease are rising steeply. For an increasing number of elderly individuals, healthcare is too often reduced to crisis management in the emergency room, painfully harsh treatments for diseases such as cancer, or best efforts at palliative care.

SENS Research Foundation exists to end aging. Since 2009 we have worked to make the concept of rejuvenation biotechnology - the repairing of the damage which occurs to our bodies as we age - into a reality. Our research, education and awareness programs have created the foundations of the Rejuvenation Biotechnology Industry, an industry that will be capable of targeting the diseases of aging with genuine, effective, affordable cures.

The 2016 Rejuvenation Biotechnology Conference is focused on taking the Rejuvenation Biotechnology Industry to the next level by addressing the question: what will it take to push emerging breakthroughs in regenerative medicine from proof-of-concept to implementation? This year's conference seeks to answer this critical inquiry by covering all the stages from securing funding, to production, to navigating regulation, to clinical evaluation and adoption of new treatments. Industry-leading experts will present real-life examples drawn from their own work followed by an open panel discussion and Q&A. As with our previous conferences, we provide ample time for networking with industry leaders, funders and researchers.

Due to our limited space the 2016 Rejuvenation Biotechnology Conference is an invitation-only event. In order for our entire community to be able to participate we will be live streaming the conference and everyone is invited to join us via the live stream. To stay in the loop for our live streaming, please register today.

Diabetes of any variety is a damaging distortion of normal metabolism. Once in progress, it causes further harm on an ongoing basis. The type 2 diabetes most often seen in older people is a lifestyle condition: the vast majority of cases are caused by being overweight, and can be reversed even at a late stage by adoption of a low-calorie diet and consequent weight loss. So when researchers note that being diabetic greatly increases heart attack risk, it is an interesting question as to the degree to which this is because patients are overweight, independently of diabetes, versus the degree to which it is due to the mechanisms of diabetes itself. Excess visceral fat tissue produces chronic inflammation, and inflammation speeds the development of all of the common age-related conditions, but here the data suggests that weight should also be given to processes and damage specific to diabetes itself.

Having diabetes increases the risk of dying from the effects of a heart attack by around 50 per cent, a study has found. Researchers tracked 700,000 people who had been admitted to hospital with a heart attack between January 2003 and June 2013. Of these, 121,000 had diabetes. After stripping out the effects of age, sex, any other illnesses and differences in the emergency medical treatment received, the team found stark differences in survival rates. People with diabetes were 56 per cent more likely to have died if they had experienced a ST elevation myocardial infarction (STEMI) heart attack - in which the coronary artery is completely blocked - than those without the condition. They were 39 per cent more likely to have died if they had a non-ST elevation myocardial infarction (NSTEMI) heart attack - in which the artery is partially blocked - than those without diabetes.

"We knew that following a heart attack, you are less likely to survive if you also have diabetes. However, we did not know if this observation was due to having diabetes or having other conditions which are commonly seen in people with diabetes. This paper is the first to conclusively show that the adverse effect on survival is linked to having diabetes, rather than other conditions people with diabetes may suffer from. These results provide robust evidence that diabetes is a significant long-term population burden among patients who have had a heart attack. Although these days people are more likely than ever to survive a heart attack, we need to place greater focus on the long-term effects of diabetes in heart attack survivors."

Link: https://www.leeds.ac.uk/news/article/3879/diabetes_raises_risk_of_heart_attack_death_by_50_per_cent

Sarcopenia is the name given to progressive age-related loss of muscle mass and strength. Here one possible contributing cause of the condition is explored: reduced levels of a protein involved in the quality control of mitochondria, which may allow damaged mitochondria to accumulate more readily in muscle tissue. Researchers have been lobbying for a decade to have sarcopenia formally defined as a medical condition, but that hasn't yet come to pass. The causes of sarcopenia are still debated; there are many possible contributions with plausible supporting evidence, but it isn't at all clear as to how they interact or which are the most important. Researchers have suggested fat tissue infiltration into muscles, the lack of exercise prevalent in older populations, rising levels of inflammation, failing leucine metabolism, vascular aging in muscles, Wnt signaling changes, and declining activity in muscle stem cells, among others. Interventions that slow aging, such as calorie restriction, also tend to slow the progression of sarcopenia, but beyond that and exercise there isn't yet much that can be done about this condition.

At about 55 years old, people begin to lose muscle mass, this loss continues into old age, at which point it becomes critical. The underlying causes of sarcopenia are unknown and thus no treatment is available for this condition. A study has discovered that Mitofusin 2 is required to preserve healthy muscles in mice. These researchers indicate that this protein could serve as a therapeutic target to ameliorate sarcopenia in the elderly, observing that during aging mice specifically lose the expression of Mitofusin 2 in muscle. They demonstrate that low activity of this protein in 24-month old mice (the equivalent of a person aged 80) is directly associated with muscle wastage and the sarcopenia observed. The scientists confirm the link between the loss of Mitofusin 2 and muscle aging when the expression of the protein is suppressed in the muscles of 6-month-old animals (equivalent to a person of 30) as these animals showed accelerated aging, reproducing the muscle conditions of aged mice.

"Over five years we have collected sufficiently significant evidence that demonstrates the contribution of Mitofusin 2 to the maintenance of good muscle health in mice and that allows us to consider a therapeutic strategy for sarcopenia. Sarcopenia is not a minor issue because it impedes some elderly people from going about their everyday lives. If we want to boost the health of the elderly then this problem has to be addressed." The researchers are running a study in collaboration with physicians working in geriatric medicine to demonstrate that Mitofusin 2 is also repressed in human aging. In addition, this group also has the technology ready to search for pharmacological agents capable of boosting Mitofusin 2 activity.

Mitofusin 2 is a mitochondrial protein involved in ensuring the correct function of mitochondria, and it has several activities related to autophagy, a crucial process for the removal of damaged mitochondria. The loss of Mitofusin 2 impedes the correct function of mitochondrial recycling and consequently damaged mitochondria accumulate in muscle cells. The researchers have also identified and described an autophagy rescue system which kicks in regardless of Mitofusin 2 levels and allows cells to partially recover the mitochondrial recycling system in skeletal muscle. The scientists suggest that this could serve as an alternative metabolic mechanism used by Mitofusin to increase skeletal muscle autophagy and to maintain a healthier mitochondrial system.

Link: http://www.irbbarcelona.org/en/news/the-absence-of-a-single-protein-spurs-muscle-aging-in-mice

Keith Comito leads the volunteers of the non-profit Life Extension Advocacy Foundation (LEAF) and the crowdfunding initiative Lifespan.io, a site I'm sure you've seen at least in passing by now. The LEAF crew have put in a lot of effort to help make fundraisers for rejuvenation research projects a success both last year and this year. Two such crowdfunding campaigns are running right now, firstly senolytic drug research at the Major Mouse Testing Program with just a few days left to go, and in its stretch goals, and secondly the recently launched drug discovery for ALT cancers at the SENS Research Foundation. Both tie in to the SENS portfolio of research programs aimed at effective treatment of aging and all age-related conditions. These are large projects when taken as a whole, but the way forward in this as in all things is to pick out smaller, achievable goals, and set out to get them done. Then repeat as necessary.

I recently had the chance to ask Keith Comito a few questions about Lifespan.io, the state of funding for the interesting end of longevity science, and what he envisages for the years ahead. This is an interesting, revolutionary time for the life sciences, in which progress in biotechnology has made early stage research very cheap. A great deal can be accomplished at the cutting edge of medical science given access to an established lab, administrators who can break out small initiatives from the larger goals, smart young researchers, and a few tens of thousands of dollars. It is an age in which we can all help to advance the research we care about, by collaborating and donating, and it has never been easier to just reach out and talk to the scientists involved. If you haven't taken a look at Lifespan.io and donated to one of the projects there, then you really should. This is a way to move the needle on aging research, and advance that much closer to effective treatments for the causes of aging.

What is the Lifespan.io story in brief? What was the spur that made you come together and decide to do your part in the fight against aging?

Lifespan.io began to take shape at the tail end of 2012, as a result of a loose discussion group based in New York which consisted of citizen scientists such as myself and Dr. Oliver Medvedik, supporters of SENS, as well as a few healthcare practitioners. We began having monthly meetings to discuss what could be done to accelerate longevity research (usually in oddball locations like salad bars or subterranean Japanese restaurants befitting our motley crew) and eventually hit upon the idea of crowdfunding. What drew us to this idea was that it was something tangible: a concrete way to move the needle on important research not only through funds, but through raised awareness. It is fine to talk and rabble-rouse about longevity, but we felt such efforts would be much more effective if they were paired with a clear and consistent call to action - a path to walk the walk, so to speak. As this idea coalesced we formed the nonprofit LEAF to support this initiative, and the rest is history. Not every one from the initial discussions in 2012 remained throughout the intervening years, but we are thankful to all who gave us ideas in those early days of the movement.

I'd like to hear your take on why we have to advocate and raise funds at all - why the whole world isn't rising up in support of treatments for the causes of aging.

The reasons why people and society at large have not prioritized anti-aging research thus far are myriad: fear of radical change, a history of failed attempts making it seem like a fools errand, long timescales making it a difficult issue for election-focused politicians to support, etc. The reason I find most personally interesting relates to cognitive bias - specifically the fact that our built-in mental hardware is ill-equipped to handle questions like "do you want to live 100 more years?" If instead you ask the questions "Do you want to be alive tomorrow?" and "Given that your health and that of your loved ones remains the same, do you suspect your answer to the first question will change tomorrow?", the answers tend to be more positive.

This leads me to conclude that the state of affairs is not necessarily as depressing for our cause as it might appear, and that reframing the issue of healthy life extension in a way that will inspire and unite the broader populace is possible. Aubrey de Grey has spoken about "Longevity Escape Velocity" in relation to the bootstrapping of biomedical research, but I think the same idea applies to the public perception of life extension as well. The sooner we can galvanize the public to support therapies that yield positive results the easier it will become to invite others to join in this great work. It is all about jump starting the positive feedback loop, and that is why we believe rallying the crowd behind critical research and trumpeting these successes publicly is so vitally important.

What the future plans for Lifespan.io and the Life Extension Advocacy Foundation?

In addition to scaling up our ability to run successful campaigns on Lifespan.io, we look forward to improving our infrastructure at LEAF by bringing on some staff members to join the team. LEAF has largely been a volunteer effort thus far, and having the support of a staff will allow us to take on more campaigns as well as further improve the workflow to create and promote them. This will also free me up personally to more actively pursue potential grand slams for the movement, such as collaborations with prominent YouTube science channels to engage the public and policy related goals like the inclusion of a more useful classification of aging in the ICD-11.

Do you have any favored areas in research at the moment? Is there any particular field for which you'd like to see researchers approaching you for collaboration?

Senolytics is certainly an exciting area of research right now (congratulations Major Mouse Testing Program!), and a combination of successful senolytics with stem cell therapies could be a potential game changer. That being said I'd also like to see projects which address the truly core mechanics of aging, such as how damage is aggregated during stem cell division, and the potential differences in this process between somatic and germ cells. How can the germ line renew itself for essentially infinity? The real mystery here is not that we grow old, but how we are born young.

A related question: where do you see aging and longevity research going over the next few years?

In the near future we will likely continue to see the pursuit of compounds which restore bodily systems failing with age to a more youthful state. This will include validating in higher organisms molecules that have shown this sort of promise: rapamycin, metformin, IL-33 for Alzheimer's, etc. This approach may sound incremental, but it actually signals a great paradigm shift from the old system of mostly ineffective "preventative measures" such as antioxidants. Things like nicotinamide mononucleotide (NMN), IL-33 - if successful these types of therapies can be applied when you are old, and help restore your bodily systems to youthful levels. That would be a pretty big deal.

Funding is ever the battle in the sciences, and especially for aging. Obviously you have strong opinions on this topic. How can we change this situation for the better?

I believe the key to greater funding, both from public and private sources, is to build up an authentic and powerful grassroots movement in support of healthy life extension. Not only can such a movement raise funds directly, but it also communicates to businesses and governments that this is an issue worth supporting. An instructive example to look at here is the work of Mary Lasker and Sydney Farber to bring about the "War on Cancer". Through galvanizing the public with efforts such as the "Jimmy Fund", they effected social and political change on the issue, and helped turn cancer from a pariah disease into a national priority. If we all work together to build an inclusive and action-orientated movement, we can do the same.

If the research community is to win in the fight to cure cancer, and win soon enough to matter for all of us, then the focus must be on technology platforms that can be easily and cheaply adapted to many different types of cancer. The biggest strategic problem in the field is that most of the expensive, time-consuming efforts to develop new therapies are only applicable to one or a few of the hundreds of types of cancer. Immunotherapies based on the use of chimeric antigen receptors are an incremental step towards solving this problem, an improvement on the present situation because this technology may cut the cost of tailoring an immunotherapy to each specific type of cancer. This approach has worked very well in trials targeting leukemia, but there was some question as to how to adapt it for use in solid tumors, and whether it would work in this context. Fortunately, it seems that this next step forward has now been accomplished, at least in a preliminary animal study:

Chimeric antigen receptor (CAR) T cell therapy, which edits a cancer patient's T cells to recognize their tumors, has successfully helped patients with aggressive blood cancers but has yet to show the ability to treat solid tumors. To overcome this hurdle, researchers genetically engineered human T cells to produce a CAR protein that recognizes a glycopeptide found on various cancer cells but not normal cells, and then demonstrated its effectiveness in mice with leukemia and pancreatic cancer. "This is the first approach using a patient's own immune cells that can specifically target this class of cancer-specific glycoantigens, and this has the great advantage of applicability to a broad range of cancers. Future cancer immunotherapies combining the targeting of cancer-specific carbohydrates and cancer proteins may lead to the development of incredibly effective and safe new therapies for patients."

T cells are collected from the patient's blood and genetically engineered to express cell-surface proteins called CARs, which recognize specific molecules found on the surface of cancer cells. The modified T cells are then infused into the patient's bloodstream, where they target and kill cancer cells. In recent clinical trials, CAR T cell therapy has dramatically improved the outcomes of blood cancer patients with advanced, otherwise untreatable forms of leukemia and lymphoma. But the full potential of CARs for treating solid tumors has not been reached because they have targeted molecules found on the surface of both normal cells and cancer cells, resulting in serious side effects.

The cancer cell marker the team identified was a specific change in protein glycosylation, that is, a unique pattern of sugars decorating a protein found on the cell surface. The researchers developed novel CAR T cells that express a monoclonal antibody called 5E5, which specifically recognizes a sugar modification - the Tn glycan on the mucin 1 (MUC1) protein - that is absent on normal cells but abundant specifically on cancer cells. The 5E5 antibody recognized multiple types of cancer cells, including leukemia, ovarian, breast, and pancreatic cancer cells, but not normal tissues. "This is really the first description of a CAR that can target multiple different solid or liquid tumors, without apparent toxicity to normal cells. While it may not be a universal CAR, it is currently the closest thing we have." Moreover, injection of 5E5 CAR T cells into mice with leukemia or pancreatic cancer reduced tumor growth and increased survival. All six mice with pancreatic cancer were still alive at the end of the experiment, 113 days after treatment with 5E5 CAR T cells. Meanwhile, only one-third of those treated with CAR T cells that did not target Tn-MUC1 survived until the end of the experiment.

Link: http://www.eurekalert.org/pub_releases/2016-06/cp-ctc061416.php

Researchers here link vascular calcification in aging with an accumulation of one of a number of related forms of undesirable metabolic waste. One of the root causes of degenerative aging is this accumulation of hardy forms of metabolic waste that our biochemistry either finds hard to break down, or simply cannot break down. This waste accumulates in cell lysosomes as a mix of compounds usually called lipofuscin or drusen, depending on the context. Lysosomes are the recycling plants of the cell, and this accumulation causes them to become dysfunctional, leading ultimately to some form of garbage catastrophe as cellular maintenance breaks down. The SENS Research Foundation is one of the few groups funding work to find ways to safely remove lipofuscin compounds, largely based on mining the bacterial world for enzymes that can be used as the basis for small molecule drugs. Once developed, clearing lipofuscin will be a form of rejuvenation therapy, removing one of the contributing causes of a number of age-related conditions.

One of the constituent compounds of liposfuscin is 7-ketocholesterol, which is known to contribute to macular degeneration as well as to various forms of damage to blood vessel walls, such as those that can lead to atherosclerosis. The SENS Research Foundation has had some success in finding candidates to digest 7-ketocholesterol, but this is still a work in progress. The research noted here provides yet another argument for the research community to invest more time and funding into finding ways to effectively break down these harmful lipofuscin constituents: vascular calcification contributes to the development of a range of ultimately fatal cardiovascular conditions.

Vascular calcification, characterized by the deposition of hydroxyapatite in cardiovascular tissue, is commonly observed in patients with diabetes mellitus, chronic kidney disease (CKD) and atherosclerosis. Several studies have indicated that the presence of calcification in coronary arteries correlates with an increased risk of myocardial infarction and is an independent predictor of future cardiovascular events in asymptomatic patients. Accordingly, treatment of vascular calcification is directly linked to decreased cardiovascular mortality. Recent findings suggest that the development of calcification is an active cell-regulated process similar to osteogenesis. Two pathological processes, osteoblastic differentiation and apoptosis of vascular smooth muscle cells (VSMCs), are mainly involved in the development of vascular calcification.

Recent studies have showed that oxidized low-density lipoprotein (oxLDL), enriched in atherosclerotic plaques, promotes osteoblastic differentiation and calcification of VSMCs. Oxysterols, such as 7-ketocholesterol (7-KC), are major components of oxLDL and are associated with its cytotoxicity. We have previously reported that 7-KC promotes osteoblastic differentiation and apoptosis of VSMCs, resulting in progression of calcification. However, whether the effects of 7-KC on calcification are related to autophagy is still unknown. Our aim was therefore to unravel the relationship between ALP and the progression of calcification by 7-KC.

The formation and accumulation of 7-KC often occur in lysosomes, and 7-KC promotes accumulation of unesterified cholesterol in the lysosome. Accumulation of cholesterol causes impairment of the lysosomal membrane, resulting in inhibition of the lysosome fusing with the autophagosome or endosome. Because 7-KC is also known to induce permeabilization of the lysosomal membrane, impairment of autophagy process by 7-KC may due to alteration of the lysosomal membrane potential. Subsequent to autophagy disruption, 7-KC causes the failure of lysosomal enzyme activity along with enlargement of lysosomes.

In our model, a high concentration of 7-KC caused further increase in calcification, and this exacerbation of calcification was closely related to apoptosis. In contrast, a low concentration of 7-KC accelerated calcification without apoptosis, and this acceleration of calcification was alleviated by inhibition of lysosomal-dysfunction-dependent oxidative stress. Recent studies have indicated that 7-KC induces the loss of mitochondrial transmembrane potential which is a marker of mitochondrial injury. Moreover, the decline of lysosomal function causes the defect of mitochondrial turnover, which induces the acceleration of reactive oxygen species (ROS) generation. These lysosomal-mitochondrial axes also induce the interaction between ROS generated from mitochondria and iron derived from lysosome, leading to the intralysosomal accumulation of more reactive ROS. In conclusion, we showed for the first time that 7-KC induces oxidative stress via lysosomal dysfunction, resulting in exacerbation of calcification.

Link: http://onlinelibrary.wiley.com/enhanced/doi/10.1111/gtc.12301

Quite a lot of research on exercise in the context of aging and age-related disease has been published in the past few months. More than usual, I think - not just a case of noticing because it is on my mind. Research moves in waves and cycles, just like all other human endeavors. Below you will find links to a selection of these items, those that caught my attention as they passed by.

Along with donating to the SENS Research Foundation and the practice of calorie restriction, regular moderate exercise is just about the best thing you can do for your long term health here and now. Both calorie restriction and exercise have been shown to slow aging to a modest degree in animal studies, and the human data is pretty compelling. It is fair to say that exercise produces greater benefits for a basically healthy individual than any presently available medical technology. It even produces better results than the available therapies for a number of age-related conditions. It is all a matter of degrees, however. That I can say this about exercise is less a glowing recommendation for working out and more a dismal review of medicine as it exists in clinical practice today. The research and development community can and will do better, and I don't think that exercise and calorie restriction will go unbeaten by therapies and enhancements for another decade at this point, but it is still frustrating to be in the midst of such a revolutionary period in life science research, yet to reap the harvest of that progress. We don't want medicine that just slows the inevitable a little, we want the inevitable defeated, removed, cured.

A sizable fraction of the aging research community is interested in mimicking the effects of calorie restriction on health and longevity, using drug discovery to find ways to tinker with the same switches in our biochemistry. The same is true of exercise, though researchers in that case are some years behind on the same path, with some catching up to do. While I'm definitely in favor of taking advantage of exercise, as it is here and it is free, and that is a cost-benefit equation hard to argue with, I'm much less enthusiastic about the panoply of approaches that aim to produce much the same outcome via drugs, some way to modestly slow the progression of degenerative aging by taking a pill or undergoing some form of enhancement such as gene therapy. I think the cost to achieve that goal though, for example, standard issue drug discovery and development is unfavorably high, given the very modest scope of the benefits expected to result. If that was all that could be done, then so be it, but it isn't. There are other alternatives, such as the SENS portfolio of research and development based on repair of the cell and tissue damage that causes aging, that have the potential to achieve rejuvenation rather than slowing of aging, and thus produce far greater benefits to health and longevity.

Exercise may have therapeutic potential for expediting muscle repair in older populations

For many mammals, including humans, the speed of muscle repair slows as they grow older, and it was once thought that complete repair could not be achieved after a certain age. This report shows, however, that after only eight weeks of exercise, old mice experienced faster muscle repair and regained more muscle mass than those of the same age that had not exercised. This is important, as it further highlights exercise's therapeutic potential. To make this discovery, researchers used three groups of mice: old mice that were exercise trained, old mice that were not exercise trained, and young mice that were not exercised trained. In the first group, old mice were trained three days/week for eight weeks. The effect of exercise in aging muscle was measured by comparing the three groups of mice. "This is a clean demonstration that the physiological and metabolic benefits of exercise radiate to skeletal muscle satellite cells, the adult stem cells responsible for repair after injury, even in senescent animals. Strikingly, even as the contractile elements of muscle tissue wane with age, the capacity of the satellite cells to respond to exercise cues is maintained. This aging-resistant retentive property could be added to the list of features that define adult stem cells."

Exercise associated with longer life in patients with heart failure

To conduct the study, the investigators identified 23 randomised trials of exercise that included at least 50 heart failure patients who were followed up for six months or longer. After asking the authors of all 23 studies for individual patient data, they received the information from 20 trials. The 20 trials included 4043 patients with heart failure. The investigators used the individual patient data to assess the impact of exercise on the time to all-cause mortality and first hospitalisation. The investigators found that exercise was associated with an 18% lower risk of all-cause mortality and an 11% reduced risk of hospitalisation compared with no exercise. "This analysis did in fact show that there is a mortality benefit from doing exercise. In other words, patients who exercised had a lower risk of death than those who didn't. Patients with heart failure should not be scared of exercise damaging them or killing them. The message for heart failure patients is clear. Exercise is good for you, it will make you feel better, and it could potentially make you live longer."

Run for Your Life: Exercise Protects against Cancer

Exercise may decrease cancer incidence and slow the growth rate of tumors. That's the conclusion of a mouse-based study, reporting that training mice regularly on a wheel decreased the growth of multiple types of tumors, including skin, liver, and lung cancers. Furthermore, mice that exercised regularly had a smaller chance of developing cancer in the first place. The beneficial effects of running went beyond tumor formation and growth, extending to cancer-associated weight loss, a process termed cachexia that is seen in cancer patients. Mice that exercised regularly showed no signs of cancer-associated weight loss in the researchers' lung cancer mouse model.

The researchers say they identified several factors behind the anti-tumor effects of exercise. These anti-cancer effects are linked to the release of adrenaline (also called epinephrine), a hormone that is central to the "fight-or-flight" response. Adrenaline production is known to be stimulated by exercise. The researchers say that, the production of adrenaline results in a mobilization of immune cells, specifically one type of immune cell called a Natural Killer (NK) cell, to patrol the body. These NK cells are recruited to the site of the tumor by the protein IL-6, secreted by active muscles. The NK cells can then infiltrate the tumor, slowing or completely preventing its growth. Importantly, the researchers note that injecting the mice with either adrenaline or IL-6 without the exercise proved insufficient to inhibit cancer development, underlining the importance of the effects derived only from regular exercise in the mice.

Midlife fitness is linked to lower stroke risks later in life

In a prospective observational study consisting of 19,815 adults ages 45 to 50, (79 percent men, 90 percent Caucasian) researchers measured participants' heart and lung exercise capacity and categorized them as having either a high, middle or low level of fitness. The study found that those with the highest level of fitness had a 37 percent lower risk of stroke after age 65, compared to their counterparts with the lowest level of fitness. This inverse relationship between fitness and stroke risks existed even after researchers considered stroke risk factors: high blood pressure, type 2 diabetes and atrial fibrillation. The study reinforces the benefits of being physically fit throughout life. "Low fitness is generally ignored as an actual risk factor in clinical practice. Our research suggests that low fitness in midlife is an additional risk to target and help prevent stroke later in life."

Besides living for nine times longer than other, similarly sized rodent species, naked mole rats are also highly resistant to cancer, to the point at which only a handful of cases have ever been observed. The scientific community is seeking the roots of this cancer resistance to see if the mechanisms involved can form the basis for human therapies. So far, research has centered on differences in the biochemistry of tumor suppressor gene p16, and hyaluronan, which may be responsible for activating p16 more aggressively in naked mole rats. Here, researchers identify another possibly relevant difference in mechanisms relating to the tumor suppressor gene ARF; in naked mole-rats, unlike other mammals, disabling this gene causes cells to halt replication and become senescent. This may act to close off a variety of mutational paths to cancer, changes that will spawn tumors in mice, but not in naked mole rats.

The research team took skin fibroblast tissue from adult naked mole-rats and reprogrammed the cells to revert to pluripotent stem cells. These are called induced pluripotent stem cells (iPSCs) and, like embryonic stem cells, are capable of becoming any type of tissue in the body. However, these stem cells can also form tumours called teratomas when transplanted back into the animals. When the naked mole-rats' iPSCs were inserted into the testes of mice with extremely weak immune systems, the team discovered that they didn't form tumours in contrast to human iPSCs and mouse iPSCs. Upon further investigation, they found that a tumour-suppressor gene called alternative reading frame (ARF), which is normally suppressed in mouse and human iPSCs, remained active in the mole-rat iPSCs.

The team also found that ERAS, a tumorigenic gene expressed in mouse embryonic stem cells and iPSCs, was mutated and dysfunctional in the naked mole-rat iPSCs. When the researchers disabled the ARF gene, forced the expression of the mouse ERAS gene in the naked mole-rat iPSCs, and then inserted them into the mice, the mice grew large tumours. When researchers suppressed the ARF gene in naked mole-rat cells during the reprogramming process to iPSCs, the cells stopped proliferation with sign of cellular senescence, while the opposite happens with mouse cells. Researchers theorize that this further helps protect the naked mole-rat by reducing the chance for tumour formation. They call this ARF suppression-induced senescence (ASIS) and it appears to be unique to the naked mole-rat.

Link: http://www.oia.hokudai.ac.jp/blog/34769/

Of late, there has been a growing interest in exploring mechanisms related to nicotinamide adenine dinucleotide (NAD) and the way in which their operation changes over the course of aging. This research has grown out of the last decade of attempts to produce calorie restriction mimetic drugs that might modestly slow aging, lengthy efforts that have resulted in a better understanding of some aspects of metabolism, but few leads to drug candidates. NAD is important in mitochondrial function, and many methods of slowing aging in laboratory species - calorie restriction included - involve changes in this part of cellular biochemistry. Increased levels of NAD in mice appear to produce better mitochondrial function and greater cellular housekeeping efforts, the second of which is fairly common among interventions that influence mitochondrial biochemistry. The flux of reactive oxygen species produced by mitochondria in the course of generating energy store molecules for the cell is used as one of many intracellular signals, and produces the housekeeping reaction when it grows larger.

Researchers have identified the enzyme, called CD38, that is responsible for the decrease in nicotinamide adenine dinucleotide (NAD) during aging, a process that is associated with age-related metabolic decline. Results demonstrated an increase in the presence of CD38 with aging in both mice and humans. "Previous studies have shown that levels of NAD decline during the aging process in several organisms. This decrease in NAD appears to be, at least in part, responsible for age-related metabolic decline." Researchers have shown that CD38, an enzyme that is present in inflammatory cells, is directly involved in the process that mediates the age-related NAD decline. Comparing 3- to 32-month-old mice, researchers found that levels of CD38 increased at least two to three times during chronological aging in all tissues tested, including the liver, fat, spleen and skeletal muscle.

To determine if the increase in CD38 observed in mice was also present in humans, researchers compared the levels in groups of individuals who were approximately 34-years-old to groups of individuals who were approximately 61-years-old. Similar to their observations in mice, researchers found that CD38 increased up to two-and-a-half times in the fat tissue of older individuals. "The future of our research will be to develop compounds that can inhibit the function of CD38 to increase NAD levels during aging. We are also investigating the mechanisms that lead to the increase in CD38 during the aging process."

Link: http://newsnetwork.mayoclinic.org/discussion/mayo-clinic-researchers-link-specific-enzyme-to-process-of-metabolic-dysfunction-in-aging/

The research materials for today offer one example of numerous parallel efforts to find a mechanism and drug candidate that can stimulate autophagy and thereby modestly slow the progression of aging. It is too early to say whether this particular mechanism is worth chasing for that part of the drug development research and development industry that sees potential in slightly slowing aging, but the initial demonstration isn't impressive. It extends mean life span in flies by about 5%, which is small enough that no-one should be holding his or her breath expecting a clear and clean replication of the results. Certainty in manipulation of the pace of aging tends to require larger gains in order for clarity to emerge across numerous studies by different research groups. Results in short-lived species like flies are rarely within a 10% of life span distance of one another from study to study and research group to research group. Statistics and chance are cruel mistresses both. It is also good to remember that short-lived species have much more plastic life spans than long-lived species. Some of the changes that extend life in flies by 30% or so do also produce benefits to health in humans, but none have such an obvious effect on life span in our species.

Autophagy is a collection of cellular housekeeping mechanisms responsible for identifying, sequestering, and removing damaged structures and proteins. The damage is contained, broken down, and the parts recycled. The more of this that takes place, the more pristine the cell, and the less time that a damaged component has to cause further problems. Many of the methods of modestly extending life in short-lived species feature enhanced autophagy, and some actually require the correct operation of autophagy in order to slow aging. Given the importance of mitochondrial damage in aging, it is reasonable to think that a large part of this results from better quality control of mitochondria. Proving which aspect of autophagy is more or less important is ever a challenge, however, as is the case for any effort to isolate just one process in the dynamic chaos of cellular biochemistry in a living individual. Everything influences everything else.

For more than a decade now, researchers been earnestly looking for drugs that can enhance autophagy to a large enough degree to make deployment as a therapy worthwhile. Some technology demonstrations suggest that there are ways to enhance autophagy greatly, and restore youthful function in at least some types of aged tissues as a result. Genetic engineering to add extra lysosomal receptors springs to mind, given its restoration of liver function in old mice. Lysosomes are the destination for structures and molecules flagged for recycling, and play an important role in the process of autophagy. Drug candidates mined from the existing catalogs are vanishingly unlikely to achieve an outcome of this magnitude, however. Given that slowed aging produced by calorie restriction has been shown to depend on autophagy to a large degree, there is the hope in some quarters that autophagy enhancement may be a path to effective calorie restriction mimetic drugs. Again, modestly slowing aging is the goal in this research.

For my part I believe that most attempts to find methods of autophagy enhancement are not useful approaches to treating aging, especially the standard drug discovery efforts. The expected gains are too small, a mere slowing of aging, in comparison to the rejuvenation that might be achieved through the repair approach espoused in the SENS research initiative. Aging is damage: researchers should be aiming to repair that damage, not to slow down its accumulation. Autophagy just isn't comprehensive enough or effective enough for this job. The types of therapy needed to repair the root cause cell and tissue damage that produces degenerative aging are no more expensive or time-consuming to develop than therapies to slow aging, but have the potential to produce rejuvenation - a much better class of outcome, a treatment that can be repeated over and again to keep producing benefits for any one individual. Unfortunately, repair as a strategy and rejuvenation as a goal is still a minority concern within the research community. Taking over the mainstream continues to be a matter of bootstrapping support, funding, and results, one small advance at a time. There is progress, certainly, and much more so in recent years, but never fast enough for my liking. The mainstream of the research community has only comparatively recently adopted the idea that aging can and should be treated as a medical condition. Most are still very fixated on the approach of altering metabolism to slightly slow aging: more radical approaches are taking time to win adoption. Time is, of course, is running out of the bottom of the hourglass for all of us, day by day. Strategy in aging research is an urgent matter precisely because this is the case. We can't aim low.

Ethanolamine: A novel anti-aging agent

Phosphatidylethanolamine (PE) is a central intermediate of lipid metabolism and a major component of biological membranes. Within cellular membranes, PE not only serves as a structural phospholipid but also regulates the tethering of proteins and fusion processes. Importantly, PE is also directly involved in the process of macroautophagy (hereafter termed autophagy), a lysosome-dependent cellular recycling mechanism that protects cells against lethal stress and extends longevity in model organisms. During autophagy, double-membraned structures that are highly abundant in PE engulf superfluous, supernumerary, or dysfunctional macromolecules or organelles contained in the cytoplasm, forming vesicles (autophagosomes). These autophagosomes then fuse with lysosomes to generate autophagolysosomes in which the luminal cargo is degraded.

Given the widespread functions of PE as a precursor of several biosynthetic pathways, there is high demand for this metabolite. A common PE pool feeds into all major cellular PE-consuming pathways, thus resulting in competition for PE between pathways. As we have recently shown, this limitation can be overcome by genetic or pharmacological interventions. External administration of ethanolamine (Etn), a precursor of PE can increase the abundance of intracellular PE. Supporting a crucial regulatory role for PE in autophagy, we observed that both external supply of PE and an increase in its internal generation similarly increased autophagic flux. Importantly, pharmacological Etn treatment extended the lifespan of yeast and fruit flies, as well as cultured mammalian cells, underlining the potential of Etn as a potent autophagy and longevity drug.

Phosphatidylethanolamine positively regulates autophagy and longevity

Autophagy is regarded as one of the major cytoprotective mechanisms during ageing, and thus is a crucial process to counteract age-associated pathologies. Age-associated neurodegenerative disorders including Alzheimer's and Parkinson's disease may be postponed or attenuated by chronic induction of autophagy, and there is substantial evidence that genetic or pharmacological induction of autophagy can increase the healthspan and lifespan of multiple model organisms including yeast, worms, flies and mice. These findings have spurred the interest in identifying novel, non-toxic pharmacological inducers of autophagy. So far, several agents have been shown to induce autophagy and increase lifespan across several species, namely rapamycin, resveratrol and spermidine. The present results suggest that ethanolamine might be yet another potent autophagy inducer that promotes longevity.

Our study provides evidence that ethanolamine-mediated autophagy induction correlates with enhanced longevity in yeast and mammalian cell culture. This is in line with a previous study in yeast demonstrating that PE is a limiting factor for autophagy. Our results demonstrate that these observations are applicable to a wild-type scenario in yeast too and can be extended to mammalian cell cultures. Still, future experiments will need to clarify if ethanolamine-induced autophagy is beneficial to higher organisms. We could indeed observe a statistically significant increase in the mean lifespan of flies upon supplementation with ethanolamine, but whether this is because of autophagy must be tackled in the follow-up studies.

Researchers have found that a reduced level of insulin-like growth factor 1 (IGF-1) in mice accelerates the progression of atherosclerosis, one of the more dangerous of age-related cardiovascular issues. Atherosclerosis involves the buildup of fatty deposits inside blood vessels, resulting from a cycle of damage and inflammation that starts with oxidized lipids, draws in macrophage cells that become overwhelmed and die, and creates growing plaques made up of of fats and cellular debris. The plaques narrow important blood vessels, contributing to hypertension and detrimental cardiovascular remodeling. When plaques rupture in their later stages, the result is blockage of important blood vessels that causes a stroke.

The researchers here suggest that increasing circulating IGF-1 above normal levels may slow the progression of atherosclerosis, though have yet to put together a demonstration of this, and it it isn't always the case that changes in the amount of a specific protein are mirrored in both directions. In this study, harmful effects due to lower levels of IGF-1 appear to result from reduced function of the macrophage cells responsible for clearing up damage in blood vessel walls. Other research groups have in recent years proposed enhancing macrophage capabilities to better cope with the mechanisms of atherosclerosis, but ultimately the best approach is to build some form of targeted therapy that can clear all of the damage and debris, not just somewhat improve existing systems so as to slow down its progression.

Atherosclerosis is a condition in which plaque builds up inside the arteries, which can lead to serious problems, including heart attacks, strokes or even death. Now, researchers have found that Insulin-like Growth Factor-1 (IGF-1), a protein that is naturally found in high levels among adolescents, can help prevent arteries from clogging. They say that increasing atherosclerosis patients' levels of the protein could reduce the amount of plaque buildup in their arteries, lowering their risk of heart disease. "The body already works to remove plaque from arteries through certain types of white blood cells called macrophages. However, as we age, macrophages are not able to remove plaque from the arteries as easily. Our findings suggest that increasing IGF-1 in macrophages could be the basis for new approaches to reduce clogged arteries and promote plaque stability in aging populations."

Researchers examined the arteries of mice fed a high-fat diet for eight weeks. IGF-1 was administered to one group of mice. Researchers found that the arteries of mice with higher levels of IGF-1 had significantly less plaque than mice that did not receive the protein. Since the macrophage is a key player in the development of atherosclerosis, the researchers decided to investigate potential anti-atherosclerosis effects of IGF-1 in macrophages. "We examined mice whose macrophages were unresponsive to IGF-1 and found that their arteries have more plaque buildup than normal mice. These results are consistent with the growing body of evidence that IGF-1 helps prevent plaque formation in the arteries." The researchers also found that the lack of IGF-1 action in macrophages changed the composition of the plaque, weakening its strength and making it more likely to rupture and cause a heart attack. The researchers plan to conduct the same study on larger animals before eventually studying human subjects.

Link: http://medicine.missouri.edu/news/20160615-preventing-heart-attacks-strokes-older-adults.php

Many signs of age-related disease start as early as the 30s, damage that is asymptomatic and minimal, but nonetheless exactly the same type of dysfunction that will later, when present to a much greater degree, cause age-related disease, frailty, and death. This is true of measures of cognitive decline for example, and here researchers demonstrate that the physical signs of Alzheimer's disease in the brain can start to occur comparatively early in life as well. It is a reminder that rejuvenation treatments based on damage repair, once developed, are not only for the old, but that everyone much over the age of 30 should use them for prevention.

Alzheimer disease has an asymptomatic stage during which people are cognitively intact despite having substantial pathologic changes in the brain. While this asymptomatic stage is common in older people, how early in life it may develop has been unknown. To test the hypothesis that asymptomatic Alzheimer disease lesions may appear before 50 years of age, we microscopically examined the postmortem brains of 154 people aged 30 to 39 years (n=59) and 40 to 50 years (n=95) for specific Alzheimer lesions: beta-amyloid plaques, neurofibrillary tangles, and tau-positive neurites. We genotyped DNA samples for the apolipoprotein E gene (APOE).

We found beta-amyloid lesions in 13 brains, all of them from people aged 40 to 49 with no history of dementia. These plaques were of the diffuse type only and appeared throughout the neocortex. Among these 13 brains, five had very subtle tau lesions in the entorhinal cortex and/or hippocampus. All individuals with beta-amyloid deposits carried one or two APOE4 alleles. Among the individuals aged 40 to 50 with genotype APOE3/4, 10 (36%) had beta-amyloid deposits but 18 (64%) had none. Our study demonstrates that beta-amyloid deposits in the cerebral cortex appear as early as 40 years of age in APOE4 carriers, suggesting that these lesions may constitute a very early stage of Alzheimer disease. Future preventive and therapeutic measures for this disease may have to be stratified by risk factors like APOE genotype and may need to target people in their 40s or even earlier.

Link: http://journals.lww.com/cogbehavneurol/pages/articleviewer.aspx?year=2015&issue=09000&article=00010&type=abstract

Type 2 diabetes is the archetypal lifestyle disease, a metabolic dysfunction run out of control to the point at which it disrupts the crucial mechanisms of insulin metabolism. Diabetes isn't accelerated aging, but it has many of the same consequences when viewed from the high level: more damage, more disease, higher mortality. The vast majority of type 2 diabetics have this condition as a result of the choices they made. It is easy to become fat in a world of low-cost calories and increasing wealth, but it is still a choice. We can turn a questioning eye to Alzheimer's disease, a progressive age-related dementia characterized by a range of changes in the biochemistry of the brain, such as amyloid and tau deposits, and ask to what degree it is a lifestyle condition, driven by visceral fat tissue, lack of exercise, and the like. When looking at lifestyle choices and risk, the answers are more ambiguous than is the case for type 2 diabetes, however. Consider cardiovascular disease, for example. You can lead a life that makes you much more likely to die young from a heart attack, but equally everyone will suffer cardiovascular failure if they live long enough - the processes that weaken the heart and corrode our blood vessels operate in everyone, just more rapidly in the obese.

Is Alzheimer's more like type 2 diabetes, 90% avoidable over a normal human life span for the diligent, or is it more like cardiovascular disease, inevitable for all of us, absent radical progress in medical science, but arriving sooner for the less diligent? You'll see arguments either way if you wander the literature, most of which lean in the direction of Alzheimer's as a lifestyle condition, but not to the same degree as type 2 diabetes. A good meta-analysis from last year puts some numbers to that summary: if nine-tenths of type 2 diabetes is self-inflicted, then one can argue for two-thirds of Alzheimer's to be self-inflicted by the same types of statistical approach. Being overweight is definitely on the list: the distortions of metabolism caused by excess visceral fat tissue impact the brain. There is even a faction within the research community who argue that Alzheimer's is a type 3 diabetes, in effect.

Perhaps a better measure of the degree to which a medical condition is a lifestyle condition is whether or not it can be effectively treated, reversed, or cured by lifestyle changes alone. This is the case for type 2 diabetes. Even fairly late in its progression, calorie restriction and consequent loss of fat tissue can turn things around for a majority of patients, to the point of a cure. It is somewhat amazing that so many people continue down the road of disability when they could turn back at any time. For cardiovascular disease, lifestyle interventions like increased regular moderate exercise are beneficial, but in the way of a delaying tactic. You can improve the present poor situation, but you can't choose your way to back to full health for your age given the tools available. When it comes to the option to turn back, is Alzheimer's disease more like type 2 diabetes or more like cardiovascular disease, once it has taken hold?

The publicity materials and paper I'll point out today add a little more data from a small set of patients to the present evidence on this topic, putting Alzheimer's more in line with what one might expect from comparing the risk factors. Note the date on the paper, two years ago, versus the date on the publicity, however, this week. These results have been languishing for a few years, and by the look of it the researchers involved are now attempting another angle to broaden support for their approach - whenever book publication is mentioned in a release, it's a fair guess that the forthcoming book is why the release exists. Pitching a strategy of lifestyle changes to the usual panoply of research funding sources has ever had the problem that lifestyle changes are a poor foundation for a for-profit business, and are in any case well outside the area of interest for most for-profit funding sources relevant to medical research. It took some years for the calorie restriction research community to figure out a way to get for-profit interests involved, for example. That sort of challenge may well be what is taking place behind the scenes here, but equally it could simply be a mundane case of business failure for reasons unrelated to the science.

Pre and post testing show reversal of memory loss from Alzheimer's disease in ten patients

Results from quantitative MRI and neuropsychological testing show unprecedented improvements in ten patients with early Alzheimer's disease (AD) or its precursors following treatment with a programmatic and personalized therapy dubbed metabolic enhancement for neurodegeneration (MEND). The study is the first to objectively show that memory loss in patients can be reversed, and improvement sustained, using a complex, 36-point therapeutic personalized program that involves comprehensive changes in diet, brain stimulation, exercise, optimization of sleep, specific pharmaceuticals and vitamins, and multiple additional steps that affect brain chemistry. "All of these patients had either well-defined mild cognitive impairment (MCI), subjective cognitive impairment (SCI) or had been diagnosed with Alzheimer's disease before beginning the program. Follow up testing showed some of the patients going from abnormal to normal."

All but one of the ten patients included in the study are at genetic risk for AD, carrying at least one copy of the APOE4 allele. Five of the patients carry two copies of APOE4 which gives them a 10-12 fold increased risk of developing AD. "We're entering a new era. The old advice was to avoid testing for APOE because there was nothing that could be done about it. Now we're recommending that people find out their genetic status as early as possible so they can go on prevention." Sixty-five percent of the Alzheimer's cases in this country involve APOE4; with seven million people carrying two copies of the ApoE4 allele. "The magnitude of improvement in these ten patients is unprecedented, providing additional objective evidence that this programmatic approach to cognitive decline is highly effective. Even though we see the far-reaching implications of this success, we also realize that this is a very small study that needs to be replicated in larger numbers at various sites."

Reversal of cognitive decline in Alzheimer's disease

Effective treatment of Alzheimer's disease has been lacking, but recently a novel programmatic approach involving metabolic enhancement was described, with promising anecdotal results. This treatment is based on connectomic studies and previous transgenic findings as well as epidemiological studies of various monotherapeutic components of the overall program. The approach is personalized, responsive to suboptimal metabolic parameters that reflect a network imbalance in synaptic establishment and maintenance vs. reorganization, and progressive in that continued optimization is sought through iterative treatment and metabolic characterization.

Here we report the initial follow-up of ten patients who were treated with this metabolic programmatics approach. One patient had well documented mild cognitive impairment (MCI), with a strongly positive amyloid-PET (positron emission tomography) scan, positive FDG-PET scan (fluorodeoxyglucose PET scan), abnormal neuropsychological testing, and hippocampal volume reduced to 17th percentile; after 10 months on the MEND protocol, his hippocampal volume had increased to 75th percentile, in association with a reversal of cognitive decline. Another patient had well documented early Alzheimer's disease, with a positive FDG-PET scan and markedly abnormal neuro-psychological testing. After 22 months on the MEND protocol, he showed marked improvement in his neuropsychological testing, with some improvements reaching three standard deviations from his earlier testing.

The initial results for these patients show greater improvements than have been reported for other patients treated for Alzheimer's disease. The results provide further support for the suggestion that such a comprehensive approach to treat early Alzheimer's disease and its precursors, MCI and SCI, is effective. The results also support the need for a large-scale, personalized clinical trial using this protocol.

When it comes to the question of whether young stem cells and a young tissue environment are necessary for the success of stem cell therapies, there is evidence to support all of the possible answers. It is a confusing picture at the moment, and it is very possible that the answer varies by cell type. Since the best option for therapy is to use the patient's own cells, it would be good to find that cell therapies can work effectively and produce meaningful benefits even when both cells and patient are old. In some studies researchers have seen little difference in short term outcomes between young and old individuals, which is the more surprising of the possible results: the intuitive expectation is that age-related damage and the signaling changes that suppress stem cell activity in response to that damage will make all forms of cell therapy less effective in old individuals. In the research linked here, the results are more in line with expectations, in that young stem cells work to promote regeneration where old stem cells do not. This sort of experimentation will in time lead to a list of things that must be changed and corrected in stem cells, probably differing by tissue type, in order to make them more effective when transplanted into older individuals:

During aging, changes in the stomach result in gastric tissue that is less capable of repairing injury correctly. These changes include decreased gastric acid secretion, cell motility, and proliferation. In addition, angiogenesis, a fundamental process essential for wound healing, is impaired with advanced age. Such pathophysiological changes are believed to result in disrupted repair in response to chronic ulceration in the elderly that can be exacerbated during chronic insults such as Helicobacter pylori infection or nonsteroidal anti-inflammatory drug administration. In elderly patients there is a strong association between ulceration with cancer or evolution of dysplasia into neoplasia. Renewal of gastric stem cells to produce committed progenitor cells that differentiate further into adult epithelial cell types is important for the structural integrity of the mucosa. However, relatively little is known regarding the age-related changes affecting gastric epithelial stem cells. Early studies have shown that in aged rats, stem cell proliferation and epithelial cell numbers are decreased compared with young animals, thus suggesting impaired tissue integrity in the aged stomach.

The origin of cells for repair of severe gastric epithelial injury has not received extensive attention. Recent investigations have indicated that loss of parietal cells, either from acute toxic injury or chronic Helicobacter infection, leads to the development of spasmolytic polypeptide/trefoil factor (TFF) 2-expressing metaplasia (SPEM) through transdifferentiation of chief cells into mucous cell metaplasia. In the face of continued inflammation and M2-macrophage influence, SPEM may progress to a more proliferative preneoplastic metaplasia. However, studies with acute injury have indicated that SPEM disappears after resolution of injury. No studies have addressed whether SPEM may contribute to the healing of gastric ulcers. We now report that SPEM represents a major reparative lineage responsible for wound healing after gastric ulcer injury.

Acetic acid ulcers were induced in young (2-3 mo) and aged (18-24 mo) C57BL/6 mice to determine the quality of ulcer repair with advancing age. Yellow chameleon 3.0 mice were used to generate yellow fluorescent protein-expressing organoids for transplantation. Yellow fluorescent protein-positive gastric organoids were transplanted into the submucosa and lumen of the stomach immediately after ulcer induction. Gastric tissue was collected and analyzed to determine the engraftment of organoid-derived cells within the regenerating epithelium. Wound healing in young mice coincided with the emergence of SPEM within the ulcerated region, a response that was absent in the aged stomach. Although aged mice showed less metaplasia surrounding the ulcerated tissue, organoid-transplanted aged mice showed regenerated gastric glands containing organoid-derived cells. Organoid transplantation in the aged mice led to the emergence of SPEM and gastric regeneration. Thus the healing of gastric ulcers in the aged stomach is promoted by the transplantation of gastric organoids.

Link: http://www.cmghjournal.org/article/S2352-345X(16)30044-3/fulltext

Researchers have announced progress in the production of larger sections of bone for transplantation. Once transplanted, the new bone serves as a template to provoke further regeneration to match the structure of the natural bone that is replaced. Based on results from animal studies, this seems a promising approach:

A new technique repairs large bone defects in the head and face by using lab-grown living bone, tailored to the patient and the defect being treated. This is the first time researchers have grown living bone that precisely replicates the original anatomical structure, using autologous stem cells derived from a small sample of the recipient's fat. "We've been able to show, in a clinical-size porcine model of jaw repair, that this bone, grown in vitro and then implanted, can seamlessly regenerate a large defect while providing mechanical function. The need is huge, especially for congenital defects, trauma, and bone repair after cancer surgery. The quality of the regenerated tissue, including vascularization with blood perfusion, exceeds what has been achieved using other approaches. So this is a very exciting step forward in improving regenerative medicine options for patients with craniofacial defects, and we hope to start clinical trials within a few years."

Researchers fabricated a scaffold and bioreactor chamber based on images of the weight-bearing jaw defect, to provide a perfect anatomical fit. The scaffold they built enabled bone formation without the use of growth factors, and also provided mechanical function, both of which are unique advantages for clinical application. They then isolated the recipient's own stem cells from a fat sample and, in just three weeks, formed the bone within a scaffold made from bone matrix, in a custom-designed perfused bioreactor. An unexpected outcome was that the lab-grown bone, when implanted, was gradually replaced by new bone formed by the body, a result not seen with the implantation of a scaffold alone, without cells. "Our lab-grown living bone serves as an 'instructive' template for active bone remodeling rather than as a definitive implant. This feature is what makes our implant an integral part of the patient's own bone, allowing it to actively adapt to changes in the body throughout its life."

The team are now including a cartilage layer in the bioengineered living bone tissue to study bone regeneration in complex defects of the head and face. They are also advancing their technology through advanced preclinical trials, and in planning stages with the FDA for clinical trials, through the company epiBone.

Link: http://engineering.columbia.edu/face-future-0

Today I'll point out progress towards an as yet unrealized category of stem cell treatments involving the wholesale replacement of entire stem cell populations and their niches, to remove age-related damage and sustain tissue maintenance for the long term. This will become an essential component for any future rejuvenation toolkit. From a stem cell perspective, rejuvenation has two components: firstly revert the root causes of signaling changes in blood and tissues that result in stem cell populations becoming less active; secondly, replace the stem cells themselves, scores of different types in different locations, to clear out damaged cells. The root cause of signaling changes in old individuals is, collectively, all of the forms of damage listed in the SENS proposals for rejuvenation treatments - a lot of work is yet to be accomplished there to reach even the initial goals of prototype treatments across the board. Nonetheless, it is still the case that replacement of aged stem cell populations with undamaged, pristine stem cells created from the patient's own cells is an important target for future development in the stem cell field.

Most stem cell therapies in use today are actually far removed from this goal: the transplanted cells do not live long, and do not integrate with recipient tissues. They achieve beneficial effects through a temporary alteration of the signaling environment that spurs regeneration and reduces inflammation. In effect the transplant temporarily overrules the evolved reaction to being aged and damaged and puts sleeping cells back to work - but without fixing that low level damage. So there can be some degree of rebuilding of worn tissues and organs, but the causes of aging are still present and continue to cause harm: cross-links, mitochondrial mutations, and so forth.

There are exceptions to the outcome of benefits through signaling mechanisms, however, and these exceptions include types of therapy in which cells are transplanted into the brain. Some of the earliest stem cell transplants trialed in humans aimed to treat Parkinson's disease, for example, and at least some of the transplanted cells survived and integrated into the brains of patients for the long term. This is still a considerable distance removed from a controlled repopulation of stem cell niches in all of the right places and with cells that will pick up tissue maintenance activities in exactly the right ways, but it is a step in the right direction. In the research materials linked below, scientists report on further progress along these lines, and that they were able to create new stem cell niches in brain tissue seems like an important advance:

Regenerating Memory with Neural Stem Cells

Although brains - even adult brains - are far more malleable than we used to think, they are eventually subject to age-related illnesses, like dementia, and loss of cognitive function. Someday, though, we may actually be able to replace brain cells and restore memory. Recent work hints at this possibility with a new technique of preparing donor neural stem cells and grafting them into an aged brain. The team took neural stem cells and implanted them into the hippocampus - which plays an important role in making new memories and connecting them to emotion - of an animal model, essentially enabling them to regenerate tissue.

"We're very excited to see that the aged hippocampus can accept grafted neural stem cells as superbly as the young hippocampus does and this has implications for treating age-related neurodegenerative disorders. It's interesting that even neural stem cell niches can be formed in the aged hippocampus." The team found that the neural stem cells engrafted well onto the hippocampus in the young animal models (which was expected) as well as the older ones that would be, in human terms, about 70 years old. Not only did these implanted cells survive, they divided several times to make new cells. "They had at least three divisions after transplantation. So the total yield of graft-derived neurons and glia (a type of brain cell that supports neurons) were much higher than the number of implanted cells, and we found that in both the young and aged hippocampus, without much difference between the two. What was really exciting is that in both old and young brains, a small percentage of the grafted cells retained their 'stemness' feature and continuously produced new neurons."

This is called creating a new 'niche' of neural stem cells, and these niches seemed to be functioning well. "They are still producing new neurons at least three months after implantation, and these neurons are capable of migrating to different parts of the brain. Next, we want to test what impact, if any, the implanted cells have on behavior and determine if implanting neural stem cells can actually reverse age-related learning and memory deficits. That's an area that we'd like to study in the future."

Grafted Subventricular Zone Neural Stem Cells Display Robust Engraftment and Similar Differentiation Properties and Form New Neurogenic Niches in the Young and Aged Hippocampus

As clinical application of neural stem cell (NSC) grafting into the brain would also encompass aged people, critical evaluation of engraftment of NSC graft-derived cells in the aged hippocampus has significance. We examined the engraftment and differentiation of alkaline phosphatase-positive NSCs expanded from the postnatal subventricular zone (SVZ), 3 months after grafting into the intact young or aged rat hippocampus. Graft-derived cells engrafted robustly into both young and aged hippocampi. Although most graft-derived cells pervasively migrated into different hippocampal layers, the graft cores endured and contained graft-derived neurons.

The results demonstrate that advanced age of the host at the time of grafting has no major adverse effects on engraftment, migration, and differentiation of grafted subventricular zone-neural stem cells (SVZ-NSCs) in the intact hippocampus, as both young and aged hippocampi promoted excellent engraftment, migration, and differentiation of SVZ-NSC graft-derived cells in the present study. Furthermore, SVZ-NSC grafts showed ability for establishing neurogenic niches in non-neurogenic regions, generating new neurons for extended periods after grafting. This phenomenon will be beneficial if these niches can continuously generate new neurons and glia in the grafted hippocampus, as newly generated neurons and glia are expected to improve, not only the microenvironment, but also the plasticity and function of the aged hippocampus. Overall, these results have significance because the potential application of NSC grafting for treatment of neurodegenerative disorders at early stages of disease progression and age-related impairments would mostly involve aged persons as recipients.

Researchers have in the past couple of years shown that GDF11 levels decline with age in mice, and that restoring youthful GDF11 in old mice improves numerous measures of health. The mechanism involved may be increased stem cell activity. There has been some debate over whether the teams involved are in fact measuring what they think they are measuring, however. New human data in the research noted here today muddies the water some more, though these researchers are also claiming an improvement in the approach to measurement of GDF11 levels. This suggests that either mice and humans are different in this aspect of aging, or that the issues in prior methods of measurement were more prevalent than thought, or both. The outcome of improved health in aged mice following introduction of additional GDF11 isn't disputed, so it will be interesting to see how these various results are reconciled:

Researchers have developed an accurate way to measure a circulating factor, called GDF11, to better understand its potential impact on the aging process. They found that GDF11 levels do not decline with chronological age, but are associated with signs of advanced biological age, including chronic disease, frailty and greater operative risk in older adults with cardiovascular disease. "Aging is the primary risk factor for the majority of chronic diseases, so it is critical to identify and understand the biomarkers, or indicators, in the body that are linked to this process. The role of GDF11 as a biomarker of aging and its association with age-related conditions has been largely contradictory, in part, because of how difficult it has been to measure. We have developed a new way to measure GDF11 that is accurate and effective."

A challenge of previous measurements was differentiating between the circulating levels of GDF11 and those of a highly-related protein, myostatin. To overcome this, researchers developed an extremely precise assay that can distinguish between unique amino acid sequence features, or "fingerprints" of GDF11 and myostatin. Using this platform, researchers compared age-associated changes in GDF11 and myostatin in healthy men and women between 20 and 94 years old. They discovered that although myostatin is higher in younger men than younger women and declines in healthy men throughout aging, GDF11 levels do not differ between sexes nor decline throughout aging. In an independent cohort of older individuals with severe aortic stenosis, researchers found that those with higher GDF11 levels were more likely to be frail and have diabetes or prior cardiac conditions. Following valve replacement surgery, increased GDF11 was associated with a higher prevalence of re-hospitalization and multiple adverse events.

Link: http://newsnetwork.mayoclinic.org/discussion/mayo-clinic-researchers-develop-accurate-way-to-measure-growth-factor-linked-to-aging/

Osteocalcin levels decline with age, one of many age-related changes in production of specific proteins. Researchers here demonstrate that introducing additional osteocalcin restores age-related loss of exercise capacity in mice. This is yet another possibility to add to the list of potential gene therapies that might be developed to offset some of the changes that occur with aging, though as for all such alterations, it doesn't address root causes. Though not mapped at the present time, the view of aging as damage accumulation expects there to be a chain of cause and effect leading from increased cell and tissue damage at the root of aging to a series of consequent changes that leads to a reduction in the gene expression of ostoeclastin.

When we exercise, our bones produce a hormone called osteocalcin that increases muscle performance. Osteocalcin naturally declines in humans as we age, beginning in women at age 30 and in men at age 50. During exercise in mice and humans, the levels of osteocalcin in the blood increase depending on how old the organism is. The researchers observed that in 3-month-old adult mice, osteocalcin levels spiked approximately four times the amount that the levels in 12-month-old mice did when the rodents ran for 40 minutes on a treadmill. The 3-month-old mice could run for about 1,200 meters before becoming exhausted, while the 12-month-old mice could only run half of that distance.

To investigate whether osteocalcin levels were affecting exercise performance, researchers tested mice genetically engineered so the hormone couldn't signal properly in their muscles. Without osteocalcin muscle signaling, the mice ran 20%-30% less time and distance than their healthy counterparts before reaching exhaustion. Surprisingly, when healthy mice that were 12 and 15 months old - whose osteocalcin levels had naturally decreased with age - were injected with osteocalcin, their running performance matched that of the healthy 3-month-old mice. The older mice were able to run about 1,200 meters before becoming exhausted. "It was extremely surprising that a single injection of osteocalcin in a 12-month-old mouse could completely restore its muscle function to that of a 3-month-old mouse."

To determine the cellular mechanisms behind osteocalcin's effects, the team measured levels of glycogen, glucose, and acylcarnitines (an indicator of fatty-acid use) in mice with and without osteocalcin. The researchers determined that the hormone helps muscle fibers uptake and catabolize glucose and fatty acids as nutrients during exercise. "It's never been shown before that bone actually influences muscle in any way. Osteocalcin is not the only hormone responsible for adaptation to exercise in mice and humans, but it is the only known bone-derived hormone that increases exercise capacity. This may be one way to treat age-related decline in muscle function in humans."

Link: http://www.eurekalert.org/pub_releases/2016-06/cp-bhb060716.php

The clock is counting down on the Major Mouse Testing Program (MMTP) fundraiser at Lifespan.io. With just over a week to go, more than 400 donors have given a total of nearly $40,000 so far. These funds will be used to run tests of senolytic drugs to clear senescent cells in aged mice, the first of what will hopefully be a series of useful studies carried out by this group, working to push treatments for the causes of aging closer to the clinic. The initial goal for the fundraiser is $45,000, and a matching fund has been announced to help close the gap in the next few days. Donate, and your donation will be matched dollar for dollar:

Hello dear friends! There are 10 days left before the Senolytics campaign ends, and it is time to make a final dash to the finish line!

Some great news from Healthy Life Extension Society (Heales) leader Didier Coeurnelle. He has offered a FUND MATCH! Whatever we will raise from Tuesday, June 14, 11 AM UTC (6 AM EST) to Thursday, June 16, 11 AM UTC (6 AM EST) up to $2500 will be doubled! Didier is Co-chair of Heales, the largest non-profit organization in Continental Europe promoting and advocating scientific research into longevity and biogerontology, and vice-president of the French association AFT-Technoprog, that aims to spread the themes and questions related to technologies that could extend and enhance the lives of individuals and of humankind.

If you will contribute during this period, every dollar you donate will become two - and the project will receive a nice push to get us to our goal!

It is generally agreed upon now in the broader research community that senescent cells are a meaningful component of degenerative aging. They accumulate over time in all tissues, and secrete a mix of signals that, among other things, spurs greater inflammation, damages tissue structure, and increases the odds of nearby cells also becoming senescent. Their presence accelerates the development of all of the major age-related diseases - but all of this could be removed given a way to selectively destroy these cells. Fortunately senescent cells are already primed to self-destruction, and all that needs to be done is to nudge them in that direction, something that can be achieved through drugs. A senolytic drug can issue a modest prompt to destruction to all cells, and only senescent cells will be pushed across the line. The Major Mouse Testing Program volunteers have an active YouTube channel, and over the past few weeks have conducted a number of video interviews with members of the research and advocacy community on the value of senescent cell clearance and mouse testing in this field. You'll find a few of these linked below:

MMTP - Major Mouse Testing Program - Interview with Joao Pedro de Magalhaes

As many people were curious about the study design, the MMTP team prepared a short version (PDF) of the study proposal so everyone could learn more about what animal study looks like. To provide you with more details, we invite you to watch a mini-interview with Dr. Joao Pedro de Magalhaes, a leading researcher of geroprotectors at Liverpool University, UK, where he is speaking about the importance of experiments and animal data.

MMTP - Major Mouse Testing Program - Interview with Daria Khaltourina - ILA

We invite you to watch a short interview with Daria Khaltourina, an International Longevity Alliance Board Member, and a famous health care advocate from Russia. Daria is currently part of an international initiative to include aging as a disease into the International Classification of Diseases (ICD-11) in 2017. This is an important change because it will allow researchers to test and register geroprotective drugs as such, and for doctors to prescribe them to prevent aging in healthy middle age people.

MMTP - Major Mouse Testing Program - Interview with Aubrey de Grey

Today we would like to help you learn more about mice. Yes, mice are nice, but apart from that they are one of the best models for aging research. Here is one of our scientific advisors Dr. Aubrey de Grey from SENS speaking about the importance and relevance of mouse studies in the research of aging and interventions against it.

Researchers have announced another step forward in the development of methods of regeneration that should one day encompass all tissue types and organs in the body. This time the pituitary gland is the target, and the approach used here well illustrates the point that engineered replacements do not have to be in any way similar to the organ they are replacing. They just have to carry out the same functions.

Researchers have successfully used human stem cells to generate functional pituitary tissue that secretes hormones important for the body's stress response as well as for its growth and reproductive functions. When transplanted into rats with hypopituitarism the lab-grown pituitary cells promoted normal hormone release. "The current treatment options for patients suffering from hypopituitarism, a dysfunction of the pituitary gland, are far from optimal. Cell replacement could offer a more permanent therapeutic option with pluripotent stem cell-derived hormone-producing cells that functionally integrate and respond to positive and negative feedback from the body. Achieving such a long-term goal may lead to a potential cure, not only a treatment, for those patients."

The pituitary gland is the master regulator of hormone production in the body, releasing hormones that play a key role in bone and tissue growth, metabolism, reproductive functions, and the stress response. Hypopituitarism can be caused by tumors, genetic defects, brain trauma, immune and infectious diseases, or radiation therapy. The consequences of pituitary dysfunction are wide ranging. Currently, patients with hypopituitarism must take expensive, lifelong hormone replacement therapies that poorly mimic the body's complex patterns of hormone secretion that fluctuates with circadian rhythms and responds to feedback from other organs. By contrast, cell replacement therapies hold promise for permanently restoring natural patterns of hormone secretion while avoiding the need for costly, lifelong treatments.

Recently, scientists developed a procedure for generating pituitary cells from human pluripotent stem cells - an unlimited cell source for regenerative medicine - using organoid cultures that mimic the 3D organization of the developing pituitary gland. However, this approach is inefficient and complicated. To address these limitations, researchers developed a simple, efficient, and robust stem cell-based strategy for reliably producing a large number of diverse, functional pituitary cell types suitable for therapeutic use. Instead of mimicking the complex 3D organization of the developing pituitary gland, this approach relies on the precisely timed exposure of human pluripotent stem cells to a few specific cellular signals that are known to play an important role during embryonic development. Exposure to these proteins triggered the stem cells to turn into different types of functional pituitary cells.

To test the therapeutic potential of this approach, the researchers transplanted the stem cell-derived pituitary cells under the skin of rats whose pituitary gland had been surgical removed. The cell grafts not only secreted adrenocorticotropic hormone, prolactin, and follicle-stimulating hormone, but they also triggered appropriate hormonal responses in the kidneys. The researchers were also able to control the relative composition of different hormonal cell types simply by exposing human pluripotent stem cells to different ratios of two proteins: fibroblast growth factor 8 and bone morphogenetic protein 2. This finding suggests their approach could be tailored to generate specific cell types for patients with different types of hypopituitarism.

Link: http://www.eurekalert.org/pub_releases/2016-06/cp-ptg060716.php

The development of treatments for Alzheimer's disease based on clearance of amyloid continues to be a struggle, and it is still unclear as to whether this is because it is an inherently hard task, or because amyloid aggregates are not the most important contributing cause of this condition. Given that theorizing is a lot easier than building therapies, all delays in evident progress tend to give rise to a lot of theorizing. There is a prolific construction of alternative hypotheses regarding the biochemistry of Alzheimer's disease, its causes and progression. This example of one such a hypothesis has little support for its thesis in the broader research community, but is interesting as an example of the range of thinking taking place on this topic:

Early-onset familial Alzheimer's disease (EOFAD) and late-onset sporadic AD (LOSAD) both follow a similar pathological and biochemical course that includes: neuron and synapse loss and dysfunction, microvascular damage, microgliosis, extracellular amyloid-β deposition (Aβ), and the deposition of phosphorylated tau protein in the form of intracellular neurofibrillary tangles in affected brain regions. Any mechanistic explanation of AD must accommodate these biochemical and neuropathological features for both forms of the disease.

Cell cycle abnormalities represent another major biochemical and neuropathological feature common to both EOFAD and LOSAD, and 1) appear very early in the disease process, prior to the appearance of plaques and tangles, and 2) explain the biochemical (e.g., tau phosphorylation), neuropathological (e.g., neuron hypertrophy) and cognitive changes observed in EOFAD and LOSAD. Since neurogenesis after the formation of a memory is sufficient to induce forgetting, any stimulus that promotes cell cycle re-entry will be a negative event for memory. In this insight paper, we propose that aberrant re-entry of terminally differentiated, post-mitotic neurons into the cell cycle is a common pathway that explains both early and late-onset forms of AD. In the case of EOFAD, mutations in APP, PSEN1, and PSEN2 that alter AβPP and Notch processing drive reactivation of the cell cycle, while in LOSAD, age-related reproductive endocrine dyscrasia that upregulates mitogenic TNF signaling, AβPP processing toward the amyloidogenic pathway and tau phosphorylation drives reactivation of the cell cycle. Inhibition of cell cycle reentry of post-mitotic neurons may be a useful therapeutic strategy to prevent or halt disease progression.

Link: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4807856/

The next stage in this year's SENS rejuvenation research funding initiatives launches today: the SENS Research Foundation is crowdfunding a search for drug candidates and mechanisms that can attack all ALT cancers, those that abuse the alternative lengthening of telomeres (ALT) processes to grow. This is a part of the OncoSENS program, which seeks to produce the grounding for a universal cancer treatment platform, based on the one commonality known to be shared by all cancers, which is that cancer cells must lengthen their telomeres, one way or another. You may recall coverage of the SENS Research Foundation ALT research in the scientific press last year. Given the ability to turn off telomere lengthening, then that is also the ability to turn off cancer, any cancer. The cost of mitigating the potential side-effects of this approach, such as loss of stem cell activity, is a small line item in comparison to the cost of present cancer research strategies, as they produce treatments that are expensive to develop, but more importantly can usually only be used for one of the hundreds of subtypes of cancerous growth. To make real progress in cancer, the research community must instead attack the shared vulnerabilities in all cancers, so as to greatly reduce the cost of building viable treatments that will work for many patients, not just a few.

Like other SENS initiatives, OncoSENS, and ALT targeting in particular, is focused on funding an area of research important to aging and longevity science that is presently languishing, largely neglected by the mainstream of the scientific community. There are many such dead zones in the sciences, where the potential for great progress is left untended, usually for no good reason, and too few people are willing to step in to do something about it. The SENS Research Foundation and Methuselah Foundation before it have in a number of cases helped to generate active research and development communities from these dead zones through advocacy and targeted philanthropic funding, and seek to do the same here. A robust and cost-effective cure for cancer is a necessary part of the future rejuvenation toolkit, and prevention of telomere lengthening is a good candidate for the job. The ALT cancer research crowdfunding campaign can be found at Lifespan.io, and I encourage you to show your support; this is yet another field that might blossom in the years ahead thanks to exactly this sort of effort.

OncoSENS: Control ALT, Delete Cancer

Of all the risk factors associated with cancer: obesity, smoking, sun exposure etc., there is none more universal than aging. Therefore it is of paramount importance to develop new anti-cancer approaches to meet the humanitarian and economic challenges associated with our aging global population. One such approach is to target cancers that employ a particular mechanism to achieve cellular immortality - Alternative Lengthening of Telomeres, or "ALT".

Every time a normal somatic cell divides, the DNA at the ends of its chromosomes, called telomeres, gets shorter. When the telomeres shorten too much, the cell permanently stops dividing and either enters senescence or undergoes apoptosis (programmed cell death). Telomere shortening thus acts as a biological mechanism for limiting cellular life span. Most cancer cells bypass this failsafe by synthesizing new telomeres using the enzyme telomerase. Several therapies targeting this well-described telomerase-based pathway are in the advanced stages of clinical development, but as with any cancer therapy there is the potential for development of resistance against telomerase-based strategies to defeat cancer. Studies using mice and human cancer cell lines have demonstrated that cancer can overcome the loss of telomerase by using a telomerase-independent mechanism called alternative lengthening of telomeres (ALT). Furthermore, existing tumor cells in mice have also been observed to switch over to the ALT pathway as a result of telomerase-inhibiting treatment. It is therefore plausible that telomerase-dependent cancer treatments will introduce selective pressures in human tumors to activate the ALT pathway and/or select for cells already using ALT within the tumor. This makes the development of ALT-specific therapies imperative for the success of complete anti-cancer approaches.

There are currently no ALT-targeted anti-cancer therapeutics, however, largely because this process is much less well understood. A key step towards the development of ALT-targeted cancer therapeutics and diagnostics was the discovery of the first ALT-specific molecule, the telomeric C-circle, by our collaborator, Dr. Jeremy Henson, back in 2009. C-circles are an unusual type of circular DNA sequences that are created from telomeres. The level of C-circles in cancer cells accurately reflects the level of ALT activity, and this biomarker can be found in the blood of patients who have bone cancers positive for ALT activity. The OncoSENS research team at the SENS Research Foundation, in collaboration with Dr. Jeremy Henson at the University of New South Wales in Australia, has developed a novel version of the C-circle assay that can be fully automated using robotic liquid handlers, making it now feasible to perform robust high-throughput screenings to search for chemical modulators of the ALT pathway.

The goal of this project is to screen a library of about 115,000 compounds containing structurally diverse, medicinally active, and cell permeable drugs from a variety of fields of medicine (oncology, cardiology, and immunology, etc.), for inhibitors of the ALT pathway. The crucial advantage of making use of such drug libraries, which are richly documented and contain some FDA approved compounds, is that once hits are identified and validated using our ALT-specific assays they can potentially be repurposed for the treatment of patients with ALT cancers through cheaper, faster and safer preclinical and clinical validation protocols. Our initial goal of $60,000 will allow us to test a significant subgroup of this library, and reaching a stretch goal of $200,000 will allow us to test them all.

While a few groups are presently working on inhibition of telomerase-based telomere lengthening in cancer, and the majority of cancers use telomerase rather than ALT when left to their own devices, as noted above it is clearly the case that ALT inhibition is an essential part of this approach to a universal cancer therapy. Unfortunately, the SENS Research Foundation is one of the very few groups funding any significant work in this area of cancer research. Still, there is a real opportunity here, and with the falling cost of early stage research, a great deal of useful work can be accomplished with comparatively little funding. Working through the most promising parts of standard drug libraries should produce leads on drug candidates and mechanisms for interfering with ALT that will attract the interest of other investigators. Taking this step is necessary if the telomere interdiction approach to cancer is to grow, and funding the important work that others do not is exactly how the SENS Research Foundation has produced considerable success in other areas of aging research.

I really can't overstate how important it is to change the nature of cancer research, steering the scientific community away from the approach of one costly research project per subtype of cancer and towards the production of a single technology that can attack all cancers with minimal adjustment. I will be donating to this OncoSENS crowdfunding initiative, and I encourage you to do so as well. It is an rare chance to nudge cancer researchers towards a better, more effective strategic direction, to help start an avalanche that will pay off greatly in the years ahead, with therapies that can target all forms of cancer.

The study linked here is one of many examples of the correlation between regular moderate exercise and mortality rate found in human epidemiological data. In animal studies it can be proven that exercise causes reduced mortality, but that is very hard to demonstrate directly in human populations - researchers can't just set up the same experimental groups and wait. So statistical methods are used, and the combination of those and the animal studies gives a good level of confidence to suggest that yes, it is a matter of exercise providing benefits rather than a matter of people more likely to live longer regardless also being more likely to exercise.

Fifteen minutes of daily exercise is associated with a 22% lower risk of death and may be a reasonable target for older adults. The authors studied two cohorts. A French cohort of 1011 subjects aged 65 in 2001 was followed over a period of 12 years. An international cohort of 122,417 subjects aged 60 was included from a systematic review and meta-analysis, with a mean follow up of 10 years. Physical activity was measured in Metabolic Equivalent of Task (MET) minutes per week, which refers to the amount of energy (calories) expended per minute of physical activity. One MET minute per week is equal to the amount of energy expended just sitting. The number of MET minutes an individual clocks up every week depends on the intensity of physical activity. For example, moderate intensity activity ranges between 3 and 5.9 MET minutes while vigorous intensity activity is classified as 6 or more. The recommended levels of exercise equate to between 500 and 1000 MET minutes every week. The authors looked at the associated risk of death for four categories of weekly physical activity in MET minutes, defined as inactive (reference for comparison), low (1-499), medium (500-999) or high (≥1000).

During the follow up there were 88 (9%) and 18,122 (15%) deaths in the French and international cohorts, respectively. The risk of death reduced in a dose response relationship as the level of exercise increased. Compared to those who were inactive, older adults with low, medium and high activity levels had a 22%, 28% and 35% lower risk of death, respectively. "These two studies show that the more physical activity older adults do, the greater the health benefit. The biggest jump in benefit was achieved at the low level of exercise, with the medium and high levels bringing smaller increments of benefit. We think that older adults should progressively increase physical activity in their daily lives rather than dramatically changing their habits to meet recommendations. Fifteen minutes a day could be a reasonable target for older adults. Small increases in physical activity may enable some older adults to incorporate more moderate activity and get closer to the recommended 150 minutes per week."

Link: https://www.escardio.org/The-ESC/Press-Office/Press-releases/Last-5-years/15-minutes-daily-exercise-may-be-reasonable-target-in-older-adults

Potential cancer therapies that can address many types of cancer should be a primary focus of the cancer research community. There are far too many varieties of cancer to do otherwise if the goal is rapid progress towards the control of cancer. In this early stage research, researchers report on an approach to using immune cells hijacked by cancerous tissue as a way to attack the cancer. This could in principle be applied to numerous types of cancer:

Along with attacking foreign pathogens like bacteria, macrophages also help the body's organs develop and its wounds heal. Their own behavior is fine-tuned by small molecules that they produce, called microRNAs. When a tumor begins to develop, macrophages attempt to block its growth. But often tumors hijack them and convert them into what are known as "tumor-associated macrophages", or TAMs for short. Now corrupted, TAMs use their microRNAs to shield the tumor from the patient's immune system, helping it grow and metastasize. This phenomenon is common across many tumor types. It is one of the major obstacles in treating cancer, and often leads to a poor prognosis for the patient.

Researchers have now found how to reclaim TAMs. The researchers genetically modified TAMs to remove their ability to produce microRNAs. As a result, the TAMs were reprogrammed dramatically. Instead of protecting the tumor, the TAMs now signaled the presence of the tumor to the immune system, triggering attacks against it - and did so very efficiently. Using a bioinformatics approach, the researchers found that the most likely culprit was a small family of microRNAs, called Let-7. This offers a more specific target: blocking Let-7 microRNAs may help instruct the TAMs to stimulate anti-tumor immunity. Interestingly, the researchers observed that reprogramming TAMs also stops cancer cells from leaving the primary tumor. This could mean that the approach can also prevent tumor metastasis, the most threatening aspect of cancer. Moreover, the researchers found that the re-educated TAMs could enhance the anti-tumoral efficacy of certain cancer immunotherapies, some of which are already approved for patients. However, more work is needed to translate all these findings to actual therapies, especially since there is currently no way to block the Let-7 microRNAs selectively in TAMs. But researchers are now working to design drugs that can target the Let-7 microRNAs specifically in the TAMs.

Link: http://actu.epfl.ch/news/reclaiming-the-immune-system-s-assault-on-tumors/

The US government is beginning to make more of an overt show of supporting tissue engineering, cryobiology, and other areas that can help move the needle in the field of organ transplantation, as demonstrated by today's White House Organ Summit. It will take some time to see how this pans out; typically the immediate outcome of this sort of public-private partnership is that it becomes easier for private and philanthropic initiatives at the cutting edge to raise funds for projects that can advance the state of the art. Familiarity with the field and its goals spreads, and that helps, as fundraising is always slower when you have to start with an explanation of the basics of what it is you are actually doing. Government funding sources tend to get directly involved only in the much less risky and much later stages of development, however, and that funding typically has much more to do with delivery of existing technology than implementation of new technology. You can look back at comparable US government efforts from past decades, such as the nanotechnology initiative back in 2004, and draw your own conclusions.

For biotechnology, one high level goal for the next twenty years is to generate a much larger and more reliably, high-quality supply of organs and tissues for transplantation. That could be achieved to some degree through better storage methodologies, such as reversible vitrification that would allow indefinite storage of large tissue sections, or through improvements in the ability to repair and make use of donor organs that are presently rejected, perhaps using decellarization approaches presently under development. Further down the line, constructing organs to order from the starting point of cells, preferably a patient's own cells, will completely remove limits on the availability of tissues for transplantation, but a lot of work remains to be accomplished in order to reach that goal. Still, there are many plausible options for near-future development when it comes to making the present situation incrementally better.

The New Organ initiative, run by the Methuselah Foundation, is one of a number of non-profits and advocacy efforts that are each independently focused on progress in tissue engineering. Another organization active in this field and mentioned here today is the Organ Preservation Alliance, for example. These groups are focused on a range of technologies that could reduce the waiting lists and risks for transplants in one way or another. Today, tissue engineering advocates are using the White House meeting on organ shortage issues as a springboard to announce a range of initiatives. This is the way publicity works: it always helps to stand beside the biggest megaphone in the room. For my money, the greater sign of progress is activity in the non-profit sector, the growth in advocacy, rather than purely government initiatives. The leadership here is provided by the non-profits and the advocates. Government agencies only follow years down the line, when the crowds grow large enough - so in a way it is reassuring to see that we seem to have reached that point in the development cycle.

Saving Lives and Giving Hope by Reducing the Organ Waiting List

There are currently more than 120,000 people on the waiting list for an organ in the United States. Every 10 minutes, someone is added to the national waiting list for a life-saving organ transplant. This is despite advances in clinical science and medical innovation over the last decade and widespread recognition by Americans that organ donation and transplantation make a real difference in people's lives. Twenty-two people die every day in the United States while waiting for a life-saving transplant.

We must and can do more. The good news is that reducing the organ waiting list is a problem that can be solved - and that's why today, the Obama Administration and dozens of companies, foundations, universities, hospitals, and patient advocacy organizations are taking steps to change that by announcing a new set of actions that will build on the Administration's efforts to improve outcomes for individuals waiting for organ transplants and support for living donors.

NASA Challenge Aims to Grow Human Tissue to Aid in Deep Space Exploration

NASA, in partnership with the nonprofit Methuselah Foundation's New Organ Alliance, is seeking ways to advance the field of bioengineering through a new prize competition. The Vascular Tissue Challenge offers a $500,000 prize to be divided among the first three teams that successfully create thick, metabolically-functional human vascularized organ tissue in a controlled laboratory environment. Competitors must produce vascularized tissue that is more than .39 inches (1 centimeter) in thickness and maintains more than 85 percent survival of the required cells throughout a 30-day trial period. Teams must demonstrate three successful trials with at least a 75 percent success rate to win an award. In addition to the laboratory trials, teams also must submit a proposal that details how they would further advance some aspect of their research through a microgravity experiment that could be conducted in the U.S. National Laboratory on the International Space Station.

The new challenge was announced as part of White House Organ Summit, which highlighted efforts to improve outcomes for individuals waiting for organ transplants and support for living donors. In a related initiative, the Center for the Advancement of Science in Space (CASIS), which manages the International Space Station U.S. National Laboratory, announced a follow-on prize competition in partnership with the New Organ Alliance and the Methuselah Foundation that will provide researchers the opportunity to conduct research in microgravity conditions. CASIS will provide one team up to $200,000 in flight integration support costs, along with transportation to the ISS National Laboratory, support on station and return of experimental samples to Earth.

Launching Programs to "Stop Biological Time" at the White House Summit on Ending the Organ Shortage

Today, on the shoulders of recent progress suggesting that true organ cryobanking for the first time may be within reach and in partnership with the Thiel Foundation, Association of Organ Procurement Organizations, American Society of Mechanical Engineers, Society for Cryobiology, and New Organ Alliance, the Organ Preservation Alliance is launching:

1) A National Roadmap to Organ Banking Program to develop a consensus national strategy to advance organ and tissue preservation technologies, announced by the White House.

2) The official report from the year long NSF-funded "beta technology roadmapping process" with participation from world leading scientists, physicians and government.

3) A follow-up Dept. of Defense funded Complex Tissue Cryobanking Analysis and Report Process, reflecting the conclusions of the recent workshop at the West Point Military Academy with DARPA and others on the topics of Organs On-Demand and Biological Time control.

4) A companion Global Summit on Organ Banking through Converging Technologies in partnership with the Center for Engineering in Medicine at Massachusetts General Hospital/Harvard/MIT, announced by the White House.

5) A Breakthrough Ideas in Organ Banking Hackathon Program to bring together teams of young scientists, engineers and technology entrepreneurs working on solving the remaining challenges, announced by the White House.

Through these programs and others, scientists, surgeons and leaders are coming together from all over the world to work on the mission to save millions of lives through enabling breakthroughs in complex tissue cryopreservation and transforming transplant, trauma, and regenerative medicine.

Researchers here identify a possible proximate mechanism associated with the age-related decline of human fertility. It is a little early in the research process to say what might be made of this, or how it connects to the underlying causes of degenerative aging, however.

Researchers have examined the sharp decline in egg quality in women 40 and older and found that egg damage is linked to oxygen-deprived cells. "More women are postponing childbearing, but with age, the cumulus cells that surround and nurture the eggs begin dying; we've found that this is caused by lack of oxygen. This follicular hypoxia triggers a cascade of biochemical changes in the cumulus cells. This may ultimately affect chromosomal abnormalities seen in eggs of older patients."

The researchers studied samples from 20 cumulus cells in 15 patients younger than age 35 and in those age 40 and older. The team looked for differences in RNA expression in both sets of patients. They found significant differences in RNA molecules in the cumulus cells of older patients when compared to RNA expressed in cells of patients younger than 35. Changes in the ovarian microenvironment, such as reduced oxygen supply to the growing follicles are likely causes of ovarian aging. "Our data show that cumulus cells from older women are affected by a chronic exposure to suboptimal oxygen levels, as indicated by an increased expression of hypoxia-induced genes when compared to the same cells collected in younger patients. Our findings shed light on the mechanisms responsible for human egg aging. We have always been intrigued by the questions, 'Who is the time keeper of egg aging?' and 'How are the eggs informed of the biological clock?' Now we know that changes in RNA of the cumulus cells triggered by aging-induced hypoxia, are the key messengers. The ability to screen cumulus cells for oxygen deprivation may help us identify healthier eggs, modify ovarian stimulation protocols, and ultimately lead to more successful in vitro fertilization treatments."

Link: http://news.yale.edu/2016/06/06/biological-clock-gets-time-stamp

Here, Greg Fahy interviews George Church on the topic of gene therapies, gene expression changes in aging, and the aim of treating aging as a medical condition in a recent issue of Life Extension Magazine. Both of these researchers are enthusiastic about the path of identifying and reverting age-related changes in gene expression, something I consider to be most likely less useful than targeting root cause damage after the SENS model for rejuvenation therapies. Still, present day stem cell therapies are probably a good indication of the sort of result that can be achieved through gene expression alteration, as they largely work through signaling changes: putting damaged machinery back to work without fixing the underlying damage that causes aging. It can be argued that these gains are large enough to pursue, and we should just be aware that it isn't the path to controlling and halting aging, only the path to a class of therapies for age-related disease that are incrementally better than existing ones.

Fahy: If aging is driven by changes in gene expression, then the ability to control gene expression using CRISPR technology could have profound implications for the future of human aging. Why do you think aging may be at least partly driven by changes in gene expression?

Church: We know that there are cells that deteriorate with age in the human body and that we have the ability to turn those back into young cells again. This means we can effectively reset the clock to zero and keep those cells proliferating as long as we want. For example, we can take old skin cells, which have a limited lifetime, and turn them into stem cells (stem cells are cells that can turn into other kinds of cells) and then back into skin cells. This roundtrip results in the skin cells being like baby skin cells. It's as if my 60-year-old cells become 1-year-old cells. There are a variety of markers that are associated with aging, and those all get reset to the younger age.

Fahy: There are several very exciting stories in aging intervention these days. In 2013, the Sinclair lab at Harvard came out with the revelation that the aging of mitochondria (which are the producers of usable energy within cells) is driven in significant part by reduced levels of one particular molecule in the cell nucleus: oxidized NAD (NAD+). Now your lab showed that there is a very exciting gene engineering alternative involving TFAM (Transcription Factor A, Mitochondrial). Why is TFAM important, and what have you done with it?

Church: TFAM is a key regulatory protein that is in this pathway of NMN and NAD+. It allows cells to manufacture the NMN precursor on their own, so you don't have to manufacture it outside the cell and then try to get it into the cell from outside. Ideally, you don't want to have to take NMN for the rest of your life, you want to fix the body's ability to make its own NMN and buy yourself rejuvenation for at least a few decades before you have to worry about NMN again. In order to accomplish this on a single cell level, we've used CRISPR to activate a TFAM activator, and we made it semi-permanent. When we activated TFAM, these changes returned to what you would expect of a younger cell state. And we built this anti-aging ability into the cell, so it's self-renewing and eliminates the need to take pills or injections.

Fahy: GDF11 has been reported to rejuvenate the heart, muscles, and brain. It restores strength, muscle regeneration, memory, the formation of new brain cells, blood vessel formation in the brain, the ability to smell, and mitochondrial function. All of this is done by just one molecule. Infusing young plasma, which contains GDF11, into older animals also provides benefits in other tissues, such as the liver and spinal cord, and improves the ability of old brain cells to form connections with one another. How would you use CRISPR to make sure that GDF11 blood levels never go down?

Church: The CRISPR-regulating GDF11 could be delivered late in life, which is exactly when such an increase would be welcome. If you really wanted to stay at a certain level, you might want to put in a GDF11 sensor to provide feedback so you could automatically control GDF11 production so as to lock in a specific GDF11 level. If necessary, you could recalibrate and fine-tune this maybe once every few decades with another dose of CRISPR. But yes, it's a great molecule, and we've got a handle on it. We are also doing a number of other projects now, dealing with a range of muscle diseases such as muscle wasting. We're working on possible treatments involving proteins such as myostatin and follistatin.

Fahy: Speaking of myostatin, the lack of which causes super-development of muscles, you mentioned in your 2014 SENS talk that you are interested in the possibility of enabling better muscle strength and less breakable bones. Is this another good treatment path for aging?

Church: Muscle wasting and osteoporosis are symptoms of aging. The key to dealing with them is to get at the core causes, even if they're complicated. There are genes known to be involved in muscle wasting and genes that can overcome that.

Fahy: What about going beyond just correcting aging and actually super-protecting people by making them augmented with stronger bones or muscles than what they would normally have?

Church: Rather than waiting until the muscles are wasting and then trying to correct the problem, or waiting until someone breaks a bone and putting a cast on, the idea is to make the muscles and bones stronger to begin with. Think of it as preventive medicine. You have to be careful, but there are people naturally walking around with much denser bones and much stronger muscles that have no particularly bad consequences, so we know such things are possible. I would say osteoporosis definitely could be reversed. The process of bone building and bone breaking down is a regulated process that responds to conditions such as the good stress of standing or running. So yes, it's an example of something that's reversible.

Fahy: Using your most favorable pathway for intervention, how long will it take before a human trial might be possible?

Church: I think it can happen very quickly. It may take years to get full approval, but it could take as little as a year to get approval for phase one trials. Trials of GDF11, myostatin, and others are already underway in animals, as are a large number of CRISPR trials. I think we'll be seeing the first human trials in a year or two.

Link: http://www.lifeextension.com/Lpages/2016/CRISPR/index

Despite rapid progress in biotechnology, cancer research is an expensive and slow-moving field when it comes to results in the clinic. Many projects that absorb years in time and millions in funding produce failures or only marginal successes, little better than presently available options. Therapies developed at great cost are in any case usually only applicable to one out of the thousands of varieties and subcategories of cancer. The oppressive regulatory environment for medicine in the US serves to make these issues far worse and more costly than they might be, but the underlying nature of the field is present in all regulatory regimes. All of this makes cancer research a comparatively unattractive option to for-profit biotechnology investors, and that is a significant problem. These investors are a vital part of the machinery of the marketplace, and the funds they provide are needed to in order to start companies that work to move new medical technology from the laboratory to the clinic.

Here, some of the researchers in our longevity science community propose a financial solution to this problem, a way to better distribute risk in for-profit medical development investment so as to encourage greater participation. It is certainly true that at the present time, due to the increasingly unwise actions of those who control the monetary systems of the developed world, there is an awful lot of money sloshing around in search of returns. Even small improvements to the risk profile of biotechnology investment at the high end could pull in greater funding for the industry by ranking it more attractively in comparison to other options - and there is a growing dearth of other options for managers sitting on hundred of millions or billions or more.

Cancer megafunds with in silico and in vitro validation: Accelerating cancer drug discovery via financial engineering without financial crisis

Biomedicine faces a dilemma. Despite many recent scientific breakthroughs demonstrating a clear potential for combating cancer, there has been no significant private investment in cancer drug research and development. Both constantly rising costs and increasing rates of failures in the late stages of clinical trials have made the pharmaceutical research and development unappetizingly risky from a financial perspective.

In particular, there are two main challenges. First, on average the success rate of clinical trials is low so that the average financial yield is low. Second, the large investments required to bring a single treatment to the market lead to an all-or-nothing result: the risk is high. To increase funding for cancer research while providing adequate financial returns to investors with wide ranging risk profiles by investing in multiple clinical trials at once thereby mutualizing investments and diluting risks, the concept of a "cancer megafund" was proposed. A massive amount of investment capital would support a portfolio of many drug development projects in order to spread the risks associated with any stand-alone biomedical project. The resulting lowered default probabilities could make returns attractive to investors. By issuing Research-backed Obligations (RBOs), it could be also possible to attract both fixed-income and equity investors.

The authors go on to present options for a cancer megafund and run the mathematics to demonstrate likely outcomes. They make some suggestions as to where a few of the problems of agency and accountability lie in the matter of assembling and managing large-scale funds, and how to approve governance so as to minimize those problems. All good insofar as it goes, but I can't help but feel that this proposes a solution to entirely the wrong problem. The problem is not risk management, the problem is that most cancer research as currently conducted by the mainstream is not delivering meaningful advances at a feasible cost. If problems are to be solved, then that is the one to be solved.

I have long said that true progress in cancer research will come from greatly expanding the range of cancers that can be treated with a given technology platform. An alternative way of looking at that is to say that true progress requires crushing down the cost of delivering an advance in the capabilities of medicine for each different type of cancer. At the moment most cancer research is very specific to one subtype of cancer, and there is no reasonable expectation that the technology used can be adapted to any other cancer. This is especially true of small molecule approaches, traditional drug discovery and development, and so on. This approach to cancer isn't producing results that are sufficiently good to pull in investors like a magnet, given current costs and risks.

There is a linked set of figures to consider here: cost of development per therapy, the number of cancer types that therapy can address, the risk of failure at the end of development, and the cost to adapt the underlying technology platform to another cancer type. Right now all of those numbers are pretty terrible for most cancer research. Pulling in more funding won't change that fact, and may just serve to let the present mainstream of the research community continue along with business as usual, as carried out for cancer research over the past couple of decades. I'm personally of the opinion that a funding crunch is probably good for the community so long as it spurs a change in research strategy, given that there are a number of possible technological options to improve some of the numbers above.

The approach I favor for the mid-term future of cancer research, beyond the coming next generation of therapies largely based on immunotherapy, is some form of temporary blockade of telomere lengthening, possibly global, possibly targeted, informed by the SENS Research Foundation outline for this class of technology. Telomeres cap the ends of chromosomes, a part of the mechanism that limits the number of times a cell can divide. Telomeres lose length with each cell division, and when they become too short the cell destroys itself or becomes senescent and ceases replication. All cancers have to abuse telomere lengthening in order to grow, and there are a limited number of mechanisms responsible for that lengthening: telomerase expression and the alternative lengthening of telomeres (ALT) processes. Turn them all off, and that is that for any cancer. Not all that many research groups are working on this front at the moment, but the work that has been accomplished is promising. The prospect of deploying a truly universal cancer treatment platform for much the same cost as a single therapy for a single type of cancer, as research proceeds in the mainstream today, is very attractive. It merits a far greater level of investment than presently exists.

The challenge in linking air pollution to age-related disease and mortality risk lies in the confounding correlation with wealth. There are plausible mechanisms involving, for example, increased levels of inflammation resulting from high levels of air pollution, but regions with lower levels of air pollution tend to have much wealthier populations, and it is well known that wealth correlates with greater life expectancy, both for individuals and in societies as a whole. This study adds more statistical data to the mix:

Air pollution - including environmental and household air pollution - has emerged as a leading risk factor for stroke worldwide, associated with about a third of the global burden of stroke in 2013. The findings, from an analysis of global trends of risk factors for stroke between 1990-2013, also show that over 90% of the global burden of stroke is linked to modifiable risk factors, most of which (74%) are behavioural risk factors such as smoking, poor diet and low physical activity. The authors estimate that control of these risk factors could prevent about three-quarters of all strokes. The study is the first to analyse the global risk factors for stroke in such detail, especially in relation to stroke burden on global, regional and national levels. The researchers used data from the Global Burden of Disease Study to estimate the disease burden of stroke associated with 17 risk factors in 188 countries. They estimated the population-attributable fraction (PAF) of stroke-related disability-adjusted life years (DALYs) - ie. the estimated proportion of disease burden in a population that would be avoided if exposure to a risk factor were eliminated.

Globally, the ten leading risk factors for stroke were high blood pressure, diet low in fruit, high body mass index (BMI), diet high in sodium, smoking, diet low in vegetables, environmental air pollution, household pollution from solid fuels, diet low in whole grains, and high blood sugar. About a third (29.2%) of global disability associated with stroke is linked to air pollution (including environmental air pollution and household air pollution). This is especially high in developing countries (33.7% vs 10.2% in developed countries). In 2013, 16.9% of the global stroke burden was attributed to environmental air pollution (as measured by ambient particle matter pollution of aerodynamic diameter smaller than 2·5 μm) - almost as much as that from smoking (20.7%). From 1990 to 2013, stroke burden associated with environmental air pollution has increased by over 33%.

Link: http://www.eurekalert.org/pub_releases/2016-06/tl-tln_1060816.php

This popular science article looks at efforts to build therapies that target aggregations of tau, thought to contribute to neurodegenerative conditions such as Alzheimer's disease, but also present in a range of diseases known as tauopathies. Some tauopathies may in effect come to serve as testbeds for later efforts to treat Alzheimer's by clearing tau aggregates, because the link between tau and pathology is more clear in these conditions:

About 100 times rarer than Parkinson's disease, and often mistaken for it, progressive supranuclear palsy (PSP) afflicts fewer than 20,000 people in the U.S. This little-known brain disorder is quietly becoming a gateway for research that could lead to powerful therapies for a range of intractable neurodegenerative conditions including Alzheimer's and chronic traumatic encephalopathy, a disorder linked to concussions and head trauma. All these diseases share a common feature: abnormal buildup of a protein called tau in the brains of patients. People with PSP lose the sense of balance, although unlike in Parkinson's they fall backward instead of forward. Many PSP patients also struggle with speaking and swallowing. The problems can be traced to loss of nerve cells in the brain areas responsible for those capabilities - such as the basal ganglia, brain stem and cerebral cortex. Under a microscope these are the very regions that accumulate tangled clumps of tau, a normal protein found mostly in neurons. It binds to structures called microtubules, which help move nutrients up and down the cell. But in PSP and related disorders something goes wrong: Tau proteins twist out of shape and start sticking to one another rather than stabilizing microtubules. Then, through a mysterious process, the tau clusters leave the cell, spread throughout the brain and muck up communication between neurons.

Beyond PSP, other brain diseases are also marked by abnormal tau clumps. Research on Alzheimer's has focused largely on another protein called amyloid beta, which clusters into "plaques" in the brain. But there is growing interest in tau's role. When researchers analyzed healthy young adults, healthy older adults and older adults diagnosed with "probable Alzheimer's," those with a lot of tau in the temporal lobes and neocortex - brain areas important for sensory perception and memory - were close to dementia onset whereas symptoms could still be years out for people with high amyloid. Examining the brain scans in the context of other disease markers in the same participants showed that the rise and spread of tau in the brain tracked more closely with declining mental function than did amyloid. Location seems critical, too. Whereas amyloid may show up in various brain areas, tau appears more restricted to regions associated with the cognitive deficits.

Because tau more closely aligns with the start of dementia, an effective therapeutic has "probably got to deal with the tau." In past years researchers have identified tau-binding antibodies that slow the spread of toxic tau clusters in a lab assay using cultured cells. When injected into mice engineered with a tau mutation that makes the protein clump abnormally in brain cells, triggering memory and motor problems, the antibodies reduced the clumping and improved the animals' behavior. Other approaches aim to decrease tau protein production by targeting RNA; blocking tau clustering by interfering with chemical modifications on the protein's surface; or binding microtubules in order to enhance a normal tau function that gets lost as the protein misfolds and aggregates. At present a few tau-targeting approaches are being evaluated in Alzheimer's clinical trials. But more are being tested in people with PSP. Scientists are eager to assess tau therapies in PSP for a number of reasons: First, it is a pure tauopathy. Whereas people with Alzheimer's can have tau as well as several other proteins clustering in their brains, PSP patients only have abnormal tau. Second, tau has a stronger genetic link to PSP than it does to Alzheimer's. Other reasons for testing tau drugs in PSP patients have more to do with clinical trial practicalities. If an intervention is effective, then the participants taking the study drug should deteriorate more slowly than those in the placebo group. In some diseases such as Alzheimer's, however, decline is slow and inconsistent to begin with. PSP, by comparison, runs its course more rapidly and predictably.

Link: http://www.scientificamerican.com/article/obscure-disease-may-offer-backdoor-to-new-treatments-for-alzheimer-s-and-other-killers/

The latest update for ongoing efforts to test destruction and recreation of the immune system in patients suffering from the autoimmune disease multiple sclerosis demonstrates that this approach is effectively a cure if the initial destruction of immune cells is comprehensive enough. Researchers have been able to suppress or kill much of the immune system and then repopulate it with new cells for about as long as the modern stem cell therapy industry has been underway, something like fifteen years or so. Methodologies have improved, but the destructive side of this process remains unpleasant and risky, something you wouldn't want to try if there was any good alternative. Yet if not for the scientific and commercial success of immunosuppressant biologics such as adalimumab, clearance and recreation of immune cell populations may well have become the major thrust of research for other prevalent autoimmune conditions such as rheumatoid arthritis. Destroying these immune cell populations requires chemotherapy, however, and with avoiding chemotherapy as an incentive for patients, and the ability to sell people drugs for life as an incentive for the medical industry, biologics won. For conditions like rheumatoid arthritis, the aim became control and minimization of symptoms rather than the search for a cure. Only in much more damaging, harmful autoimmune conditions like multiple sclerosis has this research into wiping and rebuilding the immune system continued in any significant way.

Beyond being able to pinpoint which tissues are suffering damage due to inappropriately targeted immune cells, the underlying mechanisms of most autoimmune conditions are very poorly understood. Multiple sclerosis, for example, results from immune cells attacking the myelin sheathing essential for proper nerve function. Collectively, the cells of the immune system maintain a memory of what they intend to target, that much is evident, but the structure and nature of that memory is both very complex and yet to be fully mapped to the level of detail that would allow the many types of autoimmunity to be clearly understood. That these autoimmune conditions are all very different is evidenced from the unpredictable effectiveness of today's immunosuppressant treatments - they work for some people, not so well for others. Many autoimmune diseases may well turn out to be categories of several similar conditions with different roots in different portions of the immune system.

Destruction of the immune system offers a way around present ignorance: it is an engineering approach to medicine. If immune cell populations can be removed sufficiently comprehensively, then it doesn't really matter how they are storing the bad data that produces autoimmunity. That data is gone, and won't return when immune cells are restored through cell therapies. The cost of that process today is chemotherapy, which is not to be taken lightly, as the results presented here make clear. A mortality rate of one in twenty is enough to give pause, even if you have multiple sclerosis. In the future, however, much more selective cell destruction mechanisms will be developed, such as some of those emerging from the cancer research community, approaches that will make an immune reboot something that could be undertaken in a clinic with no side-effects rather than in a hospital with all the associated damage of chemotherapy. Autoimmune diseases are far from the only reason we'd want to reboot our immune systems: as we age, the accumulated impact of infections weighs heavily upon the immune system, and its limited capacity fills with uselessly specialized cells rather than those capable of destroying new threats. Failure of the immune response is a large part of age-related frailty, leading to both chronic inflammation and vulnerability to infection, and it is something that could be addressed in large part by an evolution of this approach to autoimmune disease.

New stem cell transplantation method may halt multiple sclerosis symptoms long-term, but therapy comes with high risk

A new use of chemotherapy followed by autologous haematopoietic stem cell transplantation (aHSCT) has fully halted clinical relapses and development of new brain lesions in 23 of 24 patients with multiple sclerosis (MS) for a prolonged period without the need for ongoing medication, according to a new phase 2 clinical trial. This is the first treatment to produce this level of disease control or neurological recovery from MS, but treatment related risks limit its widespread use. Some specialist centres offer aHSCT for MS, which involves harvesting bone marrow stem cells from the patient, using chemotherapy to suppress the patient's immune system, and reintroducing the stem cells into the blood stream to "reset" the immune system to stop it attacking the body. However, many patients relapse after these treatments, so more reliable and effective methods are needed.

Researchers tested whether complete destruction, rather than suppression, of the immune system during aHSCT would reduce the relapse rate in patients and increase long-term disease remission. They enrolled 24 patients aged 18-50 from three Canadian hospitals who had all previously undergone standard immunosuppressive therapy which did not control the MS. All patients had poor prognosis and their disability ranged from moderate to requiring a walking aid to walk 100m. The researchers used a similar method of aHSCT as is currently used, but instead of only suppressing the immune system before transplantation, they destroyed it completely using a chemotherapy regimen of busulfan, cyclophosphamide and rabbit anti-thymocyte globulin. This treatment is "similar to that used in other trials, except our protocol uses stronger chemotherapy and removes immune cells from the stem cell graft product. The chemotherapy we use is very effective at crossing the blood-brain barrier and this could help eliminate the damaging immune cells from the central nervous system."

The primary outcome of the study was multiple sclerosis activity-free survival at 3 years (as measured by relapses of MS symptoms, new brain lesions, and sustained progression of Expanded Disability Status Scale (EDSS) scores) which occurred in 69.6% of patients after transplantation. Out of the 24 patients, one (4%) died from hepatic necrosis and sepsis caused by the chemotherapy. Prior to the treatment, patients experienced 1.2 relapses per year on average. After treatment, no relapses occurred during the follow up period (between 4 and 13 years) in the surviving 23 patients. These clinical outcomes were mirrored by freedom from detectable new disease activity on MRI images taken after the treatment. The initial 24 MRI scans revealed 93 brain lesions, and after the treatment only one of the 327 scans showed a new lesion. Furthermore, progressive brain deterioration typical of MS slowed to a rate associated with normal aging in 9 patients with the longest follow-up.

Immunoablation and autologous haemopoietic stem-cell transplantation for aggressive multiple sclerosis: a multicentre single-group phase 2 trial

Strong immunosuppression, including chemotherapy and immune-depleting antibodies followed by autologous haemopoietic stem-cell transplantation (aHSCT), has been used to treat patients with multiple sclerosis, improving control of relapsing disease. We addressed whether near-complete immunoablation followed by immune cell depleted aHSCT would result in long-term control of multiple sclerosis. We enrolled patients with multiple sclerosis, aged 18-50 years with poor prognosis, ongoing disease activity, and an Expanded Disability Status Scale of 3.0-6.0. Autologous CD34 selected haemopoietic stem-cell grafts were collected after mobilisation with cyclophosphamide and filgrastim. Immunoablation with busulfan, cyclophosphamide, and rabbit anti-thymocyte globulin was followed by aHSCT.

Between diagnosis and aHSCT, 24 patients had 167 clinical relapses over 140 patient-years with 188 lesions on 48 pre-aHSCT MRI scans. Median follow-up was 6.7 years (range 3.9-12.7). The primary outcome, multiple sclerosis activity-free survival at 3 years after transplantation was 69.6%. With up to 13 years of follow-up after aHSCT, no relapses occurred and no lesions were seen on 314 MRI sequential scans. The rate of brain atrophy decreased to that expected for healthy controls. One of 24 patients died of transplantation-related complications. 35% of patients had a sustained improvement in their Expanded Disability Status Scale score. In summary, we describe the first treatment to fully halt all detectable CNS inflammatory activity in patients with multiple sclerosis for a prolonged period in the absence of any ongoing disease-modifying drugs. Furthermore, many of the patients had substantial recovery of neurological function despite their disease's aggressive nature.

The Major Mouse Testing Program is a volunteer group focused on studying potential therapies to treat aging. They aim to carry out necessary mouse studies that the mainstream of the research community is neglecting, many of which are combinations of multiple treatments, so as to speed up the pace of progress in this field. The volunteers, researchers and advocates, are presently crowdfunding their first set of studies. With just a few weeks left in the fundraiser, I encourage you to help out and offer your support in this venture. The more of this work that is accomplished, the closer we come to clinical applications of the underlying technologies, ways to meaningfully treat aging to extend healthy life and prevent age-related disease.

People could live longer lives in health and vitality by taking new kinds of medicines that clean out their bodies of old, dysfunctional cells, says a Paris-based research group. The idea is - instead of waiting for bodily aging to make people vulnerable to diseases like Alzheimer's or cancer - to keep the body strong and healthy as long as possible. The International Longevity Alliance (ILA), a French foundation, says research increasingly points to damage and junk in the cells as crucial to the aging process whereas in the past it was thought aging was just a general 'wearing out' of the body which nothing could be done about.

The ILA's new research project - the Major Mouse Testing Program (MMTP) - will test a combination of three drugs of a new kind called senolytics, which have successfully demonstrated their ability to significantly improve the state of the cardiovascular system, lungs and skin in old mice, but have not yet been tested for the effects they are believed to have on longevity. To speed up the pace of the experiments, testing will be done in mice that have already reached middle age - 18 months old - corresponding to a person aged around 60. "Although your body ages every day, researchers are working to unlock the secrets of aging and volunteers are joining forces from all over the world to help medical research restore vitality. This could be part of a last big push against decrepitude. We want to find a way to help the body get rid of old cells that inhibit the body's natural capacity of regenerating its tissues."

The ILA is fundraising for the first batch of tests, which are being done on a voluntary basis, though costs of mice, their housing and food, and analysing the results, need to be covered. The results will be made freely available to scientists around the world. The crowdfunding model, and the fact that the project is volunteer-run, is deliberately non-traditional - no shareholders expecting a return, no grant applications which can fall foul of politics - with the hope of speeding up the rate of progress in anti-aging medicine. The current project is the MMTP's first stage, but it is planned it will lead to many more tests to develop an arsenal of proven treatments and to understand effects of combining them. The more money raised, the more substances researchers will test - some 200 promising ones have not been tested yet. Combining senolytics to clear toxic cells with stem cell therapy, to promote healing, is among the future projects planned.

Link: http://www.connexionfrance.com/aging-cure-International-longevity-Alliance-Major-Mouse-Testing-Program-Aubrey-De-Grey-18136-view-article.html

Researchers have produced a reliable blood test for the early stages of Alzheimer's disease. Early identification of Alzheimer's disease has long been a challenge for the medical community, and only in the past few years have inroads like this been made:

Researchers have announced the development of a blood test that leverages the body's immune response system to detect an early stage of Alzheimer's disease - referred to as the mild cognitive impairment (MCI) stage - with unparalleled accuracy. In a "proof of concept" study involving 236 subjects, the test demonstrated an overall accuracy, sensitivity and specificity rate of 100 percent in identifying subjects whose MCI was actually caused by an early stage of Alzheimer's disease. "About 60 percent of all MCI patients have MCI caused by an early stage of Alzheimer's disease. The remaining 40 percent of cases are caused by other factors, including vascular issues, drug side-effects and depression. To provide proper care, physicians need to know which cases of MCI are due to early Alzheimer's and which are not."

"Our results show that it is possible to use a small number of blood-borne autoantibodies to accurately diagnose early-stage Alzheimer's. These findings could eventually lead to the development of a simple, inexpensive and relatively noninvasive way to diagnose this devastating disease in its earliest stages. It is now generally believed that Alzheimer's-related changes begin in the brain at least a decade before the emergence of telltale symptoms. To the best of our knowledge, this is the first blood test using autoantibody biomarkers that can accurately detect Alzheimer's at an early point in the course of the disease when treatments are more likely to be beneficial - that is, before too much brain devastation has occurred."

For the study, the researchers analyzed blood samples from 236 subjects, including 50 MCI subjects with low levels of amyloid-beta 42 peptide in their cerebrospinal fluid. The latter is a reliable indicator of ongoing Alzheimer's pathology in the brain and predicts a likely rapid progression to Alzheimer's. Employing human protein microarrays, each containing 9,486 unique human proteins that are used as bait to attract blood-borne autoantibodies, the researchers identified the top 50 autoantibody biomarkers capable of detecting ongoing early-stage Alzheimer's pathology in patients with MCI. In multiple tests, the 50 biomarkers were 100 percent accurate in distinguishing patients with MCI due to Alzheimer's from healthy age- and gender-matched controls. Further testing of the selected MCI biomarker panel demonstrated similar high overall accuracy rates in differentiating patients with early Alzheimer's at the MCI stage from those with more advanced, mild-moderate Alzheimer's (98.7 percent), early-stage Parkinson's disease (98.0 percent), multiple sclerosis (100 percent) and breast cancer (100 percent).

Link: http://today.rowan.edu/home/news/2016/06/08/rowan-researchers-develop-blood-test-detects-early-alzheimers-disease

I notice that later this month there is a networking event for investors interested in longevity science and the opportunities to invest in the field, with Aubrey de Grey, Sonia Arrison, and some of the other folk who move in Thiel Capital circles. It is taking place in Menlo Park in the California Bay Area on the 21st:

Launching Longevity: Funding the Fountain of Youth

Can technology make human longevity a reality? As the pace of discovery accelerates, scientists and entrepreneurs are closing in on the Fountain of Youth. Disrupting the aging process by hacking the code of life, promises better health and longer maximum lifespans. With many layers of complexity from science to ethics, there are still skeptics placing odds against human longevity. Venture capitalists are betting on success; putting big money on the table to fund longevity startups. Google/Alphabet and drugmaker AbbVie have invested $1.5 billion on Calico, while Human Longevity Inc. recently raised $220 million from their Series B funding round. Complementing traditional venture investment, VCs like Peter Thiel and Joon Yun have established foundations and prizes to accelerate the end of aging.

Why are VCs suddenly investing heavily in longevity startups? Will extended lifespan be a privilege of the wealthy or will the benefits be accessible to all? How long before these well-funded startups bring viable products to market? Join us on June 21 to hear our panel of leading experts discuss the science and business of human longevity.

Most people have, I think, at least a sketchy idea of what it is that venture capitalists and angel investors do: they put money into young companies in exchange for an ownership stake in the hopes of making a profit. Most companies fail or settle down into a barely profitable small business, and a few succeed and grow. Investment by professionals is far from the only way that companies can be funded in their early stages, however. Founders can take loans, use debt of other sorts, their own savings, and in the rare and lucky cases nothing more than revenue from clamoring hordes of new customers in order to fund the costs of setting up and the costs of growth.

For the transition of rejuvenation research after the SENS model from laboratory to startup to clinic, the venture and angel communities are especially important, however. Much more so than for most other fields. Networking is everything, and it is no accident that the SENS Research Foundation is headquartered in the Bay Area. The community of supporters who over the past 15 years raised up the SENS initiative and other related longevity science efforts upon their collective shoulders are in large part scientists, engineers, futurists, and investors - an overlapping group in that part of the world. Scientists found companies, engineers get wealthy enough to invest, and futurists spread the word, often enough while writing code by day. All rub shoulders, and dip into one another's fields of interest. The event above is representative of many meet and greet salons held in recent years in that community, with the only difference these days being that the first startup companies implementing the first rejuvenation therapies now exist. There are now opportunities to invest for the Bay Area network, and the people who listened to the futurists and wanted this to come to pass have a chance to bend their day jobs around to help.

Investing is something that investors do moderately well - or at least those that remain investors for any length of time. There is a method and a discipline and a body of tradition and knowledge. But it arguably isn't the most important thing they can be doing at this juncture in the development of longevity science. What the investment community should do, attempts to some degree, but is very poor at accomplishing is the process of nudging along pre-commercial efforts, of funding the research that will produce a crop of companies working on the technology that they would like to see exist. This is something that will not be carried out by any of the other institutions that have traditionally funded the development of early stage companies. Yet for the most part even personally interested investors leave philanthropy in their field to other people, and thus funding for truly radical, high-risk, high-reward new research is next to non-existent. The other side of the coin, targeted funding for medical research projects with excellent prospects, or that are only a few years and a million dollars away from the leap to a candidate therapy and a startup, nudging them into the target zone, is also very thin on the ground.

This is a point that Peter Thiel has been making for a few years under the heading of "radical philanthropy." The investor community does carry out philanthropy, but in a scattershot fashion, without much organization, rigor, or discipline. There is no body of tradition and knowledge in the same way as exists for the day job of for-profit investment. So a great many philathropic ventures are ultimately largely a waste, failing to achieve practical ends because they fail to spur the practical outcome of pushing research towards the clinic. Money is poorly used. There is very little in the way of nudging promising research across the line, which is strange given that this is a very good way to be positioned as the primary investor in ventures in a field that an individual might want to see move faster.

The SENS Research Foundation and Methuselah Foundation are examples of a more ad-hoc iteration of the sort of organization that might exist were this line of thinking about research, investment, and startups taken to a more rigorous conclusion. Which is to say that launch of a company is not the start of the process, and investors should be involved well before that point if they want to better achieve their goals. Many of the donors to SENS rejuvenation research projects and Methuselah Foundation initiatives are investors themselves, and some are presently coming together as a loose community of peers to invest in the startups that are now beginning to emerge from research efforts. Yet this is still at the present time, even hard-won as it is, only one increment better than a collection of happenstance events and connections, tumbling in more or less the right direction and working out because everyone involved has much the same goal in mind - which is to say therapies to treat aging, and sooner rather than later. Building on what has been learned so far, better and more organized ways to meld philanthropy and investment might be assembled. A community with deep pockets that can build the intricate networking tools and the energetic, highly networked approach to for-profit investment that presently exists should be able to make the leap over the barrier to organize and assist the non-profit research pipeline as well.

Here is an example of ongoing work on stem cell transplants for the treatment of Parkinson's disease, in which the proximate cause of the condition is an accelerated age-related loss of a small but vital population of dopamine-generating neurons in the brain. Similar transplant therapies have been tested in a number of species, and in human patients over the past decade, but there is a great variety of possible cell sources and methodologies of treatment. Progress towards a standardized therapy emerging from all of this has been frustratingly slow.

Human parthenogenetic stem cells, derived from unfertilized oocytes, can be used to generate unlimited supply of neural stem cells for transplantation. Researchers testing the potential of cell therapy for treating Parkinson's disease (PD) has found that grafting human parthenogenetic stem cell-derived neural stem cells (hpNSCs) into non-human primates modeled with PD promoted behavioral recovery, increased dopamine concentrations in the brain, and induced the expression of beneficial genes and pathways when compared to control animals not transplanted with stem cells.

The researchers also reported that the intracerebral injection and transplantation of hpNSCs was "safe and well-tolerated" for the two transplantation test animal groups with moderate to severe PD symptoms. "Previous clinical studies have shown that grafted fetal neural tissue can achieve considerable biochemical and clinical improvements in PD, however the source of fetal tissue is limited and may sometimes be ethically controversial. Human parthenogenetic stem cells offer a good alternative because they can be derived without destroying potentially viable human embryos and can be used to generate an unlimited supply of neural cells for transplantation."

PD is characterized by a profound loss of function of the brain's basal ganglia, resulting in a loss of dopamine neurons. Experiments using stem cells have offered benefits in pre-clinical studies, but have also provided "a wide variety of patient outcomes." This study used hpNSCs because the cells demonstrate characteristics of human embryonic stem cells, but are not sourced from viable embryos, which may be destroyed in the process. Previous studies with hpNSCs had shown that the cells could also be "chemically directed" to differentiate into multipotent neural stem cells and were able to be frozen for future use. While the study was designed to determine whether the test animals showed greater improvement than the control group, researchers added that a longer outcome period than 12 months may have demonstrated continued improvement and divergence from controls.

Link: http://www.eurekalert.org/pub_releases/2016-06/ctco-nsc060716.php

Scientists have explored a wide variety of avenues that might lead to greater regeneration of nerve damage in mammals. In this promising early stage research, the focus is on mitochondrial activity in nerve tissue, and the ways in which it changes after childhood development:

Researchers have discovered that boosting the transport of mitochondria along neuronal axons enhances the ability of mouse nerve cells to repair themselves after injury. Neurons need large amounts of energy to extend their axons long distances through the body. This energy - in the form of adenosine triphosphate (ATP) - is provided by mitochondria, the cell's internal power plants. During development, mitochondria are transported up and down growing axons to generate ATP wherever it is needed. In adults, however, mitochondria become less mobile as mature neurons produce a protein called syntaphilin that anchors the mitochondria in place. Researchers wondered whether this decrease in mitochondrial transport might explain why adult neurons are typically unable to regrow after injury.

The researchers initially found that when mature mouse axons are severed, nearby mitochondria are damaged and become unable to provide sufficient ATP to support injured nerve regeneration. However, when the researchers genetically removed syntaphilin from the nerve cells, mitochondrial transport was enhanced, allowing the damaged mitochondria to be replaced by healthy mitochondria capable of producing ATP. Syntaphilin-deficient mature neurons therefore regained the ability to regrow after injury, just like young neurons, and removing syntaphilin from adult mice facilitated the regeneration of their sciatic nerves after injury. "Our in vivo and in vitro studies suggest that activating an intrinsic growth program requires the coordinated modulation of mitochondrial transport and recovery of energy deficits. Such combined approaches may represent a valid therapeutic strategy to facilitate regeneration in the central and peripheral nervous systems after injury or disease."

Link: http://www.eurekalert.org/pub_releases/2016-06/rup-mmm060716.php

One of the multiple classes of rejuvenation therapies that will have to be built in order to bring aging under medical control involves mitochondria. The medical community must either repair damage to mitochondrial DNA or make that damage irrelevant. Mitochondria are found in their hundreds in each of our cells, the evolved descendants of symbiotic bacteria that now perform many vital functions. They carry their own DNA, thirteen genes left over from the full genome of their ancestors. There are ways for this DNA to become damaged in the course of normal cellular operations, and some of that damage can spiral out of control to cause harm to cells and surrounding tissues. Over the years ever more cells fall victim to dysfunctional mitochondria, and the damage done mounts ever higher. This is one of the causes of aging and age-related disease.

There are, however, other types of disease that involve mitochondrial mutations, and in a world in which there is much left to be done to bring greater support to rejuvenation research, it is in the construction of therapies for inherited mitochondrial diseases where the foundational work is taking place for mitochondrial repair. Eight years ago, the Methuselah Foundation and later the SENS Research Foundation used the philanthropic donations of supporters like you and I to help fund the work of a French research group on allotopic expression of mitochondrial genes. This involves copying mitochondrial genes into the cell nucleus, edited in ways that ensure that the proteins produced find their way back to the mitochondria where they are needed. When accomplished, this can mean that damage to mitochondrial DNA no longer has any detrimental effect, as the necessary proteins are still being produced. The work of past years has since blossomed into Gensight, a venture-funded company putting considerable effort to bring this type of gene therapy to the clinic.

There is a lot of work to be done here. Each mitochondrial gene requires its own challenging recipe to make the process of allotopic expression work, but allotopic expression of even one gene of the thirteen can be used to cure inherited mitochondrial diseases involving mutations of that gene. So it is possible to build companies that work on that goal, and each mitochondrial gene successfully moved to the nucleus is one thirteenth of the way to building a rejuvenation therapy that can eliminate the contribution of mitochondrial DNA damage to aging, and rejuvenate the old who are already well down the road of suffering the consequences. At present the solidly accomplished count stands at three genes. ND4, where mutation is the one of the causes of Leber hereditary optic neuropathy (LHON) is the initial focus for Gensight, and was the first gene targeted in the research funded eight years ago. As of this year, Gensight is organizing a pair of phase III trials in LHON patients. Meanwhile, at the other end of the research and development pipeline, last month the SENS Research Foundation team announced success for ATP6 and ATP8, the end of a lengthy research initiative that has produced proof of allotopic expression for these two genes in cell cultures. Other mitochondrial genes have had allotopic expression demonstrated in yeast only, or the process of relocating proteins back to the mitochondria is only partly solved.

Gensight is not the only group working on human trials of allotopic expression of ND4 for the treatment of LHON. There are at least two other independent academic research groups with results from human trials to show that allotopic expression is a viable technology, and below you'll find links to their recent research results:

Efficacy and Safety of rAAV2-ND4 Treatment for Leber's Hereditary Optic Neuropathy

The aim of this study was to evaluate the efficacy and safety of a recombinant adeno-associated virus 2 (AAV2) carrying ND4 (rAAV2-ND4) in LHON patients carrying the G11778A mutation. Nine patients were administered rAAV2-ND4 by intravitreal injection to one eye and then followed for 9 months. Ophthalmologic examinations of visual acuity, visual field, and optical coherence tomography were performed. The visual acuity of the injected eyes of six patients improved by at least 0.3 log MAR after 9 months of follow-up. In these six patients, the visual field was enlarged but the retinal nerve fibre layer remained relatively stable.

Gene Therapy for Leber Hereditary Optic Neuropathy

In this prospective open-label trial, the study drug (self-complementary adeno-associated virus [scAAV]2(Y444,500,730F)-P1ND4v2) was intravitreally injected unilaterally into the eyes of 5 blind participants with G11778A LHON. Four participants with visual loss for more than 12 months were treated. The fifth participant had visual loss for less than 12 months. Treated participants were followed for 90 to 180 days and underwent ocular and systemic safety assessments along with visual structure and function examinations. Visual acuity remained unchanged from baseline to 3 months in the first 3 participants. For 2 participants with 90-day follow-up, acuity increased from hand movements to 7 letters in 1 and by 15 letters in 1, representing an improvement equivalent to 3 lines. No one lost vision, and no serious adverse events were observed.

This can all be taken as more proof to show that the SENS approach of targeted philanthropic support of critical research projects in fields that are languishing creates real results. Donating to the SENS Research Foundation and Methuselah Foundation produces meaningful results: together, we have made a difference. In this case work on allotopic expression has snowballed from a tiny, poorly supported sideline into a competitive research and development community focused on mitochondrial genes. The Gensight leadership isn't resting on its laurels and will next work on allotopic expression of ND1, one of the remaining mitochondrial genes. This is exactly what the other teams will do once they are at that stage of development. All in all this is the reassuring sight of progress, the construction of robust technology platforms that will inform the development of one very important branch of rejuvenation therapies in the years ahead, the ability to remove the harms done to us by our own mitochondria.

Protein levels are the controlling switches and dials of cellular behavior, and most are very dynamic in response to circumstances. One important set of circumstances is the damage that accumulates over the course of aging. Cells react to that damage with epigenetic changes, chemical decorations to DNA that alter the pace of production of various proteins. In some cases this helps to compensate for damage, in others it makes things worse. This open access paper reviews what is known of age-related epigenetic alterations:

Aging is characterized by progressive functional decline at the molecular, cellular, tissue, and organismal levels. As an organism ages, it becomes frail, its susceptibility to disease increases, and its probability of dying rises. In humans, age is the primary risk factor for a panoply of diseases including neurodegeneration, cardiovascular disease, diabetes, osteoporosis, and cancer. Over the past decades, a large body of research has shown that the molecular and cellular decline of aging can be organized into several evolutionarily conserved hallmarks or pillars of aging. For example, in yeast and animals, mitochondrial dysfunction increases with age and may contribute to the progression of aging. The hallmarks of aging are interconnected, and age-associated perturbations of one can affect others. While significant progress has been made in our understanding of aging, many outstanding questions remain: Which age-associated changes are causative? How are the hallmarks of aging related to each other, and are there "hubs" in this network? Which age-dependent changes occur first? When does aging begin? Can therapeutics slow aging or even rejuvenate some aging hallmarks in an animal at any stage during lifespan, or is there a "point of no return"?

The study of gene regulation is central to many of these questions. The regulation of gene expression is not only necessary for nearly every aspect of a cell's function, but it can be sufficient to alter cellular fate. While it is clear that many biological systems and hallmarks play a crucial role in the progression of aging, we propose that epigenomic changes are particularly important because of the following: (1) Changes in gene regulation (often through expression of a single transcription factor) have been shown to be key for cellular identity. Thus, age-associated changes in transcription regulatory networks are likely to impact the function of a cell or tissue and give rise to aging phenotypes and diseases. (2) Gene regulation is a natural "hub" in the cell. Transcription regulators and chromatin modifiers receive cytoplasmic and extracellular signals and, in turn, alter the responses of the cell in an orchestrated manner. For example, in response to proteostatic stress, protein chaperone expression increases. (3) Chromatin marks are long lasting and show a progressive change with age that persists through cellular divisions. Thus, they can act as a memory that helps to propagate age-associated cellular dysfunction. (4) Recent evidence suggests that epigenomic changes can occur extremely early in the aging process and be causative.

Link: http://www.cell.com/molecular-cell/fulltext/S1097-2765(16)30150-2

A recent paper provides data to show that increases in human life expectancy, so far an incidental byproduct of improvements in medical technology and lifestyle choices rather than any deliberate attempt to tackle aging, are accompanied by an increase in years spent free from disability in later life. The current slow upward trend will soon enough become a thing of the past, as the research community is presently transitioning from ignoring aging, despite it being the cause of all age-related death and disease, to attempting to intervene in processes of aging. As this approach gains wider support, a much faster upward trend in life expectancy will take hold, characterized by leaps and bounds as new technologies are introduced, such as SENS rejuvenation therapies that repair the cell and tissue damage that lies at the root of aging.

A new study that shows that the increase in life expectancy in the past two decades has been accompanied by an even greater increase in life years free of disability, thanks in large measure to improvements in cardio-vascular health and declines in vision problems. "This suggests, for the typical person, there really is an act beyond work - that once you reach age 65, you can likely look forward to years of healthy activity. So this is good news for the vast bulk of people who can now look forward to healthier, disability free life, but it's also good news for medical care because it demonstrates the value of medical spending."

The study found that in 1992, the life expectancy of the average 65-year-old was 17.5 years, 8.9 of which were free from disability. By 2008, total life expectancy has risen to 18.8 years. In addition to the overall increase, the number of disability-free years increased, from 8.9 to 10.7, while the number of disabled years fell, from 8.6 to 8.1. Driving those changes are two major treatment areas - cardiovascular health and vision treatment. "There has been an incredibly dramatic decline in deaths and disabilities from heart disease and heart failure. "Some of it is the result of people smoking less, and better diet, but we estimate that as much as half of the improvement is because of medical care, especially statin drug treatment, which is both preventing heart attacks and improving people's recovery." Much of the improvement in vision health can be summed up in a single word - cataracts. "In the past, cataract surgery was very lengthy and technically difficult. That same surgery today can be done in an outpatient setting, so that complications and disability are significantly ameliorated. It used to be that when you turn 70, your occupation became managing your health. Now you can increasingly just live your life."

Link: http://www.eurekalert.org/pub_releases/2016-06/hu-lld060616.php

Based on the lengthy history of posts here at Fight Aging!, I've put together a list of potential targets for gene therapy in the near future. Here, the focus is on relevance as compensatory therapies for aging, so this list omits the wide range of inherited disorders based on single faulty genes that will account for a large proportion of the gene therapy medical industry over the next few decades. Further, Fight Aging! only samples the stream of ongoing research, and so not every line of research ends up noted here. Thus the list is far from exhaustive. If a more complete list is needed, I recommend heading over to the GenAge online database, where you will find entries for several thousand genes in various species.

Additionally, there are many classes of gene therapy that are temporary, intended to briefly improve the situation in abnormal disease states in much the same way as drugs do, and I'm skipping most of those as well. Lastly, almost all potential gene therapies at the present time aim at best to compensate for the damage of aging in one way or another, or to very modestly slow the progression of that damage by altering the operation of metabolism is ways that are still far from fully mapped. Based on the few cases where we can compare the same genetic manipulation in mice and humans, only the mice have obvious extension of life: lifespan is much more plastic in short-lived species when it comes to altering the operation of metabolism. All of that has never been as interesting to me as the SENS model of rejuvenation through repair: fixing the cell and tissue damage that causes aging rather than papering over it, an approach that can in principle produce large gains in life span in our species, but which has little to do with most of the approaches to gene therapies currently under development.

This is the Age of Gene Therapy

That said, this is an era of enthusiasm for genetics and gene therapy, in which it is becoming possible to cost-effectively edit the levels of specific proteins in specific tissues at specific times, and in response to circumstances. Given a hammer, there will be people who see every problem in terms of nails, regardless of whether or not that is the case. Proteins are coded in our genes, produced from that blueprint by the process of gene expression. Genes can be removed, altered, or duplicated, and rates of gene expression can be selectively increased or decreased. Our cells are machines and the amounts of proteins present are both machine parts and controls to the machinery: cell activity alters in response to higher or level levels of various proteins. It is an enormously complicated and interdependent set of controls, still poorly understood to be sure, but the ability to change protein levels is in principle the ability to change cell behavior. At this stage the fastest way to find out what any specific change does is to try it, first in animal studies, and then confirming in human tests. It is possible to theorize in advance, to pick plausible targets based on past evidence and experiment, but since everything in cellular biochemistry connects to everything else, no change occurs in isolation. It will have secondary and further effects, altering mechanisms and rates of gene expression for other proteins, and thus may or may not end up achieving the result that theory suggests it will.

The rapid advances in genetic editing technologies over the past few years have handed the keys to the castle to the research and development community. Where previously it was very expensive to work on gene therapies, now it is much cheaper and much easier. Only very credible paths were previously open, and merited a lot of groundwork to ensure that efforts were not wasted. Now any single gene alteration is a viable place to start experimenting. The diverse body of scientific work from the past few decades can be trawled for any of the scores of gene therapies that existing evidence suggests might be beneficial enough in humans to be worth the effort. Sadly only a few of these are associated with an sufficiently extensive set of evidence such that responsible human trials are an immediate possibility: myostatin knockout for muscle growth and telomerase gene therapies to offset some of the declines of aging. In most cases a potential target for gene therapy might have only have a couple of animal studies backing it, if that. Thus confirming research projects would be required, additional work to establish that earlier conclusions were correct, and that undesirable side-effects are not lurking in the background.

Consider, however, that a few years from now multiple companies will likely be providing a small range of gene therapies to customers via medical tourism. That is the aim of BioViva, for example, and they are scarcely alone in the community of those interested in this field. To the extent that these companies succeed, they and those who follow in their footsteps will be mining the literature for additional genes to target. There will be a rush of new research and development to pull in the most plausible candidate genes: competition will drive this process, because specific genetic alterations will quickly become standardized, commoditized, widely cross-licensed products. There will soon enough be little difference between, say, a myostatin gene therapy carried out by one clinic versus another, and so companies will have to compete in other ways. This is the root of progress.

Potential Targets for Future Gene Therapies, Speculative and Otherwise

Angiotensin-converting enzyme (ACE): Lowered levels of ACE have been shown to extend mean life span in nematode worms. ACE inhibitors are used in medicine to treat hypertension, but the mechanism by which they extend life in nematodes - not a species that has to worry about high blood pressure - remains to be explored.

Adenylyl Cyclase Type 5 (AC5): Knockout of AC5 extends life in mice, with the most plausible mechanism being increased resilience of the cardiovascular system to the various slings and arrows of aging. Many of the other aspects of AC5 knockout mice resemble those of calorie restricted mice.

AMPK: Targeted overexpression of AMPK in the intestines of flies leads to increased life span. This is an energy sensor protein, connected to the calorie restriction response of greater cell maintenance, improved health, and modestly slowed aging. A number of related methods of improving stem cell activity in fly intestines have also demonstrated extension of life span.

Angiopoietin-like 4 (ANGPTL4): A recent study suggests that a rare variant in this gene, present in less than 1% of the European population, reduces the risk of heart attack by half. The suggested mechanism involves alternations to cholesterol metabolism. This is a great example of a potential gene therapy target that still needs a fair amount of work to validate the thesis and the initial data, but having a large number of existing human carriers is a good sign on the safety front.

Angiotensin II receptor type 1 (Agtr1a): Lowering Agtr1a protein levels protects mitochondrial function and modestly extends life in mice, though as for many of these methods of somewhat slowing aging there are probably many other changes to the operation of metabolism that are as yet unexplored.

Apolipoprotein A-1: Increased amounts of this protein can be deployed to alter cholesterol metabolism in a beneficial way, slowing progression of atherosclerosis by transporting away some of the damaged lipids where they are build up in blood vessel walls.

APOE: APOE is one of the only human genes with variants that are robustly associated with greater longevity. That said, it doesn't take a very large effect to produce such an association. Perhaps some people have a 1.2% chance of reaching age 100 rather than a 1% chance; that would be enough if the effect is fairly similar in most human populations. That isn't a great gain, and to my eyes isn't something worth chasing as the basis for a gene therapy.

ARID1A: A recent accidental discovery is that gene knockout of ARID1A produces greater regenerative capacity in mice, particularly in the liver. So far there is little to say about how ARID1A knockout produces its effect, as increased regeneration is the opposite outcome from that theorized to result from this genetic alteration.

Activating transcription factor 4 (ATF4): Increased levels of ATF4 in the liver are found in many of the methods of slowing aging in laboratory species, though it is unclear whether or not that makes this protein a useful target in and of itself.

Atoh1: Increased amounts of atoh1 have been used to spur growth of hair cells in guinea pigs, making it one of a number of possible approaches to address the proximate cause of forms of age-related deafness that result from loss of these cells, rather than from other causes.

Azot: The azot gene in fruit flies is a part of a mechanism by which cells collaborate to identify damaged or dysfunctional neighbors, flagging them for destruction and replacement. Adding an extra copy of the azot gene to increase levels of the azot protein results in more effective destruction of less fit cells, and an increase in life span - in fruit flies at least. The gene and associated mechanism of quality control appears to be conserved in mammals, but there is as yet little further research leading towards trying a similar approach in mice and humans to see what happens.

BCAT-1: Inhibition of bcat-1 is shown to extend life in nematode worms, possibly via a form of hormesis or calorie restriction effect by blocking the processing of some dietary molecules.

β2 microglobulin (B2M): B2M levels rise with age, and in mice reducing the amount of B2M in older inviduals restores some of the loss of cognitive decline that occurs in aging. The mechanism involved is up for debate, but the known role of B2M relates to the adaptive immune system.

BubR1: Mice engineered to express higher levels of BubR1 have lower levels of cancer, greater exercise capacity, and live modestly longer. The cancer effect makes sense in the context of what is known of BubR1, that it is involved in an important checkpoint mechanism of cellular replication, but the other outcomes are less well understood.

C-Myc: It is interesting that most of the genes involved in the recipes that produce induced pluripotency show up in this list, such as c-myc. Researchers have shown that lowered levels of c-myc can modestly slow aging and extend life in mice, with some evidence that this is due to effects on insulin metabolism, though there is a still a lot of investigation needed to take that as a firm conclusion.

C1Q: The C1Q gene plays a role in the immune system. Removing it from mice spurs greater regeneration via Wnt signaling. C1Q levels rise in the brain with aging, and again, removing it improves the state of cognitive function in later life in mice.

Catalase: Gene therapy to increase levels of the antioxidant catalase in the mitochondria in mice have produced mixed results, but some studies show improved health and extended life. Other approaches to mitochondrially targeted antioxidants have produced similar benefits. The prevailing theory is that this reduces damage to mitochondria occurring as a result of the reactive oxygen species generated within these organelles, with localized antioxidants soaking up reactive molecules before they can cause harm.

CLK1: Reduced CLK1 activity can extend life in mice due to altered mitochondrial function and consequently lowered generation of reactive oxygen species. There are many potential ways to tinker with mitochondrial operation, though I suspect there are diminishing returns to trying to combine most of them.

CRTC1: A reduced amount of CRTC1 can extend life in nematode worms, and is probably involved in the calorie restriction response. This protein is closely related to AMPK, and manipulations of both CRTC1 and AMPK are likely achieving much the same alterations in the operation of metabolism.

Cyclin A2: Increased levels of cyclin A2 have been shown to increase the regenerative capacity of heart tissue, one of an array of proteins that might for the basis for regenerative gene therapies for heart disease, and thus also might be beneficial to undergo far in advance of old age so as to slow or postpone degeneration in the heart.

FGF21: Overexpression of FGF21 occurs in the calorie restriction response, and when induced artificially using gene therapy it can extend life in mice. This is one of many methods of modestly slowing aging connected to the well-studied growth hormone/insulin-like growth factor-1 signaling pathway.

FKBP1b: Gene therapy to boost levels of FKBP1b to youthful levels can reverse age-related dysfunction of calcium metabolism in the brains of rats. Cognitive function improved as a result, as assessed with tests of spatial memory.

Follistatin: Increased follistatin produces increased muscle growth, a potentially useful compensation for the loss of muscle mass and strength that occurs with aging. It is the flip-side of myostatin, as increased follistatin blocks the activity of myostatin: either increased follistatin or reduced myostatin produce similar outcomes in animal studies, with treated individuals demonstrating increased muscle mass. Follistatin interventions are not as well studied as myostatin interventions, but follistatin increase rather than myostatin decrease was the therapeutic approach chosen by BioViva for development.

FOXO3: A variant of FOXO3 is associated with a modest reduction in cardiovascular disease and mortality in human data. FOXO3 is involved in many relevant mechanisms, so there is plenty of room to debate cause and consequence here, and little in the way of settled answers.

FOXN1: Increased levels of FOXN1 act to restore more youthful levels of activity in the aging thymus. The thymus is where immune cells mature, and thus this intervention improves immune function in later life by increasing the supply of new immune cells. Immune aging and dysfunction results in part from there being only a small supply of such new cells, so any method of increasing that supply will probably prove useful.

GDF11: Higher levels of GDF11 have been shown to improve numerous measures of aging in mice, such as heart function, exercise capacity, and sense of smell. This is most likely occurring due to increased stem cell activity, though there continues to be some debate as to what exactly the researchers are observing in these studies. The identification of GDF11 is one of the outcomes of the increased interest in parabiosis experiments in recent years.

GHK: The level of GHK in blood and tissues declines with aging, and is implicated in some of the detrimental changes in wound healing that occur in later life. Since delivering GHK on its own appears to be beneficial, using gene therapy to reset GHK levels may restore some of this loss of regenerative capacity.

Glycine N-methyltransferase (Gnmt): In flies, higher levels of Gnmt act to inhibit the use of methionine in protein synthesis, which mimics some of the efforts of calorie restriction on health and longevity. Reaction to lower methionine levels - or the appearance of lower methionine levels - is a key trigger for the calorie restriction response.

Growth hormone / growth hormone receptor / insulin-like growth factor / insulin receptor: The longest lived genetically altered mice are those without a functional growth hormone receptor gene. They are small and vulnerable to cold, but otherwise healthy. Many similar approaches to disrupting the well-studied operations of growth hormone and insulin metabolism also extend life in mice to various degrees, some of which are whole-body, while others are tissue-specific. There is a small human population of growth hormone receptor loss of function mutants, people with Laron syndrome. They do not appear to live any longer than the rest of us, which is a caution for anyone extrapolating effects from mice, and have a variety of medical issues associated with their form of dwarfism, but may be resistant to some forms of age-related disease. If so it isn't large enough to immediately leap out from the data, however. That data is still being gathered, but it is interesting to consider what might result from a gene therapy to interfere with growth hormone and insulin metabolism in adulthood.

Histone deacetylase 2 (HDAC2): Mice engineered to have low levels of - or entirely absent - HDAC2 have improved memory function and neural plasticity.

Heat shock proteins: Heat shock proteins are molecular chaperones involved in cellular housekeeping processes that clear out damaged or misfolded proteins. Their activity increases in response to heat, toxins, and various other forms of cellular stress, and dialing up the activity of heat shock proteins is involved in a number of methods demonstrated to slow aging in laboratory animals. Many of these invoke altering the level of other proteins that interact with or regulate heat shock proteins.

Hepatic transcription factors: A range of transcription factors are associated with development and regeneration in the liver. Researchers have demonstrated that some of these can be upregulated to reduce liver fibrosis by steering cell lineages away from the production of scar tissue and towards the production of useful liver cells.

Hepatocyte growth factor (HGF): Currently under development as a potential compensatory therapy to spur remodeling and regrowth of blood vessels in ischemic disease.

INDY: The INDY gene, I'm Not Dead Yet, was one of the first longevity-associated genes discovered in flies. Reduced levels of the INDY protein extend life, with the evidence pointing to increased intestinal stem cell function as the cause.

Interleukin-21 (IL-21): Delivering higher levels of IL-21 has been demonstrated to improve the state of the immune system by increasing the pace at which new immune cells are generated. Loss of immune function with age is an important component of age-related frailty, and even partially compensating for this decline might be very beneficial.

KLF4: Selectively lowering levels of klf4 in smooth muscle cells in blood vessel walls causes beneficial changes in the behavior of these cells. Their overreaction to damaged lipids arriving in the bloodstream is muted, which slows the progression of damage and reaction to that damage that leads towards atherosclerosis.

Klotho: Overexpression of klotho has been shown to increase life span in mice, possibly through some of the same mechanisms as calorie restriction. As for many of the methods of genetic engineering that slow aging in laboratory species, the biochemistry is very complex, the effects are not large, and there is much left to understand with regards to how it actually works.

Lamins: There are three lamin isoforms, A, B, and C. The cause of progeria, a rare condition with the appearance of accelerated aging, is a mutation in Lamin A. Much smaller amounts of malformed lamin A are found in old tissues, though it is uncertain as to whether or not this contributes in any meaningful way to the progression of aging. Intriguingly, mice engineered to produce only lamin C live modestly longer. The mechanism for this enhancement is also uncertain.

LAMP2A: The A variant of lysosome-associated membrane protein 2 is a receptor involved in the cellular maintenance processes of autophagy, but levels decrease with age, and in at least some species this appears to be one of the factors involved in the age-related decline of autophagy. Nearly a decade ago now, researchers demonstrated restoration of more youthful levels of liver function in old mice by adding a duplicate gene to increase amounts of this protein. Increased efficiency of autophagy shows up as a feature of many of the interventions shown to slow aging in animals, but this is one of the few examples in which some rejuvenation of function in old animals was observed.

Leukemia inhibitory factor (LIF): Altered LIF levels have been used to spur neural cells into greater activity that can better restore lost myelin sheathing on nerves. Since we all lose some of this sheathing with age, this is of general interest, applicable to more than just conditions such as multiple sclerosis in which a great deal of myelin is lost.

Lin28a: Increased Lin28a expression enhances regenerative capacity in mice. This is another gene that has been used in reprogramming ordinary cells to become stem cells. As for all such potential options for enhancing human biochemistry, there is the question of cancer risk to address, which may make this sort of thing a better temporary therapy than permanent change.

LOS1: LOS1 may be involved in a variety of fundamental cellular processes, ranging from protein synthesis to DNA repair. The effects of LOS1 knockout on longevity have only been explored in yeast, however, so there is a lot more work to be done to prove relevance here.

miR-195: The microRNA miR-195 interacts with telomerase, and inhibiting it has much the same beneficial effect on stem activity as increasing levels of telomerase. More stem cell activity means more regeneration, though probably also a higher risk of cancer in later life. Since stem cell activity declines with age, there are a great many research groups working on potential ways to restore that activity to youthful levels, even if only temporarily.

Mitochondrial Complex I: Partial disruption of the function of mitochondrial complex I has been shown to modestly extend life in a number of species, with the dominant theory being that this is a hormetic effect - an increase in the creation of reactive oxygen species prompts cells to react with greater repair and maintenance efforts. The degree of disruption is important: too little or too much has either no effect or a detrimental effect. Similar effects might be achieved by altering the protein machinery of this complex or others in the electron transport chain. It is certainly the case that mitochondria are important in aging, but tinkering with operation in this way seems like a low-yield approach in comparison to the SENS vision of removing the impact of mitochondrial DNA damage through allotopic expression.

Mechanistic target of rapamycin (mTOR): Alterations to the mTOR gene and levels of protein produced have been shown to modestly extend life span in several species. There are also a few synergistic genetic alterations involving mTOR and other genes discovered in lower animals that produce much larger effects. The mTOR protein is involved in many fundamental cellular processes, like many of the longevity-associated genes in laboratory species, and produces fairly sweeping alterations in cellular metabolism. Deciphering what exactly is going on under the hood is far from complete in this as in many similar longevity genes.

Myostatin: Reduced myostatin produces increased muscle growth, which may be a useful compensation for the loss of muscle mass and strength that occurs with aging. As a result of a number of natural animal lineages with this mutation, myostatin knockout is by far the most examined and tested of all potential gene therapies. There have been human trials of myostatin blockade via antibodies, for example, and there are even a few well-muscled natural human myostatin loss of function mutants.

NAD-dependent methylenetetrahydrofolate dehydrogenase-methenyltetrahydrofolate cyclohydrolase (NMDMC): Higher levels of NMDMC have been shown to modestly slow aging in flies, most likely through improved mitochondrial function.

NF-κB: Inhibition of this gene extends life modestly in a number of lower species, though given its involvement in immunity, inflammation, apoptosis, and other fundamental processes, there is an embarrassment of riches when it comes to trying to explain the roots of the effect. All such globally altered states of metabolism in which aging is slowed require a great deal of time and effort to explore in detail, and that remains a work in progress.

NRF2 / SKN-1: Increased levels of NRF2 in mice or its homolog SKN-1 in nematodes results in slower aging and modestly extended life spans - normally NRF2 levels decline with age. This can be achieved by manipulation of the levels of other, interacting proteins such as glutathione transferase (gGsta4). The mechanism of action here is thought to involve resistance to oxidative damage and increased quality control of damaged proteins. Interestingly, long-lived naked mole rats exhibit high levels of NRF2.

Oct4: One of the target genes used in reprogramming cells into induced pluripotent stem cells. It was recently found that Oct4 can act to stablize plaques in atherosclerosis to make the disease less deadly. This is intervening far too late in the chain of consequences for my taste. We should be removing plaques or preventing their development, not devoting a lot of effort towards making them less likely to kill you.

P16: P16 is perhaps best known as an indicator of cellular senescence, a part of the mechanisms that cause damaged cells or those at the Hayflick limit to become senescent or self-destruct. The best approach to senescent cells is to destroy them, but there are signs that targeted reductions in p16 levels can in some cases produce a net benefit, such as when used to make stem cell populations more active in old age.

P21: Both MRL mice and P21 knockout mice can regenerate small injuries with no scarring, something that most other mammals cannot achieve, and reduced levels of the p21 protein seems to be the common factor in these engineered mouse lineages. P21 is closely related to the tumor suppressor gene P53: cancer suppression and enhanced regeneration are frequently found to be opposite sides of the same coin. That makes this a challenging option for enhancements via gene therapy, though researchers working on P53 have found ways around the cancer risk issue.

P53: The protein p53 plays the role of tumor suppressor, but creating a general increase in p53 levels will, in addition to reducing cancer incidence, also accelerate aging by reducing tissue maintenance through the creation of new cells. There are, however, a number of ways in which p53 levels can be increased only when needed. One involves reduced levels of mdm2, a p53 inhibitor. Another involves an additional copy of the p53 gene, inserted without disrupting the existing regulatory process that manages p53 levels. In the latter case, engineered mice live modestly longer thanks to a lower rate of cancer.

Parkin: An increased level of parkin is one of the ways in which greater cell maintenance via autophagy can be induced, resulting in improved health and modestly extended life spans. There is a lot of support in the literature for more autophagy as an unalloyed good when it comes to health and aging. Many methods of extending life in laboratory species are associated with increased autophagy, and in some cases - such as calorie restriction - that autophagy has been shown to be necessary for life extension.

PCSK9: Loss of function mutations in PCSK9 reduce the risk of cardiovascular disease, most likely through lowered blood cholesterol levels. Proof of principle studies have been carried out in mice.

PER2: Deletion of the PER2 gene in mice, associated with the mechanisms of circadian rhythm, appears to improve DNA repair in stem cell populations relevant to the immune system, resulting in a healhier immune cell population, better immune function in old age, and a modestly extended life span. A caution here is that PER2 mutants do exist in the human population, and this mutation is associated with sleep dysfunctions.

PGC-1: Increased levels of PGC-1 in the intestinal tissues of flies extend life, possibly due to improved mitochondrial and stem cell function. Intestinal function is especially important as a determinant of fly aging and mortality, and many exploratory interventions target this organ. In mice, introducing a variant of PGC-1 produces enhanced muscle growth, most likely via its interaction with myostatin.

PHD1: The protein PHD1 serves as an oxygen sensor. Mice lacking this protein are protected from ischemic injury in stroke, suffering less cell death and recovering to a greater degree afterwards.

PEPCK: Increased levels of PEPCK achieved through genetic engineering produces mice that are much more energetic, eat more, but are also modestly longer lived than their unmodified counterparts.

PIM1: Overexpression of PIM1 in the heart produces mice that live longer by improving the ability of heart tissue to repair and maintain itself.

plasminogen activator inhibitor-1 (PAI-1): Reducing levels of PAI-1 appears to modestly slow aging, possibly by removing one aspect of the harmful impact of senescent cells. Still, outright destroying these cells is probably a better course of action than trying to safely alter our biochemistry to make their presence less terrible.

Pregnancy-associated plasma protein-A (PAPP-A): Knockout of the PAPP-A gene interferes with insulin metabolism, and produces a similar extension of health and life in mice when compared with other methods of achieving this end.

Phosphatase and tensin homolog (PTEN): Adding an extra copy of the tumor suppressor gene PTEN to mice produces lower rates of cancer, much as expected, but also increased life span. This is unusual for a tumor suppressor: most will reduce life span by inhibiting regeneration and tissue maintenance at higher levels.

RbAp48: Levels of RbAp48 fall with age in the hippocampus. Researchers have demonstrated that targeted restoration of youthful levels of this protein in old mice reversed a large fraction of age-related decline in memory function.

Reticulon 4 receptor (RTN4R): Lowered levels of RTN4R can increase plasticity in the adult brain in mice, improving recovery from brain injury and increasing the ability to learn new tasks. This appears to be a part of the mechanism by which plasticity is dialed down after childhood.

Rpd3: A reduction in Rpd3 level produces improved cardiac function and modestly increased longevity in flies, though the mechanism of action remains to be explored in more detail.

SERCA2a / SUMO-1: Increased levels of either of these two related proteins (SUMO-1 regulates SERCA2a activity) can produce greater beneficial remodeling of blood vessels and heart tissue than would normally take place, and is thus a potential compensatory therapy that might slow the progression of many cardiovascular and circulatory diseases.

Sirtuins: The sirtuin genes were hyped up as a target for calorie restriction mimetics, but as it turned out were not all that useful in practice. Results in mice were neither large, nor reliable, nor easily replicated. The evidence for altered levels of sirtuins to produce benefits large enough to chase is very mixed, despite the occasional study showing marginal or gender-specific outcomes.

Telomerase: Increased levels of telomerase have been shown to extend life in mice, as well as reducing cancer incidence in that species. A full accounting of what is going on under the hood still remains to be accomplished, but the most plausible mechanism appears to be increased stem cell activity, while effects on cancer may involve a more active immune system - though that is only speculative theory at this point. There is a goodly amount of research and evidence for this therapy to be beneficial, but telomere dynamics in mice versus people are sufficient different to argue for caution still. Tests in dogs, pigs, or another mammal with more human-like telomere dynamic would be wise. Still, BioViva has pressed ahead with telomerase gene therapy, and factions within the research community are also aiming for the same outcome of human tests, though through more conventional channels.

TGF-β1: TGF-β1 expression rises with age, and is implicated in loss of stem cell function. Interfering in this pathway via any of the related proteins so as to reduce TGF-β1 levels may be a viable way to increase stem cell activity in later life.

Transcription factor EB (TFEB): Increased activation of TFEB spurs greater autophagy and so helps to ensure better maintenance of cells. Higher levels of autophagy seem to be an unalloyed good in near all situations, and appear as a feature of many of the ways of modestly slowing aging in laboratory species.

Troponin C: Researchers have shown that delivering a modified version of the calcium receptor troponin C into the mammalian heart can improve heart function and the performance of the cardiovascular system.

TRPV1: Gene knockout of the pain receptor TRPV1 is one of a number of methods of slowing aging and extending life in mice that appears to work through altered insulin signaling. Another potential mechanism is that this gene knockout blocks the interaction between pain receptors and chronic inflammation, a process that is thought to cause harm in old tissues and organs. Like many of the interventions that slow aging in mice, there is much left to understand about how it works. Further, it isn't clear that this is a practical intervention for people: pain is useful, and permanent suppression of pain at the receptor level is probably not the right approach.

Uncoupling proteins (UCP): Uncoupling proteins manipulate mitochondrial function in order to regulate body heat. As is the case for many proteins that interact with mitochondrial function, altered levels or genetic variants can improve health and longevity - though this is more of a balancing act for uncoupling proteins, as too much uncoupling moves quickly from being harmful to being fatal.

Urokinase (uPA): The αMUPA mouse lineage has the addition of a urokinase gene and has a longer life span as a result. The uPA gene is related to PAI-1, also in this list, and is argued to achieve life extension in mice through behavioral change - these mice eat less, and thus the calorie restriction response comes into play. It is an interesting question as to whether this sort of alteration would be beneficial in humans: would a human respond in the same way to an alteration in urges?

VEGF plus Gata4, Mef 2c, and Tbx5: A fair number of research and development efforts have focused on delivery of VEGF to spur regeneration in the cardiovascular system, and particularly in the heart, an organ with only limited regenerative capacity in mammals. One of the more effective of these attempts in rodents used a mix of VEGF, Gata4, Mef 2c, and Tbx5 to encourage scar tissue in the heart to change itself into healthy tissue.

Mitochondria are important in aging; some forms of damage to these organelles can produce sweeping detrimental effects when they evade quality control mechanisms. There are hundreds of mitochondria inside any given cell, and the related quality control mechanisms are thought to usually involve the destruction of an entire mitochondrion. Here researchers detail a less drastic mechanism that may act to clear damaged proteins from mitochondrial structures:

Mitochondria provide cells with energy and metabolite molecules that are essential for cell growth, and faulty mitochondria cause a number of severe genetic and age-related diseases. To maintain mitochondria in a fully working state, cells have evolved a range of quality control systems for them. For example, faulty mitochondria can be removed through a process called mitophagy. In this process, which is similar to autophagy (the process used by cells to degrade unwanted proteins and organelles), the entire mitochondrion is enclosed by a double membrane. In yeast cells this structure fuses with a compartment called the vacuole, where various enzymes degrade and destroy the mitochondrion. In animal cells an organelle called the lysosome takes the place of the vacuole. Now researchers report evidence for a new quality control mechanism that helps to protect mitochondria from age- and stress-related damage in yeast. In this mechanism, a mitochondrion can selectively remove part of its membrane to send the proteins embedded in this region to the lysosome/vacuole to be destroyed, while leaving the remainder of the mitochondrion intact.

Researchers tracked the fate of Tom70, a protein that is found in the outer membrane of mitochondria, and discovered that it accumulated in the vacuole as the yeast aged. This accumulation was not the result of mitophagy, as Tom70 was directed to the vacuole even when a gene required for mitophagy was absent. Previous reports have linked cellular aging to a decline in mitochondrial activity, which is caused by an earlier loss of pH control in the vacuole. For this reason, researchers tested whether a drug that disrupts the pH of the vacuole triggers the degradation of Tom70. This appears to be the case - the drug caused Tom70 to move from the mitochondria to the vacuole for degradation.

Before Tom70 ended up in the vacuole it accumulated in a mitochondrial-derived compartment (MDC) at the surface of the mitochondria, close to the membrane of the vacuole. The formation of this compartment depended on the machinery that drives the process by which mitochondria divide. However, the subsequent delivery of the contents of the MDC to the vacuole used factors that are required for the late stages of autophagy. The researchers found that the MDC contained Tom70 and 25 other proteins, all of which are mitochondrial membrane proteins that rely on Tom70 to import them into the mitochondrial membrane. This suggests that the MDC degradation pathway selectively removes a specific group of mitochondrial proteins. The researchers hypothesize that MDC formation is linked to metabolite imbalance, as the loss of acidity inside the vacuole prevents amino acids from being stored there. This in turn leads to a build up of amino acids in the cytoplasm that can overburden the transport proteins that import them into the mitochondria. In this scenario, the selective degradation of mitochondrial transport proteins by the MDC pathway can be seen as a response that protects the organelle against an unregulated, and potentially harmful, influx of amino acids.

Link: http://dx.doi.org/10.7554/eLife.17185

The adoption of high technology endeavors by less developed regions is generally considered a sensible strategy. Developing regions can in theory leapfrog over decades of incremental technological development and start in on the latest and greatest; this worked pretty well in parts of Africa for communications infrastructure, for example. It also makes a great deal of sense to attempt this for fields that are heavily regulated in the US and Europe, and thus very expensive and slow to deliver progress, as developing regions can effectively compete on cost and speed. Medicine is one of the best examples, and you can see this at work in many parts of the world, where a diverse set of efforts are underway to grow medical tourism industries or local medical research communities. It is interesting to see that some of these initiatives are leaning in the direction of targeting healthspan and life span as metrics for success, though given their very bureaucratic, top-down nature I wouldn't hold your breath waiting for useful outcomes. Innovation and technological progress, where it happens, comes from philanthropy and the marketplace, and the best thing that regulators and politicians can do is to get out of the way:

On May 25-26, 2016, there took place at the capital of the Republic of Kazakhstan a global gathering of economic and political elite - the Astana Economic Forum 2016. The speech of Kazakhstan's president made a strong point about the fact that during the 25 years of the country's existence, since its independence in 1991, the average life expectancy of the Kazakhstan people significantly increased, reaching 72 years (compared to about 64 in the early 1990s). This suggested the improving of health and longevity of the population as one of the main parameters of the country's progress.

Going from directives to practice, it transpires that some concrete state-supported steps are now being discussed in Kazakhstan that would be explicitly dedicated to improving the country's healthspan values, via strengthening national biomedical research, development and translation capabilities. A case study has been developed for a global healthspan extension program in Kazakhstan named "The Global Healthspan Extension Initiative". The focus on healthspan extension is warranted by the increasing life expectancy and the corresponding increases in the incidence of aging-related diseases, such as cancer, diabetes, heart disease and neurodegenerative diseases, despite the demonstrated improvements in healthy life expectancy. Reducing these non-communicable diseases is a key priority.

The aim of the program would be to "create a translation biotech hub (not just for basic research) in Kazakhstan with a primary focus on personalized and precision medicine. We intend to build a translation engine to drive massive biomedical innovation into the country." The underlying idea is that it may be difficult for Kazakhstan to quickly reach the advanced research and development capabilities of the current leaders in the field by following in their footsteps. But it may be easier to "leapfrog" them - to create the favorable regulatory environment and incentives to rapidly draw in and help realize the most advanced research and development ideas that are currently struggling against various "brick walls" and "glass ceilings" in theirs countries of origin. "We will perform the meta-analysis and selection of advanced and emerging technologies in the field of healthspan extension, considering their potential efficacy and safety, with the aim to solve social and economic issues." The architects of this initiative envision an end to the entrenched dichotomy between the "developing" vs. "developed" countries, but anticipated a new distinction between "innovative" and "less-innovative" countries.

Link: http://ieet.org/index.php/IEET/more/Stambler2060605

Regenerative of tissue is a very complex affair in which all sorts of different cell types and systems participate in their own individual ways, collaborating in an intricate dance that results in reconstruction. The overall theme is the same in all tissues, but the details vary widely by tissue type. So in skin, for example, eccrine sweat glands, the primary type of sweat gland, serve as the anchor points from which new epithelium grows. The sweat glands are reservoirs of highly regenerative cells that spring into action when needed, and construct new structures outwards from the gland, meeting in the middle between glands. The research I'll point out today shows that these cell populations retain regenerative capacity even in older age, but the authors argue that age-related changes in the physical characteristics of skin act to sabotage regenerative efforts, making it harder to build cohesive cellular structures.

Physical characteristics derive from the extracellular matrix, a lattice of support constructed by the cells that occupy its spaces. The details of extracellular matrix molecular structure determine the properties of tissue for everything from skin to bone: flexibility, elasticity, stiffness, resilience, ability to bear load, and so forth. Anything that disrupts this structure and its maintenance will alter its properties, usually for the worse. One important form of age-related damage is cross-linking, in which forms of sugary metabolic byproducts bind with molecules of the extracellular matrix, linking and limiting them. Some types of cross-link are long-lived, and our biochemistry is unable to remove them. This is one of the processes responsible for loss of elasticity in skin and blood vessels. Then there are senescent cells that accumulate in tissues with age, producing inflammation and acting to remodel the surrounding extracellular matrix in uncoordinated, detrimental ways. Other aspects of aging also have their contributions to make to the declining quality of the extracellular matrix, some more direct, some less so.

What can be done about this? Periodically repair the damage. Design drugs that can break down the cross-links that our biochemistry cannot handle. Develop drugs and gene therapies that selectively kill senescent cells. Follow through to create the full SENS portfolio of envisaged rejuvenation treatments, each of which repairs one of the forms of damage that cause aging, including those that drive the aging of skin. Given a functional rejuvenation toolkit, all of our sweat glands could get back to working as they did in youth, provided with an extracellular matrix freed from the burden of molecular damage. All too little effort is directed to this goal, even in this day and age of revolutionary progress in biotechnology, and that is one of the great shames of our era.

The Healing Function of Sweat Glands Declines with Age

A group of scientists and dermatologists are now looking at the role sweat glands play in how aging skin recovers from wounds. It's a step to better learn about aging skin, in order to better treat - and slow - the process. Their research compared 18 elderly subjects' skin to 18 young adults' skin, to see how each group healed from skin lesions. The lesions were smaller than the diameter of a pencil eraser, performed under local anesthesia. The researchers had already determined eccrine sweat glands, which are located throughout the body, are important for wound closure. They are major contributors of new cells that replace the cells that were lost due to injury.

"Since we know elderly people tend to sweat less than young adults, we concentrated on this healing function of sweat glands." In young people, they discovered sweat glands contributed more cells to wound closure than in aged adults. The cells in aged skin weren't as cohesive, either. Fewer cells participating, spaced further apart, means a delay in wound closure and a thinner repaired epidermis in aged versus young skin. It wasn't that the sweat glands were less active in older people, rather, that the environment in the aging skin had been slowly degraded, making the skin structures less able to support the new cells that were generated. "Limiting skin damage during the aging process is likely to limit the negative impact of aging on wound repair. This study teaches us that poor wound healing and wrinkling and sagging that occur in aging skin share similar mechanisms."

Reduced cell cohesiveness of outgrowths from eccrine sweat glands delays wound closure in elderly skin

Human skin heals more slowly in aged vs. young adults, but the mechanism for this delay is unclear. In humans, eccrine sweat glands (ESGs) and hair follicles underlying wounds generate cohesive keratinocyte outgrowths that expand to form the new epidermis. Our results confirm that the outgrowth of cells from ESGs is a major feature of repair in young skin. Strikingly, in aged skin, although ESG density is unaltered, less than 50% of the ESGs generate epithelial outgrowths during repair (vs. 100% in young). Surprisingly, aging does not alter the wound-induced proliferation response in hair follicles or ESGs. Instead, there is an overall reduced cohesiveness of keratinocytes in aged skin. Reduced cell-cell cohesiveness was most obvious in ESG-derived outgrowths that, when present, were surrounded by unconnected cells in the scab overlaying aged wounds.

Failure to form cohesive ESG outgrowths may reflect impaired interactions of keratinocytes with the damaged extracellular matrix (ECM) in aged skin. Previous work from our group and others has characterized in detail the age-associated damage to the skin dermal ECM, which includes increased collagen fiber fragmentation, reduced ECM resistance, and decreased tissue mechanical force. Although the ECM is well known for its role in providing structural scaffolds for embedded cells, recent studies have highlighted the importance of the ECM as underlying substrate for collective cell migration. For instance, increasing ECM rigidity (Young's modulus) enhances cellular traction forces and cell-cell adhesion. Thus, it is likely that reduced rigidity of skin ECM, as it occurs with aging, would reduce cell-cell cohesiveness as we observed in vivo. Altogether, these observations suggest that damage to the ECM in aged skin may mediate reduced cell-cell cohesiveness and thereby reduce the efficiency of the re-epithelialization process in aged skin.

Fibrosis taken as a whole and in its surrounding context is more complicated than simply a matter of the wrong cells growing in the wrong place, but that is an important portion of it. The condition involves excess connective tissue forming in organs, a type of scarring process, and this degrades organ function. It is a notable component of both chronic liver and kidney disease, for example. Here, researchers demonstrate cellular reprogramming via gene therapy in mice that turns some of the connective tissue cell lineages into liver cell lineages, thus reducing the progression of fibrosis and restoring some of the lost liver cells:

Liver fibrosis, a form of scarring, develops in chronic liver diseases when hepatocyte regeneration cannot compensate for hepatocyte death. Initially, collage produced by myofibroblasts (MFs) functions to maintain the integrity of the liver, but excessive collagen accumulation suppresses residual hepatocyte function, leading to liver failure.

As a strategy to generate new hepatocytes and limit collagen deposition in the chronically injured liver, we developed in vivo reprogramming of MFs into hepatocytes using adeno-associated virus (AAV) vectors expressing hepatic transcription factors. We first identified the AAV6 capsid as effective in transducing MFs in a mouse model of liver fibrosis. We then showed in lineage-tracing mice that AAV6 vector-mediated in vivo hepatic reprogramming of MFs generates hepatocytes that replicate function and proliferation of primary hepatocytes, and reduces liver fibrosis. Because AAV vectors are already used for liver-directed human gene therapy, our strategy has potential for clinical translation into a therapy for liver fibrosis.

Link: http://dx.doi.org/10.1016/j.stem.2016.05.005

A small study of stem cell transplants into the brain has demonstrated striking benefits in stroke patients when administered long after the stroke itself, past the point at which any further natural recovery is expected:

Injecting modified, human, adult stem cells directly into the brains of chronic stroke patients proved not only safe but effective in restoring motor function, according to the findings of a small clinical trial. The patients, all of whom had suffered their first and only stroke between six months and three years before receiving the injections, remained conscious under light anesthesia throughout the procedure, which involved drilling a small hole through their skulls; the next day they all went home. Although more than three-quarters of them suffered from transient headaches afterward - probably due to the surgical procedure and the physical constraints employed to ensure its precision - there were no side effects attributable to the stem cells themselves, and no life-threatening adverse effects linked to the procedure used to administer them.

"This was just a single trial, and a small one. It was designed primarily to test the procedure's safety. But patients improved by several standard measures, and their improvement was not only statistically significant, but clinically meaningful. Their ability to move around has recovered visibly. That's unprecedented. At six months out from a stroke, you don't expect to see any further recovery." Although approved therapies for ischemic stroke exist, to be effective they must be applied within a few hours of the event - a time frame that often is exceeded by the amount of time it takes for a stroke patient to arrive at a treatment center. Consequently, only a small fraction of patients benefit from treatment during the stroke's acute phase. The great majority of survivors end up with enduring disabilities. Some lost functionality often returns, but it's typically limited.

For the trial, the investigators screened 379 patients and selected 18, whose average age was 61. Into these patients' brains the neurosurgeons injected so-called SB623 cells - mesenchymal stem cells derived from the bone marrow of two donors and then modified to beneficially alter the cells' ability to restore neurologic function. Afterward, patients were monitored via blood tests, clinical evaluations and brain imaging. Interestingly, the implanted stem cells themselves do not appear to survive very long in the brain. Preclinical studies have shown that these cells begin to disappear about one month after the procedure and are gone by two months. Yet, patients showed significant recovery by a number of measures within a month's time, and they continued improving for several months afterward, sustaining these improvements at six and 12 months after surgery. Substantial improvements were seen in patients' scores on several widely accepted metrics of stroke recovery. Perhaps most notably, there was an overall 11.4-point improvement on the motor-function component of the Fugl-Meyer test, which specifically gauges patients' movement deficits. "This wasn't just, 'They couldn't move their thumb, and now they can.' Patients who were in wheelchairs are walking now."

Link: http://med.stanford.edu/news/all-news/2016/06/stem-cells-shown-safe-beneficial-for-chronic-stroke-patients.html

The staples of cancer treatment remain chemotherapy and radiotherapy, even today. Despite tremendous progress in the laboratory and in trials, the medical community has not yet passed the point at which immunotherapy and other targeted approaches take over the mainstream. Thus cancer treatment programs are still very much a balancing act between harming the cancer and harming the patient, while metastasis is still largely the beginning of the end, in which cancer slips out of reach of the dosage of poisons a patient can survive. Neither chemotherapy nor radiation therapies are treatments that anyone would voluntarily undergo if there were any other viable options on the table, as they are simply not selective enough. The whole point of the next generation of targeted therapies is to retain the ability to harm cancer while removing near all of the harm done to the patient. That can even be achieved with present day chemotherapy drugs, if they can be delivered in minuscule doses and only to cancerous cells. It is easy to kill cells; the hard part has always been to kill only the cells that you want killed.

Thus most cancer therapy today is the carefully calibrated application of damage. Toxins and radiation cause inflammation, make cells become senescent, and create range of other effects, some temporary, some lasting. We can say the same for a smoking habit, a terrible thing to maintain unless your goal is to cut short your life and health. A useful distinction to make here is between primary aging and secondary aging. Primary aging is what your body does to you even under the best of circumstances: cell and tissue damage that accumulates as a form of biological wear and tear, created as a result of the normal, healthy operation of metabolism. Secondary aging is additional damage heaped upon you by your choices and by the environment: the effects of infectious disease, obesity, a sedentary lifestyle, smoking, and, of course, chemotherapy or radiotherapy. The line between primary and secondary aging is fuzzy at best. Senescent cells accumulate to cause harm and age-related disease even in the bodies of individuals with the best and most fortunate of lives. Their presence is one of the root causes of aging. If chemotherapy piles on an additional lingering population of these cells, secreting signals that disrupt metabolism and degrade tissue function, then do we call that accelerated aging? This paper answers that question in the affirmative:

Cancer Treatment as an Accelerated Aging Process: Assessment, Biomarkers, and Interventions

Presently, there are 8 million cancer survivors age 65 or older in the United States, and this number is anticipated to continue to grow to 11 million by 2020. A key survivorship issue facing these older adults is the short- and long-term impact of cancer therapy on the aging process. It has been suggested that cancer and/or its treatment may contribute to an accelerated aging phenotype. The majority of these data come from the pediatric literature, but a smaller yet growing body of literature points toward similar findings in the geriatric population.

The aging process is unique to the individual, and chronological age is a poor descriptor of an older adult. For example, two individuals who are chronologically age 75 can have very different functional ages. A geriatric assessment identifies factors other than chronological age that can predict the risk of morbidity and mortality in older adults. These include functional status, cognition, comorbidity, psychological state, social support, and nutritional status. Geriatric assessment is the cornerstone for assessing function in patients with cancer prior to treatment. It can be helpful in predicting survival, treatment-related toxicity, and other outcomes. However, geriatric assessment can be time consuming, and many clinicians do not have the resources to perform a geriatric assessment in daily practice. Biomarkers of aging may help fill this gap. Potential biomarkers include chronic inflammatory markers, markers of cellular senescence, and sarcopenia.

Inflammatory markers have been extensively studied, and increased levels have been shown to correlate with frailty, functional decline, and survival. These markers now are receiving wide attention, as there is good evidence that chronically elevated levels may accelerate or exacerbate the aging process. These markers, which include interleukins, tumor necrosis factors, and others, have been studied extensively in frail patients in whom they independently correlate with other measures of physical function. Interleukin-6 (IL-6) has probably been the most extensively studied cytokine and has been shown to predict functional decline, including a diminution in the ability to perform activities of daily living, poor ambulation, and decreased mobility. There also appears to be a major relationship between inflammatory markers and cell senescence. Senescent cells are viable and capable of secreting proinflammatory markers that have led to the definition of a senescence-associated secretory phenotype. To date, however, none of these markers has assumed a major role in clinical care or further studies designed to see if any single marker or combination might have an independent role in the management of the older patient with cancer. These studies would test whether such markers could be independent predictors of treatment tolerance, including acute and chronic toxicities, functional loss, and cognitive decline.

There is little doubt that the treatment of cancer, especially radiation therapy and chemotherapy, greatly accelerates aging. A recent overview of survivors of childhood cancer showed that these individuals were at greatly increased risk for substantial comorbidity and premature death. Data from one of the large cohorts described in this review demonstrated the cumulative prevalence for a serious or life-threatening chronic condition of 81% by age 45; in addition, there was an extremely high incidence of second neoplasms that was directly related to the radiation dose. In another study of survivors of childhood cancer, the prevalence of prefrailty and frailty were 31.5 and 13.1% among women and 12.9 and 2.7% among men, respectively. This prevalence of frailty among young adult survivors of cancer with a mean age of 34 years was similar to that of adults age 65 or older.

p16ink4a has major promise as a biomarker of chemotherapy toxicity. p16ink4a expression increases approximately 10-fold between ages 20 and 80, and this dynamic range provides for a more robust marker as a predictor of molecular aging. In one study of women receiving adjuvant chemotherapy for early-stage breast cancer, p16ink4a expression measured in peripheral blood T cells increased by almost one log2 order of magnitude immediately after treatment and remained elevated 12 months after treatment. This change corresponds to almost a 15-year increase in chronologic age. In this study, the cytokines VEGFA and monocyte chemotactic protein-1 also significantly increased and remained elevated at 12 months, but telomere length was not affected. In a cross-sectional cohort of patients in the same study, prior chemotherapy exposure was independently associated with increased p16ink4a expression comparable to 10 years of chronologic aging.

"Don't get cancer" is great advice. It is a pity that it is so very hard to follow in practice. For my money the most important work in the cancer research community is that focused on building technology platforms that can be applied to either all or many cancers with comparatively little additional work. Victory in the sense of control over cancer will only come by crushing down the time and cost required to defeat each new variety of cancerous cell. The present morass of slow and painstaking progress exists because it has historically required an entire lengthy research initiative to be focused on each one of the thousands of noteworthy individual types of cancer, and that is still largely how business is conducted in this industry. This must change, and thankfully the signs of that change are beginning to emerge.

One of the most promising fields of early stage cancer research, still only undertaken by a few scientific groups, is focused on interfering in telomere lengthening. Telomeres shorten with each cell division, and thus all cancers must continually lengthen their telomeres in order to survive. This is the one useful universal commonality shared by all cancers. There are a limited set of mechanism by which this telomere lengthening can take place: either telomerase or one of the less well mapped alternative lengthening of telomeres (ALT) processes. If that short list can all be blocked in a tissue-selective manner - or even blocked globally for a while - then that will be the end of cancer as a serious threat.

An approach using nanoparticles to deliver RNA to immune cells, so as to kick off an immune response targeted to a specific cancer, has been in the news of late. Immunotherapies of a wide variety of types will form the basis for the coming generation of cancer therapies, the replacements for the present staples of chemotherapy and radiotherapy, but there is far too much work taking place to comment on every single project. It is a matter of accident rather than merit as to which research results receive greater or lesser attention from the public and the media. With the immune system being as complicated as it is, there are a lot of different ways in which to manipulate its activities, and most are in principle capable of producing viable therapies. Competition in this marketplace is as much to find a reliably, cost-effective way to address many cancers with the same technology platform as it is to find treatments that work.

Researchers have published a description of the first example worldwide of a clinically relevant and systemic mRNA cancer immunotherapy. They outline a novel approach to target a nanoparticle mRNA vaccine (RNA-LPX) body-wide to dendritic cells in the spleen, lymph nodes and bone marrow, where a highly potent, dual-mechanism immune response mimicking a natural antiviral immune response is rapidly elicited. The dual mechanism involves both adaptive (T-cell-mediated) and innate (type-I interferon (IFN)-mediated) immune responses, with the IFN response being essential for full anti-tumor effects of the vaccines. "Our study introduces a novel class of extraordinarily potent cancer vaccines that enables efficient redirection of the immune system against a wide range of tumor antigens. This is a major step towards our aim to make truly personalized cancer immunotherapies available and applicable to all cancer types."

The researchers further provide mode of action and efficacy data for this novel vaccine class in several preclinical tumor models and reports early data from a phase I dose-escalation, safety and tolerability trial (NCT02410733) of an intravenous RNA-LPX vaccine in melanoma patients. Crucially, in these patients, very low initial doses, lower than those used in preclinical studies, very rapidly elicited such a strong CD4+ and CD8+ T cell response that ex vivo culture was not required for detection. To date this vaccine has been very well tolerated and no severe toxicities have been observed. The phase I melanoma study continues to recruit patients and researchers plan to execute additional RNA-LPX vaccine studies for different cancer types.

Link: http://biontech.de/2016/06/01/nature-publication-describes-first-example-of-a-clinically-applicable-and-systemic-mrna-cancer-immunotherapy-vaccine/

Researchers investigating telomeres, telomerase, and aging are now trying to isolate effects of telomere length from effects of telomerase by employing a novel method of breeding mice with very long telomeres. Telomeres are repeated DNA sequences at the ends of chromosomes that form a part of the limiting mechanism for cell division. Telomere length falls with each cell division, cells self-destruct or become senescent when telomere length is short, and stem cells employ telomerase to lengthen their telomeres to retain their ability to generate new daughter cells with long telomeres. Average telomere length in tissues then derives from some combination of cell division rates and cell replacement rates, and tends to fall over the course of aging. Work on lengthening telomeres in mice over the past decade has focused on the use of telomerase, such as via gene therapy. This has been shown to extend life and improve health, an outcome likely to derive from increased stem cell activity.

But is the telomere length or is it the telomerase? Telomerase lengthens telomeres, yes, but that isn't its only activity. Like all proteins, it plays a role in many mechanisms, not all of which are fully mapped at this point. A sizable fraction of the research community see reduction in average telomere length as an outcome of the state of age and damage - a marker of aging, and not a cause of aging. In this context, finding a way to extend telomere length without the use of telomerase is a good choice for further exploration of the mechanisms, and that is the achievement made by the research team in this case. The results of this study, demonstrating a slowing of some measures of aging purely based on longer telomeres, present a challenge to the view of telomere length as a marker only, though we can still argue over whether it is a primary or secondary mechanism of aging, especially when measured in immune cells. Possible mechanisms of enhanced health that could derive from telomere length only might include lower levels of cellular senescence, for example, and it would be interesting to see that measured.

Researchers have succeeded in creating mice in the laboratory with hyper-long telomeres and with reduced molecular ageing, avoiding the use of what to date has been the standard method: genetic manipulation. This new technique based on epigenetic changes avoids the manipulation of genes in order to delay molecular ageing. In 2009 researchers described that the in vitro culture of induced pluripotent stem cells caused the progressive lengthening of telomeres, to the point of generating what the authors called "hyper-long telomeres". Sometime later, in 2011, it was found that this phenomenon also occurs spontaneously in embryonic stem cells when cultured in vitro. The in vitro expansion of the embryonic stem cells results in the elongation of the telomeres up to twice their normal length, and without alterations in the telomerase gene. However, would these cells be capable of developing into a mouse with telomeres that are much longer than normal and that would age more slowly? Researchers now prove that this is the case.

The cells with hyper-long telomeres in these mice appear to be perfectly functional. When the tissues were analysed at various moments (0, 1, 6 and 12 months of life), these cells maintained the additional length scale (they shortened over time but at a normal rhythm), accumulated less DNA damage and had a greater capacity to repair any damage. In addition, the animals presented a lower tumour incidence than normal mice. These results show that pluripotent stem cells that carry hyper-long telomeres can give rise to organisms with telomeres that remain young at the molecular level for longer. According to the authors, this "proof of concept means that it is possible to generate adult tissue with longer telomeres in the absence of genetic modifications". The next step that the researchers are already working on will be to "generate a new species of mice in which the telomeres of all the cells are twice as long as those in normal mice. Then, we will be able to address some of the important questions that remain unanswered: would a mouse species with telomeres that are double in length live longer? Is this the mechanism that is used by nature to determine different longevities in genetically similar species? Would this new species present a higher or lower incidence of cancer?"

Link: https://www.cnio.es/ing/publicaciones/mice-with-hyper-long-telomeres-without-altering-the-genes

To follow on from the post on reactive oxygen species in aging earlier today, I thought I'd direct your attention to a few more recent papers that approach this topic from various directions. To recap, it has long been known that the level of oxidative damage in cells increases with age, a state of affairs called oxidative stress, and that this is largely a product of changes in mitochondria, the power plants of the cell where more energetic chemistry takes place. What does this mean? Cells are intricate, dynamic, mostly fluid bundles of molecular machinery, and roving reactive molecules - such as reactive oxygen species (ROS) - cause harm by reacting with this machinery so as to prevent it from functioning correctly. When there are more such reactive molecules, there is a higher rate of ongoing damage, and cells must work harder to maintain correct functionality and behavior.

Oxidative stress in the general sense of the flux of cell damage versus cell repair features prominently in the past generation of theories of aging, but since those theories were first proposed, further investigation of the roles and relationships involving ROS has considerably complicated the picture. It isn't a straightforward case of more oxidative stress creating faster aging, with a clear set of changes driving degeneration at every step. The bulk of oxidative stress inside cells may be largely irrelevant in comparison to other facets and consequences of mitochondrial dysfunction, such as the generation of oxidized lipids that then enter the bloodstream.

The big picture is still incomplete, but it nonetheless seems that there is no straightforward relationship between aging, varying levels of ROS inside cells, and the many ways to measure oxidative stress. As it turns out ROS molecules are as much useful signals inside cells as they are a part of the damage and dysfunction of aging: methods of modestly extending life span in laboratory species can involve either higher or lower levels of ROS, depending on the details, and some long-lived species have all of the biochemical markers of high levels of oxidative stress but none of the expected dysfunction. Like all aspects of metabolism, complexity is the rule, and attempts to manipulate ROS-related mechanisms to obtain health benefits via the standard process of drug discovery and development will no doubt prove to be just as slow and expensive as other, similar approaches to shifting metabolism into a more advantageous state.

The bright side of reactive oxygen species: lifespan extension without cellular demise

Oxidative stress and the generation of reactive oxygen species (ROS) can lead to mitochondrial dysfunction, DNA damage, protein misfolding, programmed cell death with apoptosis and autophagy, and the promotion of aging-dependent processes. Mitochondria control the processing of redox energy that yields adenosine triphosphate (ATP). Ultimately, the generation of ROS occurs with the aerobic production of ATP. Although reduced levels of ROS may lead to tolerance against metabolic, mechanical, and oxidative stressors and the generation of brief periods of ROS during ischemia-reperfusion models may limit cellular injury, under most circumstances ROS and mitochondrial dysfunction can lead to apoptotic caspase activation and autophagy induction that can result in cellular demise. Yet, new work suggests that ROS generation may have a positive impact through respiratory complex I reverse electron transport that can extend lifespan. Such mechanisms may bring new insight into clinically relevant disorders that are linked to cellular senescence and aging of the body's system. Further investigation of the potential "bright side" of ROS and mitochondrial respiration is necessary to target specific pathways that can impact oxidative stress-ROS mechanisms to extend lifespan and eliminate disease onset.

Roles for ROS and hydrogen sulfide in the longevity response to germline loss in Caenorhabditis elegans

Signals from reproductive tissues and germ cells influence the lifespans of many organisms, including mammals. How germ cells, which give rise to the next generation, control the aging of the animal in which they reside is poorly understood. Counter-intuitively, we found that removing germ cells in Caenorhabditis elegans triggers the generation of two potentially toxic substances, reactive oxygen species (ROS) and hydrogen sulfide (H2S), in nonreproductive somatic tissues. These substances, in turn, induce protective responses that slow aging. A cytoskeletal protein, KRI-1, plays a key role in the generation of H2S and ROS. These kri-1-dependent redox species, in turn, promote life extension by activating SKN-1/Nrf2 and the mitochondrial unfolded-protein response, respectively. Both H2S and, remarkably, kri-1-dependent ROS are required for the life extension produced by low levels of the superoxide-generator paraquat and by a mutation that inhibits respiration. Together our findings link reproductive signaling to mitochondria and define an inducible, kri-1-dependent redox-signaling module that can be invoked in different contexts to extend life and counteract proteotoxicity.

Reactive oxygen species in sarcopenia: Should we focus on excess oxidative damage or defective redox signalling?

Physical frailty in the elderly is driven by loss of muscle mass and function and hence preventing this is the key to reduction in age-related physical frailty. Our current understanding of the key areas in which ROS contribute to age-related deficits in muscle is through increased oxidative damage to cell constituents and/or through induction of defective redox signalling. Recent data have argued against a primary role for ROS as a regulator of longevity, but studies have persistently indicated that aspects of the aging phenotype and age-related disorders may be mediated by ROS. There is increasing interest in the effects of defective redox signalling in aging and some studies now indicate that this process may be important in reducing the integrity of the aging neuromuscular system. Understanding how redox-signalling pathways are altered by aging and the causes of the defective redox homeostasis seen in aging muscle provides opportunities to identify targeted interventions with the potential to slow or prevent age-related neuromuscular decline with a consequent improvement in quality of life for older people.

Mitochondrial Metabolism in the Aging Heart

Altered mitochondrial metabolism is the underlying basis for the increased sensitivity in the aged heart to stress. The aged heart exhibits impaired metabolic flexibility, with a decreased capacity to oxidize fatty acids and enhanced dependence on glucose metabolism. Aging impairs mitochondrial oxidative phosphorylation, with a greater role played by the mitochondria located between the myofibrils, the interfibrillar mitochondria. With aging, there is a decrease in activity of complexes III and IV, which account for the decrease in respiration. Furthermore, aging decreases mitochondrial content among the myofibrils. The end result is that in the interfibrillar area, there is ≈50% decrease in mitochondrial function, affecting all substrates. The defective mitochondria persist in the aged heart, leading to enhanced oxidant production and oxidative injury and the activation of oxidant signaling for cell death. Aging defects in mitochondria represent new therapeutic targets, whether by manipulation of the mitochondrial proteome, modulation of electron transport, activation of biogenesis or mitophagy, or the regulation of mitochondrial fission and fusion. These mechanisms provide new ways to attenuate cardiac disease in elders by preemptive treatment of age-related defects, in contrast to the treatment of disease-induced dysfunction.

Here, researchers use genetic engineering try to pin down specific sources of oxidizing molecules within a cell and identify their different effects on health and longevity. Cells are liquid bags of chemical machinery, and the presence of too many reactive oxygen species (ROS) - also known as free radicals - can produce a level of damage to that machinery that significantly impacts cell function, or even kills cells. This is known as oxidative stress, and levels of oxidative stress are seen to rise alongside the other manifestations of degenerative aging. However, ROS molecules are also used as signals: produced by mitochondria and triggering increased cell maintenance, among other activities. They are critical in the beneficial response to exercise, for example. Many methods of modestly extending life span in laboratory species involve reductions in levels of ROS, and many others involve increases - either can under the right circumstances extend healthy life by reducing net levels of cell damage or triggering other mechanisms relevant to health. A cell is a complex, reactive system and few aspects of cell state have straightforward relationships with one another. Oxidative stress features prominently in many theories of aging, but many of these theories are older and too simplified to be useful given the present state of knowledge and explorations of oxidative stress and ROS signaling.

Historically, mitochondrial ROS (mtROS) production and oxidative damage have been associated with aging and age-related diseases such as Parkinson's disease. In fact, the age-related increase in ROS has been viewed as a cause of the aging process while mitochondrial dysfunction is considered a hallmark of aging, as a consequence of ROS accumulation. However, pioneering work in Caenorhabditis elegans has shown that mutations in genes encoding subunits of the electron transport chain (ETC) or genes required for biosynthesis of ubiquinone extend lifespan despite reducing mitochondrial function. The lifespan extension conferred by many of these alterations is ROS dependent, as reduction of ROS abolishes this effect. Various studies have shown that ROS act as secondary messengers in many cellular pathways, including those which protect against or repair damage. ROS-dependent activation of these protective pathways may explain their positive effect on lifespan. The confusion over the apparent dual nature of ROS may, in part, be due to a lack of resolution as without focused genetic or biochemical models it is impossible to determine the site from which ROS originate.

A promising path to resolving ROS production in vivo is the use of alternative respiratory enzymes, absent from mammals and flies, to modulate ROS generation at specific sites of the ETC. The alternative oxidase (AOX) of Ciona intestinalis is a cyanide-resistant terminal oxidase able to reduce oxygen to water with electrons from reduced ubiquinone (CoQ), thus bypassing complex III and complex IV. NDI1 is a rotenone-insensitive alternative NADH dehydrogenase found in plants and fungi, which is present on the matrix-face of the mitochondrial inner membrane where it is able to oxidize NADH and reduce ubiquinone, effectively bypassing complex I. Our group and others have demonstrated that allotopic expression of NDI1 in Drosophila melanogaster can extend lifespan under a variety of conditions and rescue developmental lethality in flies with an RNAi-mediated decrease in complex I levels.

To determine the role of increased ROS production in regulating longevity, we utilized allotopic expression of NDI1 and AOX, along with Drosophila genetic tools to regulate ROS production from specific sites in the ETC. We report that ROS increase with age as mitochondrial function deteriorates. However, we also demonstrate that increasing ROS production specifically through respiratory complex I reverse electron transport extends Drosophila lifespan. We show that NDI1 over-reduces the CoQ pool and increases ROS via reverse electron transport (RET) through complex I. Importantly, restoration of CoQ redox state via NDI1 expression rescued mitochondrial function and longevity in two distinct models of mitochondrial dysfunction. If the mechanism we describe here is conserved in mammals, manipulation of the redox state of CoQ may be a strategy for the extension of both mean and maximum lifespan and the road to new therapeutic interventions for aging and age-related diseases.

Link: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4835580/

Researchers here theorize on the role of bacteria in stimulating immune function and other aspects of our biology in a positive way, with a focus on the FOXN1 protein. Increased FOXN1 in old mice has been demonstrated to restore the thymus to more youthful activity, and thus improve immune function. The thymus is where some classes of immune cell mature, and because it atrophies early in adulthood, the flow of new immune cells is much reduced over most of the life span. This low rate of production is a contributing factor to the age-related limits and decline of the immune system. Any method that rejuvenates the thymus, or that otherwise produces a large supply of new immune cells, will do a lot for immune function in old age. It isn't a fix for all of the issues by any means, but it is a fix for one of them, and in this new age of cheap and effective gene therapy, boosting the levels of individual proteins isn't an unreasonable thing to aim for in the years ahead.

The popularity of hand sanitizer and antibiotics shows how we feel about bacteria: an enemy that's bad for our health. Emerging data, however, suggest just the opposite - that exposures to certain kinds of bacteria are beneficial for a long and healthy life. Specifically, mice consuming probiotic L. reuteri were shown to have larger skeletal muscles than untreated age-matched controls. A surprising additional finding was increased thymus gland size only in mice consuming bacteria in their drinking water. The thymus was not only larger, but also had increased expression of Forkhead Box N1 (FoxN1), a feature involved in systemic programming of immune system lymphocytes.

Bacterial stimulation of FoxN1 and increased thymus gland size has enormous implications for host good health. Indeed, FoxN1 protein has been touted as a "Fountain of Youth". During childhood, a proficient thymus gland supplies adaptive immune cells that help fight pathogenic infections and discern self versus non-self, to lower risk of autoimmune diseases. With increasing age, the thymus gland naturally shrinks leading to immune dysregulation with higher risk for infections and cancer in elderly subjects. Other studies have shown that mouse models treated exogenously with FoxN1 had features of sustained youth. Interestingly, animals lacking FoxN1 failed to develop larger muscles after microbial therapy, implicating the immune system in muscle-boosting effects.

The precise mechanism by which bacteria stimulate FoxN1 expression in the thymus gland remains unknown but likely involves the wnt signaling pathway. Microbes have been shown by our own lab and by others to prime the immune system for sustained good health. At the same time, the thymus gland and muscle growth may also be stimulated through bacteria-triggered upregulation of central nervous system (CNS) hormones, for example growth hormone and oxytocin. Perhaps exposures to bacteria can be good for us, after all. Can we formulate a bacteria cocktail that prevents muscle loss with aging and imparts a long, healthy, and meaningful life? Additional research is needed to explore the vast and far-reaching potential of microbes for a long and healthy life.

Link: http://www.impactaging.com/papers/v8/n5/full/100969.html