Fight Aging! Newsletter, June 4th 2018

Fight Aging! provides a weekly digest of news and commentary for thousands of subscribers interested in the latest longevity science: progress towards the medical control of aging in order to prevent age-related frailty, suffering, and disease, as well as improvements in the present understanding of what works and what doesn't work when it comes to extending healthy life. Expect to see summaries of recent advances in medical research, news from the scientific community, advocacy and fundraising initiatives to help speed work on the repair and reversal of aging, links to online resources, and much more.

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  • Support for Longevity Science is the Most Effective Form of Philanthropy
  • When I am Eighty-Five
  • Do FOXA2-Related Changes in the Nuclear Lamina Contribute to Liver Aging?
  • An Example of the Importance of Gut Microbiota to Aging in Flies
  • Lower Levels of KIFC3 Observed in Aging are Involved in the Decline of Autophagy
  • A Commentary on Senolytic Gene Therapies to Target p16 Overexpression
  • Can Present Stem Cell Therapies Improve Vaccine Response in the Elderly?
  • Discussing the Dog Aging Project with Matt Kaeberlein
  • Exploring the Utility of Decellularized Muscle Grafts in Animal Models
  • Long Non-Coding RNA in the Aging Brain
  • No Cardiovascular Health Benefits Result from Most Common Dietary Supplements
  • Researchers Create Bioprinted Human Corneas
  • Beclin-1 Mutant Mice Live 10% Longer Due to Enhanced Autophagy
  • Higher Blood Pressure Correlates with Higher Healthcare Costs
  • A New Target Mechanism for Lowering Blood Pressure in Cases of Hypertension

Support for Longevity Science is the Most Effective Form of Philanthropy

The members of the effective altruism community are interested in rationally identifying the most cost-effective ways to make the world a better place, involving both the usual metrics by which we might judge "better," but also an analysis of whether or not those usual metrics are in fact helpful. Tear it all down and build it up again from first principles. Particularly at the large scale, a great deal of the status quo in philanthropy is wasted effort, virtue signaling, or even actively counterproductive. There are many ostensibly charitable organizations that, at best, do no good, and at worst exacerbate the problems they engage with. There are many ways to choose poorly as an individual donor. Philanthropy as an institution and as a personal choice can definitely be improved. The effective altruists are on to something there.

Quite some time ago I decided that the best and most effective form of philanthropy takes the form of supporting efforts that have a good chance of producing progress towards the medical control of aging. The rationale here is simple, possibly unfashionably so. Firstly, aging causes by far the greatest amount of human suffering and death. Secondly, aging is a tractable problem, in that the members of the research community collectively know enough to make progress rather than spinning their wheels, given suitable strategic choices in research and development. Lastly, suffering and death are bad things that should be brought to an end as soon as it is feasible to do so. That last opinion is both ubiquitous, judging by people's actions in their day to day lives, and yet somehow unpopular in our culture, a situation that has long confused me.

If one sets forth to blindly support any and all projects that claim to be doing something about aging, then a good three quarters of what is spent will be wasted. Yet the harms of aging are so great in comparison to other harms that the effort will still create more good in the world by far than for any other rational single choice in philanthropy. Given a little self-education, it is perfectly possible to avoid most of the obvious waste - the fraudulent side of the "anti-aging" marketplace, for example. The more challenging divide lies in the legitimate scientific community, between those focused on ways to modestly slow aging, such as via work on existing drugs like metformin and rapamycin, and those focused on ways to reverse aging, such as via senolytics to destroy senescent cells and the other lines of rejuvenation research advocated by the SENS Research Foundation. Few laypeople new to the field find it easy to determine what is more or less likely to be effective, and why.

I have long looked at this divide and taken the obvious position (obvious to me, anyway) that if funding and time is directed to this field, then it should be directed towards the goal of rejuvenation, not merely slowing aging. Rejuvenation is very much better than a slowing of aging. Rejuvenation via repair of fundamental molecular damage might even be easier to achieve than a method of reliably and safely slowing aging. It requires far less new knowledge about the operation of cellular metabolism, and obtaining that knowledge is slow, uncertain, and expensive. Where we can compare the pace of progress at a given level of funding, calorie restriction mimetic research from the 1990s to today, the best example of attempts to slow aging, looks like a very poor choice in comparison to the past seven years of senolytic development, the best example of attempts to reverse the causes of aging.

Returning to the topic of effective altruism, the article quoted below is an example of the sort of exercise that community specializes in: obtaining a handle on the usefulness of any given project by building a model and putting some numbers into it. The process is the important thing, thinking about it methodically, not any specific answer. In this case the analysis focuses on the TAME trial for metformin in older adults. This is a great example of work that I think has little technical merit. The evidence for metformin to reliably slow aging is terrible, the results from individual studies all over the map. Even if we take the best results as indicative of its performance, which given the full scope of the data seems unlikely, then the outcome is still significantly worse than the expected, reliable outcomes of more exercise and fewer calories. If someone can run the numbers on efforts to push forward metformin as a treatment for aging and find it to be a highly effective use of time and funding, then this says much more about the urgency of treating aging - and the waste in so much of the rest of philanthropy - than it does about the viability of metformin. Take that urgency and direct it to a better project, such as senolytics, or anything else under the SENS rejuvenation research umbrella.

Expected cost per life saved of the TAME trial

In this post I will try to calculate the expected cost per life saved of the Targeting Aging With Metformin (TAME) trial, in an attempt to improve Turchin's estimate. I found some of Turchin's assumptions were unnecessary or unjustified. He didn't provide an expected value calculation and he didn't apply the necessary discounts. His figure is true only if some of his many assumptions are, and this led to a result that I thought to be many orders of magnitudes off: 0.24 per life saved. In reality, if you look at the calculation section, you can see that, accounting for the icebreaking effect of the TAME trial on the FDA, I came to a result that isn't distant to Turchin's. This happened because Turchin didn't account for the icebreaking effect, compensating the omission of the discounts. Otherwise, if the icebreaking effect is disregarded, the results are different, yet still show high cost-effectiveness.

The TAME (Targeting Aging With Metformin) trial is motivated by two reasons: 1) According to AFAR, the TAME trial could have an icebreaking effect on the FDA. It will pave the way for the Food and Drug Administration (FDA) to consider aging a modifiable condition and an official indication for which treatments can be developed and approved, and 2) Testing metformin on a healthy population could prove its beneficial effects, and the approval of metformin by the FDA would cause physicians to start suggesting it to their patients.

The core of Turchin's idea is right: Let's say Longevity Escape Velocity (LEV) will happen at date x. If we extend the lives of people who would have died before date x, making them reach date x, we are then "saving their lives". This could be done by raising the life expectancy of a portion of the world using simple interventions such as metformin, or alternatively by accelerating research to make LEV occur sooner. The given in this rationale is that Longevity Escape Velocity will happen at some point, and I think this is very safe to assume.

Many studies suggest that metformin could postpone age-related pathologies. Data from the largest study translates to around 1 year of more life for diabetics than the non diabetic control. More important is the number of years LEV will be advanced by, considering the icebreaking effect of TAME. The model here shows that most of the cost-effectiveness of TAME comes from its icebreaking effect. Will advancing the date of the icebreaking effect by x years result in an advance of LEV of x years? Probably not, since the FDA not recognising aging as an indication doesn't stop aging research, and it's not clear if the icebreaking effect is a bottleneck for achieving LEV. Such an effect could, though, increase the budget of aging research and make research in this field more focused on translation and on the hallmarks of aging instead of single diseases.

If the icebreaking effect enables the funding of one or more projects which are bottlenecks to LEV, then LEV's date is advanced. The main probability at play here is if the NIH would indeed increase its budget on aging or spend it better. If this doesn't happen I don't anticipate other actors would step in who wouldn't otherwise. The expert opinion on this is that such a thing will happen - it is the objective of TAME as stated by the organizers.

When I am Eighty-Five

I will be 85 somewhere in the mid 2050s. It seems like a mirage, an impossible thing, but the future eventually arrives regardless of whatever you or I might think about it. We all have a vision of what it is to be 85 today, informed by our interactions with elder family members, if nothing else. People at that age are greatly impacted by aging. They falter, their minds are often slowed. They are physically weak, in need of aid. Perhaps that is why we find it hard to put ourselves into that position; it isn't a pleasant topic to think about. Four decades out into the future may as well be a science fiction novel, a far away land, a tale told to children, for all the influence it has on our present considerations. There is no weight to it.

When I am 85, there have been next to no senescent cells in my body for going on thirty years. I bear only a small fraction of the inflammatory burden of older people of past generations. I paid for the products of companies descended from Oisin Biotechnologies and Unity Biotechnology, every few years wiping away the accumulation of senescent cells, each new approach more effective than the last. Eventually, I took one of the permanent gene therapy options, made possible by biochemical discrimination between short-term beneficial senescence and long-term harmful senescence, and then there was little need for ongoing treatments. Artificial DNA machinery floats in every cell, a backup for the normal mechanisms of apoptosis, triggered by lingering senescence.

When I am 85, the senolytic DNA machinery are far from the only addition to my cells. I underwent a half dozen gene therapies over the years. I picked the most useful of the many more that were available, starting once the price fell into the affordable-but-painful range, after the initial frenzy of high-cost treatments subsided into business as usual. My cholesterol transport system is enhanced to attack atherosclerotic lesions, my muscle maintenance and neurogenesis operate at levels far above what was once a normal range for my age, and my mitochondria are both enhanced in operation and well-protected against damage by additional copies of mitochondrial genes backed up elsewhere in the cell. Some of these additions were rendered moot by later advances in medicine, but they get the job done.

When I am 85, my thymus is as active as that of a 10-year-old child. Gene and cell therapies were applied over the past few decades, and as a result my immune system is well gardened, in good shape. A combination of replacement hematopoietic stem cells, applied once a decade, the enhanced thymus, and periodic targeted destruction of problem immune cells keeps at bay most of the age-related decline in immune function, most of the growth in inflammation. The downside is that age-related autoimmunity has now become a whole lot more complex when it does occur, but even that can be dealt with by destroying and recreating the immune system. By the 2030s this was a day-long procedure with little accompanying risk, and the price fell thereafter.

When I am 85, atherosclerosis is curable, preventable, and reversable, and that has been the case for a few decades. There are five or six different viable approaches in the marketplace, all of which basically work. I used several of their predecessors back in the day, as well. Most people in the wealthier parts of the world have arteries nearly free from the buildup of fat and calcification. Cardiovascular disease with age now has a very different character, focused more failure of tissue maintenance and muscle strength and the remaining small portions of hypertension that are still problematic for some individuals. But that too can be effectively postponed through a variety of regenerative therapies.

When I am 85, there is an insignificant level of cross-linking in most of my tissues, as was the case since my early 60s. My skin has the old-young look of someone who went a fair way down the path before being rescued. Not that I care much about that - I'm much more interested in the state of my blood vessels, the degree to which they are stiff and dysfunctional. That is why removal of cross-links is valuable. That is the reason to keep on taking the yearly treatments of cross-link breakers, or undergo one of the permanent gene therapies to have your cells produce protective enzymes as needed.

When I am 85, I have a three decade patchwork history of treatments to partially clear this form of amyloid or that component of lipofuscin. Modified enzymes are delivered here, a gene therapy applied there. I will not suffer Alzheimer's disease. I will not suffer any of the common forms of amyloidosis that degrade heart muscle performance or disrupt function in other organs. The potential for such conditions is controlled, shut down with the removal of the protein aggregates that cause cellular dysfunction. There is such a breadth of molecular waste, however: while the important ones are addressed, plenty more remain. This is one of the continuing serious impacts to the health of older individuals, and a highly active area of research and development.

When I am 85, I am the experienced veteran of several potentially serious incidences of cancer, all of which were identified early and eradicated by a targeted therapy that produced minimal side-effects. The therapies evolve rapidly over the years: a bewildering range of hyper-efficient immunotherapies, as well as treatments that sabotage telomere lengthening or other commonalities shared by all cancer cells. They were outpatient procedures, simple and quick, with a few follow-up visits, so routine that they obscured the point that I would be dead several times over without them. The individual rejuvenation technologies I availed myself of over the years were narrowly focused, not perfect, and not available as early as I would have liked. Cancer is an inevitable side-effect of decades of a mix of greater tissue maintenance and unrepaired damage.

Do we know today what the state of health of a well-kept 85-year-old will be in the 2050s? No. It is next to impossible to say how the differences noted above will perform in the real world. They are all on the near horizon, however. The major causes of age-related death today will be largely controlled and cured in the 2050s, at least for those in wealthier regions. If you are in your 40s today, and fortunate enough to live in one of those wealthier region, then it is a given that you will not die from Alzheimer's disease. You will not suffer from other common age-related amyloidosis conditions. Atherosclerosis will be reliably controlled before it might kill you. Inflammatory conditions of aging will be a shadow of what they once were, because of senolytic therapies presently under development. Your immune system will be restored and bolstered. The stem cells in at least your bone marrow and muscles will be periodically augmented. The cross-links that cause stiffening of tissues will be removed. Scores of other issues in aging process, both large and small, will have useful solutions available in the broader medical marketplace. We will all live longer and in better health as a result, but no-one will be able to say for just how long until this all is tried.

Do FOXA2-Related Changes in the Nuclear Lamina Contribute to Liver Aging?

The structure of the cell nucleus is determined by the nuclear lamina, protein filaments that support the nuclear membrane and anchor the important components within the nucleus. Correct function of the lamina and its component parts are required in order for the cell to carry out vital functions such as nuclear DNA maintenance and repair, gene expression, and cell replication. In a cell with faulty nuclear lamina, the nucleus is misshapen and all these processes run awry. Such cells tend to become senescent in response to internal dysfunction, and cause damage to surrounding tissue via their inflammatory secretions if they are not then destroyed promptly by the immune system. Internal self-destruction mechanisms exist, but problems with gene expression may cause them to fail.

Regular readers will recall that this is the scenario in progeria, a condition with the appearance of accelerated aging. Progeria is caused by mutation in the lamin A gene that codes for a protein that is an important component the nuclear lamina. Progeria patients have dysfunctional, broken cells with misshapen cell nuclei, and as a consequence they die young of cardiovascular disease that is very similar to the conditions such atherosclerosis that normally only affect much older individuals. Researchers have found that lamin A is broken in small amounts over the course of normal aging, with damaging results, but it is an open question as to whether that is significant in comparison to the other causes of aging.

In the research noted here, a more subtle age-related disruption to the nuclear lamina is examined, connected to the behavior of FOXA2 and lamin B1. The researchers focus on liver tissue, and suggest that problems with nuclei in the aged liver cause sufficient change in gene expression to contribute to organ dysfunction and age-related disease. The mechanism seems plausible, but the question as before is the degree to which it occurs, and whether it is possible to definitively tie it to systematic changes in gene expression that are broadly similar in all individuals. That last point seems at least at first a challenge; one might expect problems with nuclear structure to have more random effects on the capacity of a cell to carry out its operations. Nonetheless, it is interesting work and worth a look in the broader context of whether or not the structure of the nucleus is a major, minor, or insignificant process in normal aging.

We could reverse aging by removing wrinkles inside our cells, study suggests

A new finding suggests that fatty liver disease and other unwanted effects of aging may be the result of our cells' nuclei - the compartment containing our DNA - getting wrinkly. Those wrinkles appear to prevent our genes from functioning properly. The location of our DNA inside the cell's nucleus is critically important. Genes that are turned off are shoved up against the nuclear membrane, which encases the nucleus. But with age, our nuclear membranes become lumpy and irregular, and that prevents genes from turning off appropriately.

Looking at a model of fatty liver disease, researchers found that our livers become studded with fat as we age because of the wrinkly nuclear membranes. "When your nuclear membrane is no longer functioning properly, it can release the DNA that's supposed to be turned off. So then your little liver cell becomes a little fat cell." The accumulation of fat inside the liver can cause serious health effects, increasing the risk of type 2 diabetes and cardiovascular disease, even potentially leading to death. The membrane wrinkling stems from a lack of a substance called lamin, a cellular protein that comes in various forms. By putting the appropriate lamin back, we might smooth out the membrane.

Researchers suspect the wrinkling of the nuclear membrane is responsible for unwanted effects of aging in other parts of the body as well. "Every time I give this talk to colleagues, they say, 'Well, do you think this is a universal mechanism?' In my opinion, I think it is."

Changes at the nuclear lamina alter binding of pioneer factor Foxa2 in aged liver

Increasing evidence suggests that regulation of heterochromatin at the nuclear envelope underlies metabolic disease susceptibility and age-dependent metabolic changes, but the mechanism is unknown. Here, we profile lamina-associated domains (LADs) in young and old hepatocytes and find that, although lamin B1 resides at a large fraction of domains at both ages, a third of lamin B1-associated regions are bound exclusively at each age in vivo. Regions occupied by lamin B1 solely in young livers are enriched for the forkhead motif, bound by Foxa pioneer factors.

We also show that Foxa2 binds more sites in Zmpste24 mutant mice, a progeroid laminopathy model, similar to increased Foxa2 occupancy in old livers. Aged and Zmpste24-deficient livers share several features, including nuclear lamina abnormalities, increased Foxa2 binding, de-repression of PPAR- and LXR-dependent gene expression, and fatty liver. In old livers, additional Foxa2 binding is correlated to loss of lamin B1 and heterochromatin at these loci. Our observations suggest that changes at the nuclear lamina are linked to altered Foxa2 binding, enabling opening of chromatin and de-repression of genes encoding lipid synthesis and storage targets that contribute to etiology of hepatic steatosis.

An Example of the Importance of Gut Microbiota to Aging in Flies

If we paint with very broad strokes, we can say that flies generally die from intestinal failure in the same way that humans generally die from cardiovascular failure. For flies, the intestine is at the center of the mechanisms determining the pace and manifestations of aging in that species, and the cause of a majority of deaths. While being far from the only organ to consider in fly aging, it does appear to take center stage. Bear this in mind while looking at the research noted here.

All in all, it isn't too surprising to hear that researchers have been able to demonstrate a 60% life extension in flies through a method that involves suppressing some of the detrimental age-related changes in gut bacteria. (Though it appears that almost everything else of interest to the aging process in metabolism is also adjusted via the approach taken here - which makes it hard to ascribe the outcome to any one specific item). In recent years the research community has given ever more attention to the activities of the microbial population of the intestines in various species including our own. Evidence suggests thatthe way in which populations of gut bacteria change over a life span are influential in aging to a degree that may be in the same ballpark as, say, exercise or other noteworthy environmental factors.

Nonetheless, I think caution is wise when extrapolating any research of this nature carried out in flies, given the enormous importance of intestinal function in fly aging. It would be logical to expect to find similar effects in mammals, but nowhere near as large in their consequences. The intestine doesn't seem as central to aging in mammals as it is in flies: the importance of various organs and bodily systems shifts and becomes more distributed as one moves from lower to higher animals. Quite aside from this, we should remember that there are many ways to significantly extend life in short-lived species such as flies that (a) touch on the mechanisms affected here, and (b) are known to do little for human longevity. Large numbers in life extension mean little on their own when demonstrated in worms, flies, and the like.

When thinking about the mechanisms involved in the connection between gut bacteria and aging, inflammation is likely one of the most important. Gut microbes interact with the immune system, and some are more capable of provoking inflammatory reactions. If, for reasons relating to the many complex changes in lifestyle and immune function and other tissues that occur with age, more inflammatory bacteria come to dominate, then that will cause harm over the long term. There are, however, a growing number of other more subtle mechanisms to consider. Given the comparative recency of this part of the field of aging research, it is fair to say that much remains to be discovered.

The secret to longevity is in the microbiome and the gut

Scientists fed fruit flies with a combination of probiotics and an herbal supplement called Triphala that was able to prolong the flies' longevity by 60% and protect them against chronic diseases associated with aging. The study adds to a growing body of evidence of the influence that gut bacteria can have on health. The researchers incorporated a synbiotic - made of probiotics with a polyphenol-rich supplement - into the diet of fruit flies. The flies fed with the synbiotic lived up to 66 days old - 26 days more than the ones without the supplement. They also showed reduced traits of aging, such as mounting insulin resistance, inflammation, and oxidative stress.

"Probiotics dramatically change the architecture of the gut microbiota, not only in its composition but also in respect to how the foods that we eat are metabolized. This allows a single probiotic formulation to simultaneously act on several biochemical signaling pathways to elicit broad beneficial physiological effects, and explains why the single formulation we present in this paper has such a dramatic effect on so many different markers. The effects in humans would likely not be as dramatic, but our results definitely suggest that a diet specifically incorporating Triphala along with these probiotics will promote a long and healthy life."

The findings can be explained by the "gut-brain axis," a bidirectional communication system between microorganisms residing in the gastrointestinal tract - the microbiota - and the brain. In the past few years, studies have shown the gut-brain axis to be involved in neuropathological changes and a variety of conditions such as irritable bowel syndrome, neurodegeneration, and even depression. Few studies, however, have successfully designed gut microbiota-modulating therapeutics having effects as potent or broad as the formulation presented in the new study.

Longevity extension in Drosophila through gut-brain communication

The gut microbiota is complex ecosystem of bacteria, fungi, and microorganisms residing in the gastrointestinal tract, which impart many health benefits onto the host. Distinct variations in the composition of the gut microbiota in the elderly have been identified and could contribute to frailty, disease development and aging itself. A diet rich in probiotics and prebiotics may help prevent chronic age-related disease. Changes in the gut microbiota of aging individuals has a high inter-individual variability due to disease manifestation, medication, diet, and environmental exposure.

In general, aging subjects have a decline in the phyla Firmicutes, elevation in Bacteriodetes, reduction of Bifidobacteria, elevation in the proinflammatory Proteobacteria accompanied by a decline in overall diversity, which is associated with various health risks and fraility. Indeed, a general decrease in the level of short-chain fatty acids (SCFAs) is apparent in aging individuals which is linked to inflammation and adipose tissue dysregulation.

The gut-brain-axis (GBA) is a bidirectional communication system between the gastrointestinal tract microbiota and the brain including various metabolic, immunological, endocrine, and neuronal signals derived from individual bacterial cells and their metabolites. Through this axis, the gut microbiota was recently identified as a target for therapeutic intervention against age-related diseases. For example, several probiotic bacteria have shown beneficial effects in managing symptoms of neurodegeneration.

The present study describes how a novel probiotic and synbiotic formulation impacts Drosophila melanogaster longevity through mechanisms of the GBA. It was previously shown that the probiotic and synbiotic formulation used in the present study has beneficial effects on aging. The present probiotic and synbiotic formulations showed combinatorial action on reducing markers of physiological stress, oxidative stress, inflammation and mitochondrial electron transport chain complex integrity therefore targeting most of the main aging mechanisms. This action benefits not only longevity but would prevent many age-related chronic diseases that are associated with the aforementioned states.

Lower Levels of KIFC3 Observed in Aging are Involved in the Decline of Autophagy

Autophagy is the name given to the collection of cellular processes that recycle broken and unwanted proteins and cell structures. More autophagy is a good thing, and many of the methods demonstrated in the laboratory to modestly slow aging in flies, worms, and mice involve enhanced autophagy. You might look at a recent experiment demonstrating a 10% gain in mouse life span via a narrowly targeted method of increasing autophagy, for example. Calorie restriction, the gold standard in reliability when it comes to slowing aging, depends upon autophagy: it doesn't work when autophagy is disabled.

Unfortunately, autophagy declines with age. But why? There are undoubtedly many answers to that question, a layered set of mechanisms that directly or indirectly arise from the root causes of aging, the accumulation of molecular damage as outlined in the SENS rejuvenation research proposals. In the direct case, autophagy suffers because persistent metabolic waste accumulates in lysosomes, the structures responsible for disassembling proteins and cell components. They are packed full of enzymes capable of dismantling near all of what they encounter, but near all isn't good enough over the long term. Long-lived cells in older people contain dysfunctional lysosomes packed full of a mix of hardy waste compounds collectively known as lipofuscin.

Autophagy is a complicated multi-stage process, however. Function isn't just a matter of the state of lysosomes, but also of the mechanisms responsible for flagging proteins and structures for recycling, constructing membranes around that material, and delivering the membrane-wrapped packages to the nearest lysosome. If any of that falters, then the pace of autophagy declines. The open access research here reports on an example of issues in the transport portion of autophagy, and the authors make some headway into understanding why it happens, associating it with reduced levels of KIFC3. While pinpointing age-associated changes in the expression of a particular gene is a first step, it has to be said that this rarely leads to the root cause damage without a great deal of further work.

Defective recruitment of motor proteins to autophagic compartments contributes to autophagic failure in aging

Autophagy is a highly conserved catabolic process responsible for the delivery of cytoplasmic materials (proteins and organelles) into lysosomes for their degradation. Autophagy contributes to maintain cellular and tissue homeostasis by assuring protein and organelle quality control. A growing number of reports have linked malfunctioning of autophagy with aging, highlighting the role of autophagy as an anti-aging cellular mechanism. Furthermore, genetic inhibition of this degradative process recapitulates features associated with aging and age-related diseases. Loss of protein/organelle quality control is a universal hallmark of aging, and malfunctioning of autophagy with age contributes to this gradual accumulation of damaged proteins and dysfunctional organelles. However, the cellular and molecular mechanisms underlying this progressive decline in autophagy during aging remain unknown.

Delivery of cargo (material to be degraded) to lysosomes via macroautophagy, the most conserved and best characterized type of autophagy (hereafter denoted as autophagy), requires regulated trafficking of autophagic vesicles (AVs), the compartments where cargo is sequestered, for their fusion with lysosomes. Subcellular positioning of organelles is mainly determined by the microtubule network. Interaction of these vesicles with microtubules is mediated by motor proteins that provide the force necessary to move them along the tubulin tracks. Vesicle-associated motors are of two types depending on the direction in which the vesicle is transported: plus-end-directed motor proteins (N-kinesins) that transport vesicles toward the cellular periphery and minus-end-directed motor proteins (dynein and members of the C-kinesin family such as KIFC2 and KIFC3) that move vesicles to the perinuclear area.

The balance between active plus-end- and minus-end-directed motors bound to a vesicle's surface determines the directionality of its intracellular movement. In the case of autophagy, the balance of active motor proteins on the surface of autophagosomes has been proposed to prevent their premature or random fusion with lysosomes. In most cells, autophagosome-lysosome fusion occurs mainly in the perinuclear region where it is facilitated through both physical proximity of the organelle and slowing of vesicular trafficking. Consequently, efficient positioning of these degradative compartments in the vicinity of the nucleus in a microtubule-dependent manner is an essential step for the final completion of the autophagic process.

Failure to reposition autophagosomes and lysosomes toward the perinuclear region with age reduces the efficiency of their fusion and the subsequent degradation of the sequestered cargo. Hepatocytes from old mice display lower association of two microtubule-based minus-end-directed motor proteins, the well-characterized dynein, and the less-studied KIFC3, with autophagosomes and lysosomes, respectively. Using genetic approaches to mimic the lower levels of KIFC3 observed in old cells, we confirmed that reduced content of this motor protein in fibroblasts leads to failed lysosomal repositioning and diminished autophagic flux. Interestingly, the motor defect seems to preferentially affect basal quality control autophagy whereas induction of autophagy by starvation restores in part association of specific motor proteins with autophagosomes and lysosomes. These findings highlight the feasibility of activating inducible autophagy in old organisms to compensate for their defective basal autophagy.

A Commentary on Senolytic Gene Therapies to Target p16 Overexpression

This short commentary discusses the utility of Oisin Biotechnologies' initial strategy for destroying senescent cells, which is to use p16 expression as the determining sign of senescence. Oisin's implementation involves delivering dormant DNA machinery indiscriminately to all cells, and then triggering it only in cells with high levels of p16. This particular implementation is one of many possibilities in the gene therapy space, and thus various other groups are working on their own p16-based approaches as senolytic development as a treatment for aging grows in funding and popularity.

It isn't just senescence and aging in which this is a topic of interest, of course. There is a strong overlap with cancer, and the search for ways to selectively destroy the most aggressive cancerous cells. In many of these forms of aberrant cell the mechanisms of senescence are broken in some way. These cells have at least some of the chemical signatures of senescence, but fail to shut down and cease replication. Thus targeting expression of senescence-associated genes may work fairly well against cancer as well as the contribution of cellular senescence to aging - something that Oisin Biotechnologies is also working on.

p16Ink4a (p16) is an important tumor suppressor which is upregulated in senescent cells and in aged tissues. p16 acts as an inhibitor of the interaction between Cyclin-Dependent Kinases (CDK) 4/6 and CyclinD1 leading to the activation of retinoblastoma protein (RB). Consequently, active RB interferes with the translocation of E2F1 into the nucleus and arrests cells in the G1-S phase of the cell cycle. In cancer cells with mutations in RB or CDK4/6, p16 is normally overexpressed but unable to induce cell cycle arrest. p16-overexpressing cancer cells are found in different types of carcinomas and are considered highly aggressive and invasive.

Several drugs in recent years have been shown to have senolytic properties (i.e. being toxic for senescent cells) and to remove p16+ cells from a variety of tissues. Among these compounds, ABT-737 and its orally-available analogue ABT-263 target the anti-apoptotic proteins BCL-2, BCL-W and BCL-XL, considered essential pro-survival players in senescent cells. The effects of these compounds in mice almost completely overlap with a suicide gene strategy activated by the p16 promoter, thus suggesting specific targeting p16+ cells.

However, when we tested ABT-737 and ABT-263 against p16-overxpressing murine sarcomas we failed to observe any toxicity, despite p16+-cancer cells upregulating both BCL-2 and BCL-XL. These data could be interpreted in 3 ways: 1) ABT compounds are specifically active against non-proliferating p16+-cells; 2) the efficacy of ABTs requires upregulation of BCL-W, which we have recently shown being a common feature of senescent cells; 3) ABTs act independently of p16 expression levels. The latter hypothesis would represent a critical issue, as p16 is used as a major readout for the efficacy of senotherapies.

Since we have recently developed an inducible suicide gene regulated by the full p16 promoter, we have then studied whether the use of this strategy could be effective against p16+ tumors. Indeed, most p16-overexpressing cancer cells were efficiently eliminated by the activation of the suicide gene in both culture and in vivo conditions. These data suggest that p16 upregulation is maintained by active transcription, possibly mediated by emergency signaling pathways attempting to restrain cellular proliferation.

Our study supports the idea that the overexpression of oncosuppressors could be exploited for interventions against cancer. While we studied a specific context in which p16 is present in its wild-type form, this strategy could potentially work in situations of overexpression (by transcriptional regulation) of mutated forms, which is a common feature of cancer cells. On this line, similar strategies against additional oncosuppressors such as p14 and p53 could be effective.

In parallel, it will be of interest to understand whether a p16-based suicide gene therapy could be used in other contexts. Studies in transgenic mouse models have shown that elimination of p16+ cells using suicide genes can significantly delay the onset and progression of a number of age-related pathologies, eventually leading to lifespan extension. Whether a similar strategy could be used for human interventions is still matter of debate.

Can Present Stem Cell Therapies Improve Vaccine Response in the Elderly?

Mesenchymal stem cell therapies fairly reliably reduce chronic inflammation for some period of time following the transplantation of cells. The cells don't survive long in the patient, and this effect is mediated by the signals they produce while present. Chronic inflammation causes many issues, including a disruption of tissue maintenance and regeneration. It contributes directly to the progression of numerous age-related conditions, including the components of frailty syndrome, but it is an open question as to the degree to which it is required to maintain the current state of those conditions. If inflammation is suppressed for an extended period of time, will there be some improvement in the patient?

The company Longeveron has been running trials in older frail people to examine the degree that benefits result from suppression of inflammation via stem cell therapies. Of interest is the latest trial announced here, in which they are looking at vaccine response. It is well known that older people have less functional immune systems, and one of the many consequences is that vaccination, such as against influenza, isn't as effective. It is interesting to speculate on the likely mechanisms by which stem cell induced reductions in inflammation might help: increased delivery of new immune cells due to enhanced native stem cell activity, or perhaps suppression or some degree of removal of malfunctioning immune cells?

Longeveron, a biopharmaceutical company that develops stem cell therapies for aging-related conditions, announced that it has received a 750,000 grant from the Maryland Technology Development Corporation (TEDCO). Longeveron will apply the funding towards its clinical trial examining the safety and efficacy of its allogeneic mesenchymal stem cell (MSCs) product to improve flu vaccine immune response in elderly patients with frailty. "Last year's flu season was one of the worst and deadliest in recent years, and seniors are typically the most vulnerable. Regenerative stem cell therapies hold great promise to bolster the immune systems of older people for greater resistance to flu."

"This is an important test of cell therapy technology and may have long term implications in vaccine strategies in older adults. Immune functional decline, or immunosenescence, is a hallmark feature of aging. Elder patients, particularly those who are frail, are at high risk for influenza and its complications. Data from our previous study indicate that aging frailty is associated with poor antibody response to, and clinical protection from, vaccination with standard dose trivalent inactivated influenza vaccine. While newer influenza vaccines have become available in recent years, MSCs represent a novel immunization strategy."

Longeveron's MSC product is derived from the bone marrow of young, healthy adult donors, and is currently being tested in a variety of indications in clinical trials, including Aging Frailty. In 2017, the company published positive Phase I and Phase 2 Aging Frailty study results in the Journals of Gerontology. Frail patients showed marked improvement in physical performance, lung function, and inflammation, with no serious adverse effects attributed to the treatment.The company also recently completed enrollment in the first phase of its flu vaccine immune-response trial.

Discussing the Dog Aging Project with Matt Kaeberlein

The Life Extension Advocacy Foundation volunteers recently interviewed Matt Kaeberlein on the topic of the Dog Aging Project, a venture that aims to try in dogs some of the more credible and safe interventions shown to modestly slow aging in mice. When initially proposed, senolytics to clear senescent cells were not in that list, but we might hope to see that change in the years ahead. I'm not overly optimistic about the performance of the other possibilities, such as mTOR inhibitors and other candidate calorie restriction mimetic or exercise mimetic pharmaceuticals. In some cases the evidence is good for these items to work, in the sense of improving health and longevity to some degree, but in general we should expect the effects on life span to be small in longer-lived mammals. All of the mechanisms based on enhanced stress responses, such as those triggered by a lack of nutrients or undertaking strenuous exercise, scale down in their effect on life span for longer-lived species; short-lived species have a much greater plasticity of aging in response to environmental circumstances.

Could you tell us the story of Dog Aging Project? How did it all start?

About five years ago, a new recruit to the University of Washington Healthy Aging and Longevity Institute had recently obtained a small grant to develop companion dogs as a model to understand the genetic and environmental determinants of aging. After a series of discussions, it occurred to me that we had an opportunity not just to study aging in dogs but to potentially develop interventions to delay or even reverse aspects of aging in dogs from those that had already been shown to increase lifespan and healthspan in laboratory rodent models. I decided to focus on rapamycin first, because it was (and still is) the most validated and effective pharmacological approach for increasing longevity in mice, and it has the added benefit that it is effective even when initiated in middle age. After spending a couple of months convincing myself that we could safely perform a rapamycin veterinary clinical trial in dogs, I organized a conference in Seattle in 2014, where I pitched the idea. Soon after that, we started getting quite a bit of media attention, and we decided that we should officially form the Dog Aging Project.

What can you tell us about trials you've already run and their results?

So far, we've only completed one trial, a 10-week, randomized, double-blind, placebo-controlled study of rapamycin in pet dogs. The results of that study were as positive as we could have hoped. We saw no evidence for increased side effects in the dogs that received rapamycin and statistically significant improvements in two of the three measures of age-related cardiac function that we looked at.

Are there any trials you're running right now or are preparing to launch soon?

Yes, the Phase 2 rapamycin intervention trial is currently enrolling dogs. That trial is funded by the Donner Foundation and is a one-year trial to, again, assess effects of rapamycin on cardiac function and to also look at effects on cognitive function and activity. Depending on the outcome of our submitted NIH grant, we hope to begin officially enrolling dogs into the Longitudinal Study of Aging and Phase 3 of the rapamycin intervention trial toward the end of 2018 or early 2019. We hope to have an official announcement on the outcome of that proposal within the next 3-4 weeks.

Can I volunteer my dog for the program, and how do I do that?

Anyone can nominate their dog to participate in either the Longitudinal Study of Aging or the Rapamycin Intervention Trials through the Dog Aging Project website. The Longitudinal Study is currently open to all breeds, ages, and sizes of dogs. The Rapamycin Intervention Trials are restricted to healthy dogs of at least 6 years old and at least 40 lbs in weight.

Exploring the Utility of Decellularized Muscle Grafts in Animal Models

In this open access paper, researchers explore the utility of decellularized muscle grafts to repair severe injury. Decellularization is the process by which a donor tissue is cleared of cells, leaving behind the extracellular matrix. This intricate structure includes capillary networks and chemical cues to guide cells, line items that the research community has yet to reliably recreate when building tissue from scratch. Over the past decade, researchers have demonstrated the ability to repopulate decellularized tissue with patient-derived cells, a capacity that in principle allows for the production of patient-matched donor organs. This is an important stepping stone on the path towards fully tissue engineered organs grown from a cell sample, and offers the potential for incremental improvement over the present situation for organ donation and transplantation. It can expand the donor pool to include tissues that would be rejected, allow the possibility of transplantation across species, and greatly improve patient prognosis by near eliminating transplant rejection issues.

Injuries to the extremities affect soft and hard tissues and can result in permanent loss of skeletal muscle mass, termed volumetric muscle loss (VML). Treatments for VML include muscle transfers or stem cell injections, but they are not effective procedures to restore muscle function and can require additional surgeries and tissue harvest. Extensive research has been done to identify more effective VML treatments using animal models with severe functional deficits. In these models, VML typically exceeds 20% of the affected muscle mass and results in reduced muscle function. Wounds this large are far beyond the natural healing capacity, making them a gold standard for regenerative medicine research.

Extracellular matrix (ECM) structure and chemistry are key elements involved in muscle regeneration and taking advantage of those elements is important to restore function in VML injuries. Muscle ECM is a matrix rich in laminin, fibronectin, collagens, proteoglycans, and growth factors, which play a role in myoblast differentiation and muscle fiber formation. Biomaterials derived from soft tissues can retain these ECM components and have already shown promise. Several decellularized allogenic and xenogenic matrices are currently available for clinical use, but are exclusively produced from thin tissues such as the skin, small intestine submucosa, and bladder. Those thin-walled tissues do not possess specific properties found in skeletal muscle such as alignment and muscle-specific chemistry.

Decellularized muscle matrices (DMMs) retain the native morphology of muscle ECM, support muscle healing, and promote a proregenerative immune response. These matrices release factors in vivo that promote constructive remodeling of tissue by macrophages and suppress a cytotoxic T cell response, resulting in implant integration and tissue regeneration. Properties like these are critical to elicit a regenerative response that activates muscle progenitors (satellite cells and myoblasts) to differentiate into myocytes, and fuse together to form muscle fibers. Without ECM cues to direct muscle progenitors, muscle healing is delayed.

We compared the ability of DMM, autologous muscle grafts (clinical standard), and type I collagen plugs (negative control) to support muscle regeneration. DMM supported regeneration over a 56-day period in 1×1 cm and 1.5×1 cm gastrocnemius muscle defects in rats. Muscle function tests demonstrated improved muscle recovery in rats with DMM grafts when compared to collagen. DMM supported muscle regeneration with less fibrosis and more de novo neuromuscular receptors than either autograft or collagen. Overall, our results indicate that DMM may be used as a muscle replacement graft based on its ability to improve muscle function recovery, promote muscle regeneration, and support new neuromuscular junctions.

Long Non-Coding RNA in the Aging Brain

The first step of gene expression, the process of producing proteins from the genetic blueprint of DNA, is the production of an RNA molecule. This RNA is then used as an intermediary working model from which the final protein is produced. Non-coding RNA molecules are those that do not translate into a protein, but otherwise serve one of a wide variety of purposes in the cell. Many of these non-coding RNA molecules are in some way involved in regulating gene expression; the production of proteins in a cell is a highly complex, many-layered, and dynamic collection of processes. It is also far from being completely mapped in detail in its youthful, fully functional state, never mind the countless changes to that state that take place in reaction to the accumulating molecular damage of aging. There is much yet to be discovered about the roles played by specific RNA molecules in cellular metabolism and its alterations over the course of aging.

Alterations in the aging brain include changes in the epigenetics and transcription of both coding and non-coding regions of the genome. Among non-coding transcripts, long non-coding RNAs (lncRNAs) have recently emerged as key regulators of the molecular processes that underlie age-associated phenotypes. lncRNAs are transcripts that are longer than 200 nucleotides in length with virtually no protein-coding capacity. These transcripts are mostly uniquely expressed in cell types - both spatially and temporally - and are particularly enriched in the brain, where they play functional roles in neuroplasticity, cognition, and differentiation of neural stem cells. Additionally, lncRNAs are known to orchestrate epigenetic processes through their interactions with epigenetic machinery.

This review proposes ways by which lncRNAs may contribute to neural aging and how their functions can be altered across the human lifespan. We discuss that antisense lncRNAs can regulate pathological protein aggregation and that subnuclear compartment specific lncRNAs can regulate neuronal splicing, transcription, and sponging of ion channels in aging. Other pre- and post-transcriptional regulatory roles performed by lncRNAs are also discussed in the context of cognition, neurogenesis, and neurodegeneration in aging, including the possible influence of lncRNAs on the maintenance of the 3D nuclear architecture.

In summary, the coding/non-coding interactome that sustains important processes of cognition and adult neurogenesis may become compromised during neuronal aging. It is not yet known whether changes in the transcription of lncRNAs are reactive, compensatory, or causative of aging. However, rapidly accumulating evidence supports the vital contribution of lncRNAs in neuronal aging.

No Cardiovascular Health Benefits Result from Most Common Dietary Supplements

It is well known within the research community that dietary supplements as a class achieve next to nothing for basically healthy people, those lacking any specific deficiency or medical condition that might cause that deficiency. In fact the evidence strongly suggests that some supplements, antioxidants for example, may even be modestly harmful over the long term. This scientific consensus has to compete with the marketing budget of the supplement industry, which seems to be doing fairly well for a community focused on selling a mix of largely useless and mildly harmful products. So studies such as this one continue to roll out, and perhaps one day there will be meaningful change as a result, but I'm not holding my breath.

Treatment and prevention of micronutrient deficiencies with vitamins and minerals in the last two-and-a-half centuries are among the most dramatic achievements in the history of nutritional science. However, interest in micronutrients has shifted recently from prevention of classic deficiency states to prevention of possible subclinical deficiencies and promotion of overall health and longevity using supplemental vitamins and minerals (supplement use). Here, the data are less clear, but supplement use is widespread.

Using the National Health and Nutrition Examination Survey data (1999 to 2012) on 37,958 adults, it was estimated that supplement use was high in 2012, with up to 52% of the population taking supplements. Multivitamins were taken by 31% of the population, vitamin D by 19%, calcium by 14%, and vitamin C by 12%. Despite high supplement use by the general public, there is no general agreement on whether individual vitamins and minerals or their combinations should be taken as supplements for cardiovascular disease (CVD) prevention or treatment.

We conducted a systematic review and meta-analysis of existing systematic reviews and meta-analyses and single randomized controlled trials (RCTs) published in English from 2012 to 2017. Where both supplements and dietary intakes of nutrients in foods were combined as total intakes, data were not used unless supplement data were also presented separately. We assessed those supplements previously reported on by the US Preventive Services Task Force (USPSTF): vitamins A, B1, B2, B3 (niacin), B6, B9 (folic acid), C, D, and E, as well as β-carotene, calcium, iron, zinc, magnesium, and selenium.

The following supplements were associated with no significant effect on CVD outcomes and all-cause mortality: vitamins A, B6, and E; β-carotene; zinc; iron; magnesium; selenium; and multivitamins. In general, the data on the popular supplements (multivitamins, vitamin D, calcium, and vitamin C) show no consistent benefit for the prevention of CVD, myocardial infarction, or stroke, nor was there a benefit for all-cause mortality to support their continued use. At the same time, folic acid alone and B-vitamins with folic acid, B6, and B12 reduced stroke, whereas niacin and antioxidants were associated with an increased risk of all-cause mortality. Overall, the effects were small; the convincing lack of benefit of vitamin D on all-cause mortality is probably the reason for the lack of further studies published since 2013. The effects of folic acid in reducing stroke is also convincing, with a 20% reduction.

Researchers Create Bioprinted Human Corneas

The cornea is a good target for tissue engineering efforts in these early years of the field. It is small, easily accessible, comparatively simple in structure, and the processes for corneal transplantation are already well established. Many older people suffer from corneal damage or degeneration of one form or another, and these patients might benefit from the cost-effective availability of corneas generated from their own cells. Bioprinting is one approach to reducing the cost of building such patient-matched tissue sections, and as noted here, researchers have recently reported success in rapidly printing corneas in this way.

The first human corneas have been 3D printed. The technique could be used in the future to ensure an unlimited supply of corneas. At present there is a significant shortage of corneas available to transplant, with 10 million people worldwide requiring surgery to prevent corneal blindness as a result of diseases such as trachoma, an infectious eye disorder. In the proof-of-concept research, stem cells (human corneal stromal cells) from a healthy donor cornea were mixed together with alginate and collagen to create a solution that could be printed, a 'bio-ink'. Using a simple low-cost 3D bio-printer, the bio-ink was successfully extruded in concentric circles to form the shape of a human cornea. It took less than 10 minutes to print.

"Many teams across the world have been chasing the ideal bio-ink to make this process feasible. Our unique gel - a combination of alginate and collagen - keeps the stem cells alive whilst producing a material which is stiff enough to hold its shape but soft enough to be squeezed out the nozzle of a 3D printer. This builds upon our previous work in which we kept cells alive for weeks at room temperature within a similar hydrogel. Now we have a ready to use bio-ink containing stem cells allowing users to start printing tissues without having to worry about growing the cells separately."

The scientists also demonstrated that they could build a cornea to match a patient's unique specifications. The dimensions of the printed tissue were originally taken from an actual cornea. By scanning a patient's eye, they could use the data to rapidly print a cornea which matched the size and shape. "Our 3D printed corneas will now have to undergo further testing and it will be several years before we could be in the position where we are using them for transplants. However, what we have shown is that it is feasible to print corneas using coordinates taken from a patient eye and that this approach has potential to combat the world-wide shortage."

Beclin-1 Mutant Mice Live 10% Longer Due to Enhanced Autophagy

Autophagy is the name given to a collection of cellular housekeeping processes responsible for recycling damaged or unwanted proteins and cellular structures, preventing them from causing further harm within the cell. Many of the methods of modestly slowing aging in laboratory species are observed to involve increased levels of autophagy. For some, such as calorie restriction, there is evidence to demonstrate that functional autophagy is required for aging to be slowed.

Researchers have long been interested in developing pharmaceutical means to enhance autophagy as a form of therapy. This is arguably even more the case these days, now that treating aging as a medical condition is considered to be a respectable goal. Despite the many years of work, therapeutic enhancement of autophagic processes has yet to progress all that far the laboratory, however. Trials have been conducted, but reliable, safe autophagy enhancing drugs have yet to emerge at the far side. The research here is one of many examples in which researchers identify a possible target mechanism for further development.

Researchers found that mice with persistently increased levels of autophagy - the process a cell uses to dispose of unwanted or toxic substances that can harm cellular health - live longer and are healthier. Specifically, they have about a 10 percent extension in lifespan and are less likely to develop age-related spontaneous cancers and age-related pathological changes in the heart and the kidney.

Twenty years ago, researchers discovered beclin 1 - a key gene in the biological process of autophagy. The group's research has since shown that autophagy is important in many aspects of human health, such as preventing neurodegenerative diseases, combating cancer, and fighting infection. In 2003, the team found that the genetic machinery required for autophagy was essential for the lifespan extension observed in long-lived mutant roundworms. "Since then, it has become overwhelmingly clear that autophagy is an important mechanism necessary for the extended lifespan that is observed when model organisms are treated with certain drugs or when they have mutations in certain signaling pathways. The body's natural ability to perform autophagy declines with aging, which likely contributes to the aging process itself."

Yet a crucial question remained unanswered: Is increased autophagy throughout mammalian life safe and beneficial? In other words, can autophagy extend lifespan and improve healthspan? To answer this question, researchers created a genetically engineered mouse that had persistently increased levels of autophagy. The researchers made a mutation in the autophagy protein Beclin 1 that decreases its binding to another protein, Bcl-2, which normally inhibits Beclin 1's function in autophagy. As the researchers expected, these mice had higher levels of autophagy from birth in all of their organs. "The results suggest that it should be safe to increase autophagy on a chronic basis to treat diseases such as neurodegeneration. Furthermore, they reveal a specific target for developing drugs that increase autophagy - namely the disruption of Beclin 1 binding to Bcl-2."

Higher Blood Pressure Correlates with Higher Healthcare Costs

Risk factors associated with age-related disease and mortality tend to also associate with higher medical costs. Obesity, for example, both shortens life span and increases lifetime medical costs thanks to the impact it has on health. High blood pressure, the condition known as hypertension, is another measure that reliably predicts a higher risk of mortality and poor health in later life. Here researchers run the numbers to show that it also results in higher medical costs, much as expected.

Hypertension isn't too far removed from the root causes of aging. High blood pressure is a direct result of arterial stiffening, as that detrimental change disrupts the finely tuned feedback mechanisms that balance blood pressure. Stiffening of blood vessels is caused by a mixed bag of mechanisms from the SENS rejuvenation research portfolio, such as cross-linking of the extracellular matrix in blood vessel walls, and the presence of senescent cells producing inflammation that both encourages calcification and disrupts the function of the smooth muscle responsible for dilation and contraction of blood vessels.

Raised blood pressure harms sensitive tissue structures such as those of the brain and the kidneys. It causes an increased rate of rupture of capillaries on a day to day basis, each destroying a tiny area of tissue. In later life it interacts with atherosclerosis, which weakens and narrows blood vessels with fatty plaques, to increase the risk of a fatal structural failure, a stroke or heart attack. More subtly, hypertension also causes the heart to reshape itself for the worse, the muscle growing larger and weaker, leading to heart failure. All of this is why methods of forcing lower blood pressure can be beneficial, even when they don't address the underlying root causes of hypertension, as is the case for all of the present approaches available in the clinic. In the future, we would expect to see far better outcomes for patients result from rejuvenation therapies that reverse the causes of blood vessel stiffening, thereby turning back hypertension.

Adults with high blood pressure face 1,920 higher healthcare costs each year compared to those without high blood pressure, according to new research. Based on the U.S. prevalence of hypertension, researchers estimate the national adjusted annual cost for the adult population with high blood pressure to be 131 billion higher compared to those without the disease. It is important to note that this twelve-year study was conducted using previous hypertension guidelines - which defined high blood pressure as 140/90 mm Hg or higher. In 2017, the American Heart Association and the American College of Cardiology lowered the definition of high blood pressure to 130/80 mm Hg or higher. "The new lower definition of high blood pressure will increase the number of adults in the hypertensive population. This may decrease the average cost of hypertension for individual patients while increasing the overall societal costs of hypertension."

Compared to patients without high blood pressure, those with high blood pressure had: 2.5 times the inpatient costs; almost double the outpatient costs; and nearly triple the prescription medication expenditures. "While the increased cost for patients with high blood pressure remained stable from 2003-2014, the rising prevalence of hypertension will become an increasingly large burden on the U.S. population for hypertension expenditures. The better we can learn to recognize high blood pressure, treat it and manage it, the better we'll be able to address these costs." National statistics from the 2017 hypertension guidelines estimate that 46 percent of U.S. adults - 103 million people - have high blood pressure, but only about half of those have their blood pressure controlled despite improvements in diagnosing, treating, and controlling hypertension.

A New Target Mechanism for Lowering Blood Pressure in Cases of Hypertension

Hypertension, high blood pressure, is caused by arterial stiffness, which is in turn caused by a combination of mechanisms such as the accumulation of persistent cross-links that alter the structural properties of tissue, and chronic inflammation produced by senescent cells that alters the behavior of cells in blood vessel walls. Hypertension damages fragile tissues, causes the muscle of the heart to become larger and weaker, and ultimately interacts with the corrosive effects of atherosclerosis on blood vessel walls to produce a fatal rupture, leading to a stroke or heart attack.

The work noted here is representative of most efforts to safely lower blood pressure, in that it attempts to force cellular mechanisms in blood vessel walls into a more functional state without addressing the underlying causes of dysfunction - those that stiffen blood vessels. All too much of medical research has this focus: tinker with cell state in patients, but don't repair the damage that is causing those cells to run awry.

In the case of raised blood pressure, however, this condition directly causes a varied package of downstream harm, and is an important mediating mechanism between low-level molecular damage and high-level structural consequences to organs. So it is possible to make some progress, produce some degree of benefits to patients, by lowering blood pressure without addressing the causes of hypertension. That doesn't make it the best strategy, and it certainly shouldn't be the most effective approach. That most effective approach would have to involve repair of molecular damage that in turn reverses arterial stiffening.

Researchers have demonstrated that Galectin-1, a protein in our body, influences the function of another protein known as L-type (Cav1.2) calcium channel found on the arteries that normally acts to contract the blood vessels. By reducing the activity of these calcium channels, Galectin-1 is able to lower blood pressure.

Hypertension is a common problem worldwide. Importantly, age is a major risk factor for the development of hypertension. According to the World Health Organization, elevated blood pressure is estimated to cause 7.5 million deaths globally, which represents more than 12 per cent of the total of all deaths. This is because hypertension is associated with major killers like coronary heart diseases and stroke. In addition, hypertension can also cause renal impairment, retinal haemorrhage, and visual impairment.

As hypertension is a common denominator to many serious conditions described above, nipping the problem at its bud will significantly improve our health. Although patients with Stage I hypertension are mostly recommended to make lifestyle changes to reduce the risks of suffering other cardiovascular diseases, those with Stage 2 hypertension or above have to take anti-hypertensive medicines to control blood pressure.

Calcium channel blockers (CCB) are traditionally used in the clinics to lower blood pressure, but the use of such medications was reported to be associated with increased risk for heart failure in hypertensive patients particularly those with heart problems due to their bad side effects. Therefore, the development of drugs that could adjust the activity of L-type (CaV1.2) calcium channel, rather than blocking its normal function altogether, has emerged as a novel research direction for anti-hypertensive therapeutics. The discovery that Galectin-1 can perform such a desired function represents a pathway to control blood pressure. The good news is that Galectin-1 only targets L-type (CaV1.2) calcium channel in the blood vessels. It spares other types of calcium channels that are important for the general functions of our body.

"The reported effects of Galectin-1 protein, and of its analogues, on the blood pressure in various models of human arteries and the circulatory system are encouraging. The results suggest that there is a reasonable likelihood of fabricating an antihypertensive treatment-molecule, based on Galectin-1, which will consistently suppress, without negating, the Cav1.2 calcium channel in human arteries, so lowering the blood pressure in persons with pulmonary hypertension. The results from human pulmonary arteries suggest that the candidate treatment-molecule might also be useful in the condition known as pulmonary arterial hypertension, for which highly cost-effective drugs are lacking."


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