Fight Aging! Newsletter, July 4th 2016

July 4th 2016

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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  • Aging Research: Fewer Resources, Less Visibility, and Less of a Sense of Urgency
  • Alkaline Water Very Modestly Slows Aging in Mice
  • Reviewing What is Known of Dietary Protein Intake in Aging
  • Mutant p53 as a Potential Target Across Many Cancer Types
  • Aubrey de Grey on the Dominance of Bad Strategy in Aging Research
  • Latest Headlines from Fight Aging!
    • An Interview with Laura Deming of the Longevity Fund
    • A Small Clinical Trial for Nicotinamide Mononucleotide in Japan
    • An Interview with an Anti-Aging Drug Researcher
    • Blocking c-Abl Halts Parkinson's Progression in a Mouse Model of the Condition
    • A New Printing Method for Cartilage Tissue
    • Exercise Promotes Cathepsin B Expression, Neurogenesis, and Memory Function
    • Producing More Blood Vessels in Heart Tissue as a Way to Increase Resistance to the Damage of a Heart Attack
    • There is a Wide Distribution of Outcomes in Aging
    • Proposing that Human B Cells Show Little Sign of Aging for Much of Life
    • Chimeric Antigen Receptor Strategies can be Used to Target and Destroy Specific Classes of Unwanted Immune Cell


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.


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.


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.


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.


Most research programs that purportedly aim to extend human life by intervening in the aging process do not in fact have a good expectation of producing meaningful results. They typically involve searching the existing drug catalog for ways to alter the operation of metabolism so as to, for example, recapture some of the effects of calorie restriction, as lowering calorie intake is well proven to improve health and slow aging. This has turned out to be expensive, time-consuming, and challenging. So far very little of practical use has been achieved on this front after fifteen years of focus involving hundreds of scientists, at a cost of billions. Expense and difficulty are not the primary objection, however: it comes with the territory at the cutting edge of the life sciences. The primary objection to this branch of research is that even if these researchers achieved a perfect replication of calorie restriction, and so far they aren't close to achieving even a fraction of this goal, that wouldn't extend human life by more than a couple of years.

If all that the research community could do was this, then so be it. We would have to resign ourselves. But it isn't: much greater goals in extended health life span are possible with the same expenditure of time and funding, given a different research strategy. It is particularly frustrating to see this continued focus on slightly slowing aging at great cost when there is, in fact, a much better path forward. That better path consists of the research strategies described in the SENS vision for rejuvenation biotechnology, a package of approaches to aging and its causes drawn from the work of researchers across the breadth of the field. In short, the research community has a good catalog of the forms of cell and tissue damage that distinguish old tissue from young tissue, has had that catalog in a fairly complete state for more than two decades, and there exist detailed plans for treatments capable of repairing the damage. Repairing the damage that causes aging will be no more expensive and challenging than trying to alter metabolism to slow aging, but it has the possibility to create rejuvenation, to extend healthy life span indefinitely when the repair is comprehensive enough. Some of the technologies needed to create repair therapies to treat aging have been demonstrated in the laboratory, and a few are even at the stage of startup companies building treatments.

These days there is a lot of agitation for greater progress and greater investment in efforts to find drug candidates to alter metabolism in ways that may modestrly slow aging: calorie restriction mimetics, autophagy enhancers, exercise mimetics. This coincides nicely with the scientific urge to completely map the large blank regions in the grand map of human biochemistry. It is a huge project. But as Aubrey de Grey of the SENS Research Foundation points out below in a quite clear outline of his view of the field, metabolic adjustment to slightly slow aging is the wrong focus. The majority of the research community is forging ahead on a path that will produce only very small gains in lifespan and health, while ignoring what is known of how to repair the causes of aging completely. While there is certainly progress towards both repair therapies and persuading more of the research community to support that path to rejuvenation therapies, it is taking far too long and far too much effort to turn this ship. There is optimism in some quarters, but I fear that this process will remain slow and painful even after the first of the portfolio of SENS rejuvenation therapies, such as senescent cell clearance, are robustly demonstrated in human studies, as they have been mice. The inertia of large, heavily regulated research and development communities is a hard thing to wrestle with.

Future Trends in Aging Research

I'm going to make a claim that will outrage many of my colleagues, but which I think is robustly defensible: in the last 35 years we have not made one single discovery that has substantially changed what we think we know about mammalian aging. The last two discoveries that, in my view, reach that level of significance were made just around that time and were first published that year and the following year. Specifically, certain nonenzymatic changes were found to accumulate throughout life with potentially deleterious consequences in old age. Initially, such changes were found to affect long-lived proteins in the extracellular matrix; subsequently, they were found to affect the epigenetic state of the genome.

Is this a basis for consternation and despondency? Quite the opposite: it is a cause for unalloyed celebration. The analytical methods available to biologists have advanced beyond all recognition in those years, and the number of laboratories studying aging has also risen dramatically. Therefore, the lack of any major breakthrough in understanding aging constitutes extremely strong, albeit admittedly circumstantial, evidence that there is probably no such breakthrough yet to be made: in other words, that we really truly do already understand aging pretty well.

The modern restoration of biogerontology began with the discovery of simple genetic and pharmacological interventions that can greatly extend the lifespans of rodents. The implication that we will soon be able to do the same in humans is too obvious to ignore, especially since (at least in rodents) the extra life is added overwhelming to the healthy period before decline set in and not to the frail end of life. Since their very discovery (or very soon after, anyway), it was established that the most successful laboratory interventions I referred to above achieved, in one way or another, the same end. They tricked the organism into performing very much the same changes of gene expression and consequent metabolic activity that occur when it is starved.

So here's the problem. As biogerontology has become more intervention-friendly again, its translational research focus has centered overwhelmingly on this class of manipulations. Well, you may retort, so it should, since they are the things that work! But there's a catch-well, two catches. First, they don't work nearly so well when started in middle age as when lifelong, and second, they work far less well in long-lived species than in short-lived ones. In combination, these facts make the biomedical relevance of such manipulations very modest indeed. Unfortunately and inevitably, however, the field is spectacularly adhering to Upton Sinclair's aphorism that it is hard to make people understand something when their salaries depend on not understanding it, and is single-mindedly maintaining its intense focus on such interventions both in the lab and on camera, so as to similarly maintain its ability to keep funders convinced that they placed good bets in the past and to induce them to carry on funding the same people.

In the relative shadows, a few biogerontologists have been beavering away developing an alternative approach to maintaining health in old age-and though such work is at an early stage, its logic is steadily chipping away at the old-style thinking in the field and it is rising to bona fide orthodoxy. I speak, of course, of regenerative medicine for aging-a concept that I habitually refer to as rejuvenation biotechnology. There are many distinct avenues of research encompassed by this, but they have one thing in common: rather than manipulating our metabolism to slow the rate at which it inflicts accumulating damage on our tissues and organs, rejuvenation biotechnology is all about repairing that damage even after it has accumulated substantially. In the past few years, key proof-of-concept breakthroughs have been made in both realms, and highly respected and credentialed biogerontologists have endorsed a combined approach as a (or even the most) promising way forward, even to the extent of presenting it as if it were their idea. In conclusion, therefore, I can say with confidence that the future of aging research is extremely bright, both scientifically and medically. The pace of progress must now be sharply accelerated, via the injection of the funds that should for many years have been allocated at far higher a level than has actually occurred.



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.


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.


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.


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.


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.


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.


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."


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.


As we all well know, the adaptive component of the immune system deteriorates with age for a number of reasons. There is the toll of cell and tissue damage, there is a structural issue in which too many cells become uselessly devoted to persistent viral infections and can no longer respond to new pathogens, there is inflammaging, in which the immune system is constantly overactive, producing chronic inflammation to no good end, and there is the atrophy of the thymus where T cells mature, which greatly reduces the pace at which new T cells are generated. B cells, however, do not mature in the thymus, and here researchers provide evidence to suggest that the B cell population of the active immune system doesn't meaningfully age for much of life in our species. They didn't look at everything, however, and you might compare this open access paper with evidence from past years of a decline in B cell function.

We analysed the genome-wide expression profiles of naive and whole B cell populations from young and early aged healthy donors under 60 years. We revealed large homogeneity of all analysed genome-wide expression profiles but did not identify any significant gene deregulation between young (30-45 years) and early aged healthy donors (50-60 years). We argue that B cells avoid the aging program on molecular level until 60 years of age.

Genome-wide analyses have detection limits, which in turn could limit identification of age-specific genes. Only minor gene alteration might be hidden below the detection threshold and unrecognized in this study. Nevertheless, our genome-wide analysis homogeneity indicated result robustness and confident reliability. We summarize surprising observations that human B lymphocytes remain almost identical at the molecular level during 30 to 60 years of age. As the immune system declines, the predispositions to B cell lineage malignancy manifested in some individuals below 60 years of age could not be addressed to natural healthy aging of B lymphocytes. Rather, other aspects might be involved including compromised body environment, declined cell stimulation, immune cell population disorders, clonal accumulations, infection history, life style and other individual behaviour contributing to early onset of aging.

The molecular identity of young and early aged B cells demonstrated potential of hematopoietic stem cells to generate uncompromised progenitor lymphocytes, naive and mature B cells in early elderly. These are very encouraging findings for general health, because the immunity maintenance does not seems to needed artificial intervention to keep B cells uncompromised in the early elderly.


The work noted here is targeted at curing autoimmune conditions by removing the misconfigured immune cells that attack important infrastructure in tissues. This is good news for all autoimmunity in which the relevant biochemistry is fairly well understood - where the target immune cells can be well described in terms of their distinctive surface chemistry. However this is also very good news for the prospects of rejuvenating the aged adaptive immune system, wherein much of the problem is that the available capacity for immune cells is used up by an excess of cells uselessly specific to persistent viruses such as cytomegalovirus. There are too many of those cells and too little space left over for cells capable of responding to new threats. Clearing out the majority of those unwanted cells would go a fair way towards removing the contribution of the failing immune system to increased vulnerability to pathogens, cancer risk, and presence of senescent cells in aging. All that is needed is a good technology platform on which to build such a targeted therapy, and the work here seems like a sizable step in the right direction.

Researchers have found a way to remove the subset of antibody-making cells that cause an autoimmune disease, without harming the rest of the immune system. The key element in the new strategy is based on an artificial target-recognizing receptor, called a chimeric antigen receptor, or CAR, which can be engineered into patients' T cells. In human trials, researchers remove some of patients' T cells then engineer them in a laboratory to add the gene for the CAR so that the new receptor is expressed in the T cells. The new cells are then multiplied in the lab before re-infusing them into the patient. The T cells use their CAR receptors to bind to molecules on target cells, and the act of binding triggers an internal signal that strongly activates the T cells - so that they swiftly destroy their targets.

Since 2011, though, experimental CAR T cell treatments for B cell leukemias and lymphomas have been successful in some patients for whom all standard therapies had failed. B cells, which produce antibodies, can also cause autoimmunity. Researchers took an interest in CAR T cell technology as a potential weapon against B cell-related autoimmune diseases. "We thought we could adapt this technology that's really good at killing all B cells in the body to target specifically the B cells that make antibodies that cause autoimmune disease. Targeting just the cells that cause autoimmunity has been the ultimate goal for therapy in this field."

In the new study the team took aim at pemphigus vulgaris. This condition occurs when a patient's antibodies attack desmoglein (Dsg1 and Dsg3) molecules that normally keep skin cells together. When left untreated, PV leads to extensive skin blistering and is almost always fatal. To treat PV without causing broad immunosuppression, the team designed an artificial CAR-type receptor that would direct patients' T cells to attack only the B cells producing harmful anti-Dsg3 antibodies. The team developed a "chimeric autoantibody receptor," or CAAR, that displays fragments of the autoantigen Dsg3 - the same fragments to which PV-causing antibodies and their B cells typically bind. The artificial receptor acts as a lure for the B cells that target Dsg3, bringing them into fatal contact with the therapeutic T cells. Testing many variants, the team eventually found an artificial receptor design that worked well in cell culture, enabling host T cells to efficiently destroy cells producing antibodies to desmoglein, including those derived from PV patients. The engineered T cells also performed successfully in a mouse model of PV, killing desmoglein-specific B cells and preventing blistering and other manifestations of autoimmunity in the animals. "We were able to show that the treatment killed all the Dsg3-specific B cells, a proof of concept that this approach works."


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