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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- On the Topic of Senescent Cells: Should We All be Trying to Take Navitoclax?
- SENS Rejuvenation Research Fundraiser Launched: Become a SENS Patron!
- An Interview with the Bioquark CEO
- Complicating the Picture for Aging, Cellular Senescence, and Bcl-xL
- Reduced Levels of Myc Regulator Mtbp Modestly Extend Life in Mice
- Latest Headlines from Fight Aging!
- Continued Interest in Nicotinamide Mononucleotide
- Tau Aggregate Structure Determines the Type of Dementia it Causes
- Additional TP53 Copies as the Cause of Reduced Cancer Risk in Elephants
- Using Hypoxia to Induce Heart Regeneration in Mice
- Aging, Just Another Disease
- Continued Efforts to Alter the Behavior of Senescent Cells Without Destroying Them
- A Discussion with the KrioRus Founders
- Heat Shock Protein Hsp60 Involved in Regeneration and Wound Healing
- BACE1 Inhibition as an Alzheimer's Treatment
- Senescent Cells May Enhance Viral Replication, Making Infections More Dangerous
On the Topic of Senescent Cells: Should We All be Trying to Take Navitoclax?
Senescent cells accumulate with age, and secrete an unfortunate combination of signals that harms organs and tissues in numerous ways, such as via the production of increased chronic inflammation. This is one of the root causes of aging and age-related disease. Safe and effective clearance of senescent cells has been on the SENS rejuvenation biotechnology agenda for fifteen years, but only recently has progress in scientific funding and demonstrations of improved health and life spans in mice snowballed to the point at which startup companies could make a real go of it. Things are moving fairly rapidly in this field now. With the recent 116 million venture investment in UNITY Biotechnology's work on senescent cell clearance, and other companies angling for their own launch, it is fair to say that this line of research and development is underway for real. Clinical trials of senescent cell clearance will be underway soon, funded by UNITY Biotechnology, and using drug candidates such as navitoclax developed in the cancer research community, noted for their ability to induce apoptosis, a form of programmed cell death. Senescent cells are primed for apoptosis, and it takes little to tip them over the edge in comparison to a normal somatic cell, which means that there may well be quite a large stable of existing drugs that will have some useful effect.
The question here is one that is only now starting to be useful to ask: should we all be running out today to obtain and take a drug (such as navitoclax) or drug combination (such as dasatinib and quercetin) that were shown to clear some fraction of senescent cells in rodents? Certainly there have been no shortage of people chasing after whatever the current hype of the day was in past years; I'm sure you all recall resveratrol and other alleged calorie restriction mimetics or telomere length enhancers. All a waste of time and effort. The difference between the science behind those and the science behind senescent cell clearance is considerable, however. The items of the past have all been associated with altering metabolism so as to modestly slow aging, at best, and we have the very good examples of calorie restriction and exercise to show us the immediate bounds of the plausible on that front in our species. Senescent cell clearance on the other hand is legitimately and actually a form of rejuvenation, turning back one facet of the aging of your tissues to an earlier time. You probably don't have to keep taking the treatment, unlike those that slightly slow aging. An efficient senescent cell clearance treatment is something that you would undergo once every few years, perhaps. These first attempts won't be efficient, of course, but they should certainly have a sizable effect in comparison to most of the nonsense that gets peddled to the credulous.
It is helpful to look at the question of whether you and I should jump on this bandwagon through the lens of navitoclax, or ABT-263, which is a likely candidate for UNITY Biotechnology to choose for their trials. The people involved with UNITY Biotechnology have worked with it, and it has been used in a range of clinical trials for cancer, which makes it harder for the FDA to mount their usual expensive objections and requests for more data. Navitoclax can be purchased, and dosages can be established from the human cancer studies and the senescent cell clearance rodent studies (there is a fairly standard method of going from mouse or rat dosage to human dosage). There is comprehensive human safety and side-effect data to look at, but only rodent data for its effects on senescent cells - no-one was looking at that in the cancer studies, which is entirely understandable, but a pity. The current methods of senescent cell clearance with published rodent data show a degree of clearance for fairly short treatments varying from negligible to more or less 50% by tissue type, with different drugs having different profiles. So from a technical point of view, the open question is whether or not it works in people to a useful degree. It is entirely reasonable to expect some drugs to do well in mice and terribly in people when it comes to killing senescent cells, and vice versa. The only real way to find out is to try it. Since clinical trials are coming up soon, from my perspective you would have to be something of an enthusiast to jump in ahead of that right now; a year or two seems a fine amount of time to wait for more certainty.
If taking the leap now, you would have to establish the degree of effect yourself. To do that rigorously you'd need a friendly lab capable of a biomarker assay in a skin sample before and after, say, which isn't impossible to find, just quite specialized. The necessary equipment for those who know how to use it is certain readily available for sale. But without that, you might want to try before and after comprehensive bloodwork to look at markers of inflammation, or even simpler assessments such as blood pressure, given the recent suggestions that senescent cell clearance might help with tissue elasticity, and loss of elasticity in blood vessel walls drives age-related increase in blood pressure. There are other possible options to consider. The point being, don't just run the experiment and feel good about it. Prove to yourself that something happened.
The real issue that puts navitoclax on the wait and see list is that it is expensive, a fairly common problem for newer drug candidates. There is no widespread usage yet, so no-one has invested in the facilities needed for mass production at a reasonable cost, and until such time as someone invents some sort of nanotechnological universal chemical synthesis device, it will remain an expensive, people-intensive business to run up custom lots of specific drug compounds to order. In this case, replicating the doses used in cancer trials would cost something like 700-1500 per day, which makes it less a matter of thinking carefully about costs and benefits and more a matter of being beyond affordable to anyone inclined to self-experiment. This, more than any of the other factors tells us that we're all going to be waiting on the matter of navitoclax. What if the price was low, however? Would it be worth it? I'd say probably yes as an experiment, if you were comfortable with what you read of the side effects in the results from the cancer trials, and were willing to put in the work to gather some data about its effects on your own tissues.
As a comparison, we can consider the combination of dasatinib and quercetin - which actually doesn't turn out to be much of a comparison at all. It is very similar, starting with being in much the same place as navitoclax from the point of view of data: dasatinib is used in human cancer trials, but senescent cell clearance results have been published for mice only. Based on the mouse data, you would have to use both rather than just the one: it is a synergistic effect, and just the one or the other isn't anywhere near as useful. Quercetin is a readily available supplement and pretty cheap, so there is that at least. Dasatinib is not, however. It isn't as costly as navitoclax, but still hundreds for the sort of daily dose used in human trials. Further, the side-effects for dasatinib at these dosages appear somewhat worse that those for navitoclax.
This is the sort of thing that should be going through your mind when looking into making the plunge: cost and reliability of the source; finding good data on dosage, safety, and side-effects; ability to determine whether or not it is actually doing something if you are taking it. In addition, think about what is coming down the line. Is new human data to be expected soon that would reduce the risk of trying something that works in rodents but not so well in people? Are better approaches in the works, such as the gene therapy from Oisin Biotechnologies that should have few to no side-effects? Would it hurt to wait two years, or five years, for an actual product to arrive and for the costs to fall as production increases? These are all questions that we can only answer for ourselves, for our own case.
SENS Rejuvenation Research Fundraiser Launched: Become a SENS Patron!
The year-end fundraiser in support of the SENS Research Foundation kicks off today - and all donations are matched. Funds raised will, as always, go towards speeding up and unblocking currently languishing fields of research that are necessary for the production of effective, working rejuvenation therapies in the years ahead. The SENS Research Foundation has a proven track record on this front, and for years now has used the philanthropic donations provided by our community to generate meaningful progress in research like mitochondrial repair, clearance of senescent cells, clearance of cross-links that stiffen tissues, building the basis for a universal cancer therapy, and much more. More than just funding research directly, the SENS Research Foundation has also brought new attention and new sources of funding to formerly stuck and slow moving fields of research, and is working to assemble the biotechnology industry needed to move research from lab to clinic. This is working: areas like senescent cell clearance that ten years ago were going nowhere are now heading towards clinical therapies by leaps and bounds.
There is much more to be done yet, however! When the wheel is finally starting to turn, that is no time to slacken in our support. This is why Josh Triplett and Fight Aging! have put up a 24,000 matching fund, and will match the next year of donations for anyone that signs up as a SENS Patron. Head over the SENS Research Foundation site, take a look at their new home page presentation that shows off the high points of this past year of achievements, and pledge a recurring monthly donation. Every donation made that way over the next year, we'll match. This support makes a real difference, but don't take our word for it. David Spiegel is a noted researcher who runs the Spiegel Research Group at Yale University and works on finding ways to safely remove glucosepane cross-linking, one of the forms of tissue damage that causes aging. In his view, funding from the SENS Research Foundation has been instrumental to the creation of important progress in this field:
The SENS Research Foundation funding has been critical to our work studying and developing methods to reverse the effects of advanced glycation end-products (AGEs) in aging. AGEs are non-enzymatic modifications that build up on proteins as people age, leading to inflammation and tissue damage. Early on, our lab focused significant effort on developing the first total synthesis of glucosepane - a major AGE cross-link found in human tissues - but we were unable to find funding from any of the traditional sources. The SENS Research Foundation came to our aid, and supported this research for over 5 years. In 2015, our glucosepane synthesis efforts were published in Science, and lay a foundation for developing drugs capable of detecting and reversing tissue damage in aging. We are deeply grateful to the SENS Research Foundation and Fight Aging! for all of their support and look forward to exciting, life-extending work to come!
If becoming a SENS Patron for the long term isn't for you, then you can still make a year-end charitable donation to support this research and have it matched, as the Forever Healthy Foundation has put up a 150,000 matching fund for donations made between now and the end of the year. You might recall that this is Michael Greve's venture, and earlier this year he pledged 10 million to SENS rejuvenation research, half to advance the research, and half to support the startup companies that will be needed to take these therapies to the marketplace. It is more or less our duty as a community to ensure that this matching fund is met, as thanks for his generous support of these vitally important scientific projects. We will all live that much better and that much longer in the future as a result. From the latest SENS Research Foundation newsletter:
SENS Research Foundation's year end fundraising goal this year is 150,000. Every one of your contributions will be matched by the generous grant we have received from the Forever Healthy Foundation. So every donation will be doubled with the Forever Healthy Foundation's support. Please help us reach our 150,000 goal (which could turn into 300,000 thanks to the matching grant!) by donating generously today! Remember, your support is crucial to our continued fight against age-related disease.
Finally, please help spread the word. Mention the work of the SENS Research Foundation in your circles. Talk to your friends. A movement is made up of many small efforts, one person talking to another. That is how the tipping point of support is reached, how bootstrapping towards large-scale support for the development of rejuvenation therapies works. By all means make use of these simple fundraising posters as well. As they say, aging is a medical condition, and it is well past time to treat it like one.
2016 SENS Patron Fundraiser #1: 4200 x 2800px and 600 x 400px
2016 SENS Patron Fundraiser #2: 4200 x 2800px and 600 x 400px
An Interview with the Bioquark CEO
My attention was recently drawn to Bioquark, where the principals are clearly interested in tackling regeneration and aging. The founders and scientific staff originate from the clinical stem cell medicine and medical tourism end of the spectrum, and appear to be approaching their goals via a programmed aging framework, the view of aging as a genetic program that can in principle be reversed by providing suitable signals to cells and the cellular environment. This stands in opposition to the more mainstream view of aging as an accumulation of cell and tissue damage, as expressed in the SENS rejuvenation research view, for example, but also by most researchers, even those who disagree with SENS. The various SENS damage repair companies, such as those working on senescent cell clearance, represent efforts to step beyond the present medical paradigm of merely patching over symptoms of aging, to produce large effects by repairing the damage that causes aging, taking the view of aging as damage to its logical conclusion. Bioquark might be seen an an analogous attempted leap forward for the programmed aging view, taking the very same critique of the present medical paradigm, and seeking large gains by adjusting the cellular environment to incorporate a more regenerative, youthful set of signals - taking the programmed view of aging to its logical conclusion.
To be clear, personally I'm solidly in the aging as damage camp, and I think that efforts like Bioquark are doomed to, at best, produce marginal success since their high level strategy is based on an incorrect view of aging. In particular, I think that any view that sees reversal of aging via cell signaling alone as a possibility for humans is badly misguided: it ignores, for example, the evidence for forms of harmful metabolic waste such as persistent cross-links that our biology cannot clear through its normal operation, even when youthful. The folk at Bioquark might nonetheless turn out to have found a decent path towards recapturing some of the known effects of stem cell transplantation via the use of cell signal molecules only; we shall see. Either way, the sooner we get to the point at which rejuvenation through damage repair after the SENS model is conclusively demonstrated to work well, and rejuvenation by adjusting cell behavior after the programmed aging model is conclusively demonstrated to work poorly, the better off we all are. The present medical paradigm of patching over symptoms without addressing causes should be cast into the waste basket of history. High profile failure has an important and necessary role to play in the near future of medical research, now that things are moving rapidly and biotechnology is cheap. Proving specific theories of aging right and wrong by building interventions that either work or do not work is an important activity.
One of the reasons I found the high level philosophy of action at Bioquark to be interesting is that it is one of the first new companies I've seen to start down the path of explicitly rejecting the cell therapy and transplantation side of regenerative medicine in favor of aiming towards in situ regeneration. It is my view that stem cell therapies in the current model, as well as a fair amount of tissue engineering for transplantation, will be replaced at some point in time by sophisticated ways to reprogram and direct existing patient cells in situ. It is an exercise in futurism and speculative economics to predict just how this will pan out over the decades ahead, but there is a fair amount of preliminary work along those lines taking place in the laboratory even now. Will we see 50 years of increasingly effective tissue engineering and transplantation, coupled to ever-better cell therapies and cell source production lines, or will those fields fade by the early 2030s in the face of surprisingly effective ways to make existing patient cells perform extensive regrowth and healing? Very hard to say at this point.
Who wants to live forever?
So, what's novel about Bioquark?
Bioquark is an innovative life sciences company focused on the development of novel products focused on complex organ regeneration, disease reversion, and age reversal in humans. Today, if a person loses their leg, it's forever. However, some animals can replace lost or damaged organs and tissues. Many of the species that can do this regrowth trick also have the ability to repair and reverse disease-causing cellular and genetic damage. We focused on the three "Rs": regeneration, reversion, and rejuvenation. What we ultimately discovered was that these were connected by an underlying capability in such organisms to turn back biological time in targeted tissues, and start the development process over again. In essence, we found that disease, degeneration, and aging were all intimately connected by this single underlying biological regulation process. This realisation led us to develop an integrated platform, which could eventually help humans to reawaken and mimic these abilities for purposes of health, wellness and longevity. This is a platform which the company believes can change the paradigm, and the way we think about healthcare and disease.
How does this area of regenerative medicine compare to what currently goes on in the pharmaceutical industry in regard to traditional drug development?
This is a very different approach. The current model is based primarily on treating disease, while regenerative medicine offers the promise of actual cures for these ailments. For the last century, the pharmaceutical industry has attempted to reduce and study human health and disease at the level of their most basic components - proteins, genes, cells, etc. They're continually looking for new drug targets, so that they can interfere in some fashion with specific biological processes. This approach has allowed the pharmaceutical industry to grow in size to around 1 trillion in annual sales. However, with exceptions such as antibiotics, we still have very few real cures for disease. Most drugs are developed without regard for, or knowledge of, any of the biological factors that precede these abnormalities. In short, the current healthcare model usually ignores the actual causes of disease. Additionally, this reductionist approach used to identify therapeutic targets continues to ignore the fact disease is not usually a result of an abnormality in a single gene product. Instead, it is an emergent state - involving multiple biological processes that interact in complex ways. Regenerative medicine offers to completely change the status quo, by finally allowing us to alter the underlying causes of disease. This gives us the hope of developing actual cures.
How does aging and longevity relate to regeneration?
Aging and longevity, like all of the chronic diseases mentioned above, are purely a function of your cell's regulatory states. If that regulatory state can be altered from point B back to point A, a human can technically become biologically younger. Some animals can do this already. This is how several species of jellyfish accomplish real time, whole body "age reversal". This is the ultimate path humans will follow, in order to achieve the same results.
How widely accepted are the claims you're making?
Actually, quite widely. The concept of using combinations of biologic materials derived from eggs (ooplasms) for age reversal has its beginning in the original cloning experiments of the 1950s. The study of regenerative biology, and dynamics such as tumour reversion, began prior to that - in the 1940s. Hence, we are just revisiting and recombining an old body of knowledge for a new and beneficial purpose.
Bioquark: Therapeutic Programs
Our lead candidate BQ-A, directly alters the regulatory state of diseased, damaged, or aged tissues, creating micro-environments that provide for both efficient regeneration and repair. BQ-A is a novel combinatorial biologic that mimics the regulatory biochemistry of the living human egg (oocyte) immediately following fertilization. During this period, oocytes perform an unparalleled set of tasks including: resetting cell age, reprogramming DNA to eliminate genetic and epigenetic damage, remodeling of organelles, and protection of the embryo from inflammatory, oxidative, and infectious damage. All of this is done in synergy to initiate the embryo's developmental genetic program, and start it on its complex, stepwise path through organogenesis and morphogenesis. In developing BQ-A, Bioquark has found a novel way to standardize this unique combinatorial biochemistry, in the form of a biologic, and apply it for the induction of tissue specific micro-environments that lead to effective regeneration and repair.
BQ-A has been tested in animal models and has been administered by several methods including subcutaneously, intraperitoneally, intratumorally, and topically. These studies have served to highlight broad potential across a range of tissues and administration methods, as well as to validate the universal nature of its tissue remodeling concept. ... Conducted chronic administration in both mice and fruit flies (Drosophila melanogaster) - Experimental mice lived 1.7 times longer than animals in control group and experimental Drosophila melanogaster flies lived 2.2 times longer than control group.
It is true that early human embryonic development involves a lot of very interesting processes. Rejuvenation of cellular features of aging certainly happens at that stage - babies are, after all, born young. It is one of their defining characteristics. The big question is the degree to which that sort of process is in any way safe to deploy in adult tissues, or how to make it safe, or at least to explore it further with these questions in mind. So it is good that some people are thinking along those lines and feel themselves sufficiently far along to be launching a company.
That said, the scientific materials they provide fail to cover and support all of their claims. To pick on one thing that jumped out at me, the figures given for life span effects only make sense if they are using accelerated aging models, for example. Those numbers would be big news if true in normal mice, since that is around the record for mouse life extension, achieved through forms of growth hormone signaling suppression. A doubled lifespan is still pretty unusual and interesting in flies, as few interventions achieve that in normally aging individuals. But in accelerated aging models, this size of effect can be entirely expected if using a therapy that in some way rescues the biological damage in the model that produces pathology and a shorter life span - and that may or may not have anything useful to say about aging and longevity in normal individuals. It depends strongly on the details. Unfortunately, the available materials don't clarify these life span claims. So on the whole I'd be inclined to wait and see on this company; the people seem legitimate, but I'd want to see trials and peer reviewed studies beyond the couple they have on their site to cover the various claims they are making.
Complicating the Picture for Aging, Cellular Senescence, and Bcl-xL
Efforts to build rejuvenation therapies that work by selectively destroying senescent cells are very much in the news of late. One class of senolytic drug candidates works by inducing apoptosis, a form of programmed cell death, via reduced levels of Bcl-2 family proteins, such as Bcl-2 itself, Bcl-xL, and Bcl-W, all of which normally act to suppress apoptosis. Senescent cells are inclined towards apoptosis already, so a modest nudge in that direction can destroy a fair proportion of these unwanted cells without causing harm to healthy cells. These apoptosis-related proteins have numerous other roles as well, however, since evolution is very much in favor of reusing the tools to hand. For example, Bcl-xL is also involved in mitochondrial damage protection, the immune response, cellular respiration and DNA repair: quite the portfolio, and all items that are connected to aging in one way or another. I noted an open access paper today that muddies the water considerably on the topic of Bcl-xL, as it shows that more Bcl-xL rather than less (a) reduces incidence of cellular senescence in tissue cultures, (b) extends life in nematode worms, and (c) is found in human centenarians, but not younger individuals.
Ordinary somatic cells, the vast majority of the cells in the body, become senescent when they reach the Hayflick limit at the end of their replicative life span, or in response to damage, or a toxic local environment, or as a part of the wound healing process. Senescent cells cease dividing, and most either self-destruct or are destroyed by the immune system soon afterwards. This behavior has evolved because it suppresses cancer incidence, at least initially, by removing those cells most at risk. Unfortunately not all are destroyed, and those that linger cause harm to surrounding tissues via a potent mix of inflammatory signals known as the senescence-associated secretory phenotype (SASP). Given enough senescence cells, as few as 1% or less of all the cells in an organ, significant dysfunction and inflammation is the result, contributing to the development and progression of age-related disease. It even comes to a point at which the presence of larger numbers of senescent cells raises the risk of cancer and allows tumors to grow more readily. Getting rid of these cells has been demonstrated to improve tissue function and extend healthy life spans in mice, and we are all looking forward to forthcoming human trials of this class of rejuvenation therapy - the first of which will most likely use apoptosis-inducing drugs that work via inhibition of Bcl-2 family proteins.
Given this, how is it that increased levels of Bcl-xL can be associated with longevity and lesser degrees of cellular senescence? The authors in the paper linked below, perhaps wisely, do not speculate all that much and largely restrict themselves to reporting their findings. The lesson we must constantly learn is that biochemistry is complicated. It is a linked system of countless feedback loops, many of which share protein machinery. Nothing can be accomplished in isolation, and there is always a way for very similar interventions to result in diametrically opposed results. Once might speculate that, for example, reduced levels of Bcl-xL are only useful in conjunction with reduced levels of other Bcl-2 family members. Or that drugs like navitoclax are pushing other levers and buttons whose significance is not yet as well understood in this picture. Alternatively, consider that in the short term reduced levels of Bcl-xL could induced senescent cell destruction, and resulting health benefits, but in over the long term, and without any intervention to clear senescent cells, higher levels of Bcl-xL could aid cellular health via other mechanisms such as mitochondrial function, immune function, and DNA repair. It is plausible that better functionality for those line items might reduce the number of cells entering senescence. Or, alternatively, there is the explanation proposed by the authors of the paper involving different paths to apoptosis under different circumstances, not all of which are necessarily desirable. But this is all speculation at this stage, to be confirmed by further research. Regardless of the role of Bcl-xL in natural variations in longevity, it is certainly the case that senescent cell clearance will be a beneficial procedure. Someone who undergoes that procedure will have an incrementally longer life expectancy than someone who didn't - and the plan is to keep doing it as often as needed to keep senescent cell counts beneath the level at which they produce a meaningful contribution to aging and age-related disease.
Human exceptional longevity: transcriptome from centenarians is distinct from septuagenarians and reveals a role of Bcl-xL in successful aging
Centenarians, for example, exhibit medical histories with remarkably low incidence rates of common age-related disorders such as vascular-related diseases, diabetes mellitus, Parkinson's disease, and cancer. Over 80% of centenarians delay their first experience of diseases often associated with high mortality till beyond the age of 90 years or escape these morbidities entirely. Moreover, centenarians may have better cognitive function and require minimal assistance for activities of daily living compared with younger elderly who exhibit normal aging. The Spanish Centenarian Study Group, founded in 2007 as a population-based research program focused on centenarians living in various areas of Spain, previously investigated molecular mechanisms by which centenarians maintain homeostasis and thereby evade age-related morbidities as evidenced by changes in their microRNA (miRNA) expression profiles in peripheral blood mononuclear cells (PBMCs). Our previous analysis of miRNA microarray data ("miRNome") showed that miRNA expression in centenarians (successful aging) exhibited significant overlap with that in young people but not with septuagenarians (normal aging). We thus hypothesized that expression patterns of mRNAs in centenarians versus septuagenarians and young people might provide further insights into what discriminates those with exceptional longevity from normal aging. In the present study we sought to identify expression patterns of mRNAs in centenarians as means to elucidate factors that influence why these individuals live such long, healthy lives. We have identified Bcl-xL as one of these factors that influence longevity in humans.
Analysis of the genes over-expressed in centenarians reveals relations to three genes: Bcl-xL (also known as BCL2L1), Fas and Fas ligand (FasL), all of them involved in the control of apoptosis. Moreover, using Gene Ontology we detected that apoptosis is one of the processes most commonly conserved in centenarians. Fas and FasL are mainly involved in the control of the extrinsic pathway to apoptosis, whereas Bcl-xL inhibits the intrinsic, mitochondrial pathway to apoptosis. Bcl-xL down regulates apoptosis and promotes cell survival by migrating to mitochondrial outer membrane, counteracting mitochondrial permeabilization (pore formation) activity, and inhibiting cytotoxic adaptors needed for activation of caspases that dismantle the cell. We evaluated centenarians' expression of BcL-xL and confirmed that it is indeed up-regulated compared with septuagenarians and young people. To validate the results obtained in the Spanish cohort, we measured BcL-xL expression in another well characterized centenarian population, i.e., that of the Sardinian centenarians. We found that, as in the Spanish cohort, Sardinian centenarians display a higher Bcl-xL expression than septuagenarians and maintain an expression similar to young individuals. The same pattern is shown when measuring Bcl-xL protein expression.
As stated before, BcL- xL is important in the development and maintenance of the immune system. Moreover, immunosenescence (age-related decline of immune function) has been posited responsible at least in part for the well-known increased incidence rates of infections, cancer, and autoimmune diseases that arise in elderly persons who display normal aging. We thus analyzed lymphocyte function in centenarians and showed that leukocyte chemotaxis and NK cell activity were significantly impaired in septuagenarians compared with young people whereas in centenarians these indicators of immunosenescence were similar to the picture noted in young people. Therefore, using centenarian-donated PBMCs, we observed a number of similarities between centenarians and young persons, which were not reflected in cells donated by septuagenarians, in a variety of biological factors suggestive that centenarians may evade the relentless onset of immunosenescence that is seen in normal aging.
The general picture that emerges from our series of experiments is that centenarians have an intact extrinsic pathway of apoptosis thus killing cells that may be damaged by environmental insults but down-regulated intrinsic apoptosis thus sparing cells that have not been exposed to genotoxic or other challenges. Upregulation of Bcl-xL as noted in our gene expression studies suggests that regulation of apoptosis is deranged in septuagenarians (normal aging) yet preserved in centenarians (exceptional aging). Taken together, our results demonstrate that, similar to what we found in microRNA expression, septuagenarians (normal aging) display a cell health impairment which is not so evident in young people or centenarians (exceptional aging). Moreover, they suggest that Bcl-xL may play a major role in healthy aging.
To assess if increased activity of Bcl-xL promotes longevity in vivo we turned to the simple model organism C. elegans. This nematode has several advantages for aging studies: it has a short life span of around twenty days, it shares the main hallmarks of human aging and around 70% of the human genome has a C. elegans ortholog, including the apoptotic pathway that was originally described in this organism. ced-9 is the only C. elegans member of the Bcl2 anti-apoptotic family and thus the ortholog of human Bcl-xL, showing 44% homology and the same protein domains. Among the multiple available ced-9 alleles, ced-9(n1950) is a missense G to A substitution that confers constitutive activity to the CED-9 protein. We hypothesized that this mutation could mimic the increased Bcl-xL levels of centenarians and thus we performed longevity curves of ced-9(n1950) compared to wildtype worms. Interestingly, ced-9(n1950) animals showed a significant increase both in the mean and maximum survival time. Moreover, at 25 days, which can be considered a very advanced age for a worm, the percentage of ced-9(n1050) survivals was more than double compared to wildtype.
Reduced Levels of Myc Regulator Mtbp Modestly Extend Life in Mice
Despite the fact that we stand within reach of human rejuvenation, to be achieved through repair of the known forms of biological damage that cause aging, the majority of research into aging and longevity has next to nothing to do with that goal. It is instead a slow and painstaking process of mapping, an attempt to understand how exactly cellular biology produces aging, at the detailed level of genes and protein interactions. It takes years of work to obtain a useful amount of new information about the role of one specific gene, and there are thousands of genes of interest, formed into networks. There are many ways to influence the behavior of these networks - pick a gene, alter its structure or the amount of protein produced, and the entire network is affected. Pick another gene and the network reacts in a different way.
This is why those researchers who believe that the only way forward is to produce the map, and then use it to alter the operation of metabolism to slow the rate at which it causes aging, generally have a pessimistic view of the future of medicine to enhance human longevity. There is too much work, too little funding, and too few researchers. Further, the gains are modest at best, on a par with the results of practicing calorie restriction or regular exercise. This is why we need a revolution in the field of aging research, one that directs far more resources towards initiatives like SENS rejuvenation research: instead of prioritizing mapping, rather prioritize the application of what is already known about the forms of cell and tissue damage that causes aging, prioritize building the envisaged repair biotechnologies that should result in rejuvenation. Clear the damage in the metabolism we have rather than trying to build an incrementally better form of human being - it will be faster, cheaper, and more effective by far. We don't have all the time in the world to get this job done.
This is a fight that continues. Damage repair is a minority concern in aging research, despite the recent interest and funding for senescent cell clearance. The vast majority of aging research looks exactly like the example presented here, which is to say a matter of exploring genetic alterations known to modestly alter the course of aging in short-lived species. Researchers move step by step and protein by protein by following relationships and correlations. In this case the starting point is established knowledge: when gene expression of Myc is inhibited, the outcome is modestly slowed aging in mice. Further, Mtpb is known to be a regulator of Myc activity, one of the many ways in which proteins can be related to one another. Thus the researchers followed this link to carry out a study on Mtpb and aging in mice, showing that reduced levels of Mtpb also slow aging in mice.
As is usually the case when the effects of two related genes are explored, the result is only similar to the outcome for reduced levels of Myc, not the same. There are always differences: genes and proteins form large networks of cascading interactions, and this network is the machine to keep in mind, built of intricate repeated molecular interactions extending over time. Tinkering with different parts of the network will inevitably alter its operation in somewhat different ways. As you might imagine, at this pace, and at the present size of the research community, it will take a very long time indeed to make meaningful progress towards the grand map of metabolism and aging. No-one alive today should be placing any great hope of a longer healthy life achieved through life-extending medication on such work. If our lives are extended, it will come from the engineering approach exemplified by the SENS portfolio of proposed rejuvenation therapies.
Haploinsufficiency of the Myc regulator Mtbp extends survival and delays tumor development in aging mice
Aging is a complex biological process controlled by both environmental and genetic factors; however, twin studies suggest 20-30% of lifespan variation is genetic. Altering the activity or expression of specific genes significantly impacts lifespan in animal models. For example, increased expression of the protein deacetylase Sirt1 is known to slow the effects of aging and increase lifespan. In contrast, reduced levels of the oncogenic transcription factor c-Myc (Myc), due to heterozygosity, was recently reported to significantly increase longevity in mice. Myc is estimated to transcriptionally regulate 10-15% of the genome. While Myc has been implicated in processes such as stem cell maintenance, differentiation, and apoptosis, Myc transcriptional activity is closely linked to cell-cycle progression and the vast metabolic machinery required for cellular proliferation. Notably, Myc regulates mitochondrial biogenesis, providing sufficient mitochondria to maintain increased cellular metabolism. Myc also increases overall protein synthesis, a known modulator of longevity, through regulation of genes that control ribosomal assembly.
Based on the broad control Myc exerts over cellular processes relevant to aging and the recent publication directly linking Myc to longevity, proteins that regulate Myc represent potential modulators of the aging process. We recently reported that Mtbp is a Myc transcriptional co-factor. In mice, Mtbp heterozygosity resulted in reduced Mtbp protein expression without altering Myc levels, and this inhibited Myc-mediated transcriptional activation of target genes, proliferation, and B cell lymphoma development. Knockdown of Mtbp expression delayed cell cycle progression. In contrast, elevated Mtbp expression increased the number of cells in S-phase and enhanced Myc-mediated transcription and tumor development. These data indicate Mtbp is a positive regulator of Myc transcriptional activity and downstream biological functions. Thus, we tested whether reduced Mtbp expression would alter aging in similar ways to decreased Myc expression.
Since Myc+/- (heterozygous) mice have increased longevity and we have shown that Mtbp is a positive regulator of Myc, we investigated the contribution of Mtbp to longevity using a cohort of littermate-matched Mtbp+/+ (homozygous) and Mtbp+/- (heterozygous) mice. Mtbp heterozygous mice had increased longevity compared to wild-type controls, exhibiting a median survival of 785 days compared to 654 days, a 20% increase. This significant difference in lifespan was represented in both male and female populations. Mtbp heterozygous males had a median survival of 774 days, compared to 672 days for wild-type control males, a 15.2% increase. Mtbp+/- females had a median survival of 790 days, compared to 650.5 days for Mtbp+/+ females, a 21.4% increase. In addition to median lifespan, Mtbp heterozygosity also increased maximum lifespan. Specifically, Mtbp+/- mice were overrepresented in the longest living decile and quartile of mice with 9 of 11 (81.8%) and 19 of 26 (73.1%) of the mice, respectively. In contrast, Mtbp wild-type mice were disproportionally represented in the shortest lived decile and quartile of mice 90.9% and 80.8%, respectively.
As is commonly seen in C56BL/6 mice, gross and histopathological tissue analysis at time of death of representative mice demonstrated the majority had cancer (17 of 23 Mtbp+/+ mice and 29 of 34 Mtbp+/- mice). Notably, 32.4% of Mtbp+/- mice had lymphoma, which was twice the incidence of lymphoma in Mtbp+/+ mice (17.4%). The lymphomas were detected at an average age of 840 days in heterozygotes, compared to 682.3 days in wild-type controls, a significant delay. Similarly, Mtbp+/- mice developed carcinomas later in life at 848 days (8.8%) compared to 694 days for Mtbp+/+ mice (13.0%). Although twice the proportion of Mtbp wild-type control mice were cancer free at time of death (30.4%) compared to Mtbp heterozygous mice (14.7%), the Mtbp+/- cancer-free mice lived an average of 836.4 days compared to 640.3 days for cancer-free wild-type controls. This difference in Mtbp+/- mice represents a significant delay in mortality among cancer free mice. These data collectively indicate a decrease in Mtbp expression alters the tumor spectrum and age of onset as mice age, as well as extends overall survival independent of cancer development.
Long-lived mouse models will often retain elevated motor function compared to controls, particularly as they age. To determine if Mtbp heterozygosity improved locomotor activity, open field testing was performed for 1 hour on two days with a cohort of old (1.5 year) littermate matched mice. Although there was a trend for Mtbp heterozygotes to travel a greater distance (5737.7 cm) compared to wild-type controls (4551.0 cm), this difference did not reach statistical significance. When locomotor function was actively challenged using a rota-rod endurance test, the Mtbp+/- mice (78.0 seconds) performed similarly to Mtbp+/+ mice (73.6 seconds) after training. In nature, many animal species with increased longevity have reduced reproductive capacity to limit overpopulation. This trend has been reported in some long-lived mouse models. Thus, we compared the reproductive efficiency of Mtbp+/+ and Mtbp+/- female mice. This examination did not reveal a significant difference in the average number of pups per litter birthed by Mtbp+/+ and Mtbp+/- females. Some long-lived mouse models reported to have reduced growth, resulting in smaller body size. We detected no size differences in mature Mtbp+/- mice. Given this observation, it was not surprising that analysis of serum isolated and frozen at time of sacrifice did not show a statistically significant difference in the level of circulating insulin-like growth factor-1, a major growth-promoting factor.
In addition to increased longevity and modulated cancer development, long-lived Mtbp heterozygous mice exhibited a global trend toward elevated cellular metabolism in the liver. Collectively, increased expression of metabolic markers suggests retained vitality in the livers of old Mtbp+/- mice, which coincides with the elevated expression of the well-known anti-aging gene Sirt1. Collectively, the data suggest Mtbp impacts longevity and cellular metabolism, particularly in the liver. These results are in line with a recent report on Myc as well as our previous reports indicating Mtbp is a positive regulator of Myc transcriptional activity. However, the effect of Myc heterozygosity appears broader than the effects observed for Mtbp heterozygosity. The precise reason for these differences is unclear at this time. Part of the downstream effects of Myc are mediated through direct binding to or displacement of other factors. It is unknown how Mtbp expression impacts these functions of Myc or whether these functions of Myc change as animals age. Moreover, it is possible Mtbp may only orchestrate a sub-set of Myc's overall transcriptional activity and may have Myc-independent functions. Therefore, additional research is needed on the interaction between Mtbp and Myc, and Mtbp itself, to better understand the contribution of Mtbp to aging.
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Continued Interest in Nicotinamide Mononucleotide
In the aging research community as it stands today there is much more work on approaches that can at best produce only small effects on the course of aging than there is work on approaches capable of rejuvenation and large gains in life span. The present growth of interest in supplementation with nicotinamide mononucleotide (NMN) falls into the former camp, shown to modestly slow aging in animal studies. We know that effects on aging in short-lived species are much larger than they are in humans, where there is the data to make direct comparisons of the same method or genetic alteration. The life spans of short-lived species are much more plastic in response to circumstances. Investigations of NMN, like the sirtuin research that led to it, cannot possibly produce large gains in human health. It is somewhat frustrating to see significant time and effort once again be directed towards a line of research in which the potential outcomes are so very limited, analogous to those produced by exercising a little more and eating a little less. Yes, it is more evidence for the importance of mitochondrial function in aging, but in a rational world that should be taken as nothing more than a sign that the research and development communities should put more effort into mitochondrial repair strategies, or the backup approach of allotopic expression so as to completely fix the problem in older individuals, not just slightly slow it down.
Much of human health hinges on how well the body manufactures and uses energy. For reasons that remain unclear, cells' ability to produce energy declines with age, prompting scientists to suspect that the steady loss of efficiency in the body's energy supply chain is a key driver of the aging process. Now, scientists have shown that supplementing healthy mice with a natural compound called NMN can compensate for this loss of energy production, reducing typical signs of aging such as gradual weight gain, loss of insulin sensitivity and declines in physical activity. "This means older mice have metabolism and energy levels resembling that of younger mice. Since human cells rely on this same energy production process, we are hopeful this will translate into a method to help people remain healthier as they age."
With age, the body loses its capacity to make a key element of energy production called NAD (nicotinamide adenine dinucleotide). Past work has shown that NAD levels decrease in multiple tissues as mice age. Past research also has shown that NAD is not effective when given directly to mice so the researchers sought an indirect method to boost its levels. To do so, they only had to look one step earlier in the NAD supply chain to a compound called NMN (nicotinamide mononucleotide). The new study shows that when NMN is dissolved in drinking water and given to mice, it appears in the bloodstream in less than three minutes. Importantly, the researchers also found that NMN in the blood is quickly converted to NAD in multiple tissues.
To determine the long-term effects of giving NMN, researchers studied three groups of healthy male mice fed regular mouse chow diets. Starting at five months of age, one group received a high dose of NMN-supplemented drinking water, another group received a low dose of the NMN drinking water, and a third group served as a control, receiving no NMN. The researchers compared multiple aspects of physiology between the groups, first at 5 months of age and then every three months, until the mice reached 17 months of age. Typical laboratory mice live about two years. The researchers found a variety of beneficial effects of NMN supplementation, including in skeletal muscle, liver function, bone density, eye function, insulin sensitivity, immune function, body weight and physical activity levels. But these benefits were seen exclusively in older mice. "When we give NMN to the young mice, they do not become healthier young mice. NMN supplementation has no effect in the young mice because they are still making plenty of their own NMN. We suspect that the increase in inflammation that happens with aging reduces the body's ability to make NMN and, by extension, NAD."
In skeletal muscle, the investigators found that NMN administration helps energy metabolism by improving the function of mitochondria, which operate as cellular power plants. They also found that mice given NMN gained less weight with aging even as they consumed more food, likely because their boosted metabolism generated more energy for physical activity. The researchers also found better function of the mouse retina with NMN supplementation, as well as increased tear production, which is often lost with aging. They also found improved insulin sensitivity in the older mice receiving NMN, and this difference remained significant even when they corrected for differences in body weight.
Tau Aggregate Structure Determines the Type of Dementia it Causes
Researchers here take what seems to be an important step forward in understanding how aggregates of altered tau protein produce forms of age-related neurodegeneration such as Alzheimer's disease. You might be more familiar with amyloid deposits in the brain in the context of Alzheimer's, but it is becoming clear that tau is probably just as important in this condition, and there are other tauopathies in which it is the dominant cause of cell death and dysfunction. Efforts to safely remove harmful forms of tau are unfortunately lagging behind efforts to clear amyloid, but that should change in the years ahead.
The distinct structures of toxic protein aggregates that form in degenerating brains determine which type of dementia will occur, which regions of brain will be affected, and how quickly the disease will spread, according to a new study. The research helps explain the diversity of dementias linked to tau protein aggregation, which destroys brain cells of patients with Alzheimer's and other neurodegenerative syndromes. The study also has implications for earlier and more accurate diagnoses of various dementias through definition of the unique forms of tau associated with each. "In addition to providing a framework to understand why patients develop different types of neurodegeneration, this work has promise for the development of drugs to treat specific neurodegenerative diseases, and for how to accurately diagnose them. The findings indicate that a one-size-fits-all strategy for therapy may not work, and that we have to approach clinical trials and drug development with an awareness of which forms of tau we are targeting."
Researchers had previously determined that tau acts like a prion - an infectious protein that can self-replicate and spread like a virus through the brain. The lab has determined that tau protein in human brain can form many distinct strains, or self-replicating structures, and developed methods to reproduce them in the laboratory. This research led the team to the latest study to test whether these strains might account for different forms of dementia. To make this link, 18 distinct tau aggregate strains were replicated in the lab from human neurodegenerative disease brain samples, or were created from mouse models or other artificial sources. Researchers inoculated the strains into different brain regions of mice and found striking differences among them. Each form created different pathological patterns, recapitulating the variation that occurs in diseases such as Alzheimer's, frontotemporal dementias, and traumatic encephalopathy. The different forms of tau caused pathology that spread at different rates through the brain, and affected specific brain regions. This experiment demonstrated that the structure of pathological tau aggregates alone is sufficient to account for most if not all the variation seen in human neurodegenerative diseases that are linked to this protein. "The challenge for us now is to figure out how to rapidly and efficiently determine the forms of tau that are present in individual patients, and simultaneously, to develop specific therapies. This work says that it should be possible to predict patterns of disease in patients and responses to therapy based on knowledge of tau aggregate structure."
Additional TP53 Copies as the Cause of Reduced Cancer Risk in Elephants
Cancer is a numbers game: there is some risk per unit time of cells acquiring the necessary mutations, coupled to some risk of the immune system failing to destroy those cells before they get going in earnest. Cancer is predominantly an age-related condition because the number of mutations rises with age, the cellular environment becomes progressively more inflammatory and conducive to cancer growth, and the immune system declines in effectiveness. But if cancer is a numbers game by count of cells, why do mammals with a very large total number of cells, such as elephants and whales, have a low rate of cancer incidence? Obviously whales could not have evolved to in fact have hundreds of times the cancer incidence of humans to match the hundreds of times as many cells in their bodies. What are the mechanisms in these larger species that reduce the cancer risk per cell? Researchers are interested in this aspect of comparative biology from the perspective of determining a potential basis for new cancer prevention strategies. Here, the authors of this commentary review the evidence for low cancer risk per cell in elephants to result from extra copies of the TP53 gene:
Cancer is a genetic disease in which cells divide uncontrollably. Some of the mutations that cause cancer are inherited, but most are the results of mistakes made when DNA is copied during cell division. By the time a person reaches adulthood, their DNA will have been copied about 30 trillion times, and each of these events could result in a cancer-causing mutation. Since large, long-lived organisms experience more cell divisions than small, short-lived ones, they have a greater chance of accumulating cancer-causing mutations. Indeed, models suggest that if elephants and whales had the same risk of cancer per cell division as humans they could not exist. Instead, they would all die of cancer at a young age. Clearly elephants and whales do exist, and neither of them have unusually high rates of cancer. This puzzle is referred to as Peto's Paradox, and it hints that large-bodied animals must have mechanisms to compensate for experiencing so many cell divisions. Recently, two groups of researchers set out to discover how elephants evolved to prevent or suppress cancer, and both arrived at a single gene - TP53.
In humans, the TP53 gene protects against cancer, and mutations that prevent the gene from working are behind many cancers in adults. Last year, researchers reported a number of interesting results on TP53 genes in elephants. First they confirmed that an elephant's cancer risk is about 2-5 times lower than a human's; they then went on to show that elephants actually have 20 copies of TP53. They also noted that while one of the elephant's TP53 genes was comparable to those in other mammals, the other 19 were slightly different. Most genes contain a mix of protein coding sections (which are called exons) and non-coding sections (called introns). Typically, introns are removed after a gene has been transcribed into messenger RNA but before it is translated into a protein. However, all but one of the TP53 genes in elephants lacked true introns. This indicates that the 19 extra TP53 genes likely originated when an edited RNA molecule, which had had its introns removed, was converted back to DNA. Genes with this kind of history are known as "retrogenes". One way that the TP53 gene protects against cancer is by causing cells with damaged DNA (which is likely to contain cancer-causing mutations) to commit suicide, via a process known as apoptosis. The researchers exposed elephant cells to ionizing radiation (which causes DNA damage) and found that they were twice as likely to undergo apoptosis as cells from healthy humans. However, based on this pair-wise comparison, it was not clear whether the elephant cells are more prone to apoptosis, or if human cells are relatively insensitive to DNA damage.
Now another team report answers to many of the remaining open questions about TP53 in elephants. First they searched 61 genomes of animals ranging from aardvarks to whales for TP53 genes and retrogenes. Some of these animals - such as manatees and the rock hyrax - had only a few TP53 retrogenes, whereas others had multiple copies of TP53 retrogenes. By mapping the data onto a phylogenetic tree, the researchers showed that the number of TP53 genes had increased as body size increased in the lineage that led to elephants. They confirmed that some of the TP53 retrogenes are transcribed and translated in elephant tissue, and that these transcripts give rise to multiple forms of the proteins. Also, elephant cells up-regulated TP53 signaling and induced apoptosis in response to lower levels of DNA damage (from drugs and radiation) than cells from other mammals. This indicates that elephant cells are especially sensitive to DNA damage and more prone to apoptosis. Next, the researchers showed that elephant cells need the retrogenes for their enhanced apoptosis response. Finally, adding the same retrogenes to mouse cells made these cells more sensitive to DNA damage too. Cell division despite DNA damage is a hallmark of cancer, and so the researchers concluded that elephants had likely solved Peto's Paradox (at least in part) by enhancing TP53 signaling, a feat that they achieved by duplicating the TP53 gene.
Using Hypoxia to Induce Heart Regeneration in Mice
The heart is one of the least regenerative organs in mammals, and the scientific community has for some time put in considerable effort to search for viable strategies to overcome this limitation. While much of the focus of this research is on cell therapies, such as the use of stem cell transplants, there are other possible approaches. The researchers here uncover an interesting possibility involving decreased oxygen intake, or hypoxia. It is known that mild hypoxia induces many of the same beneficial responses, such as increased cellular repair and maintenance, as are produced by calorie restriction. That seems to be enough to generate a greater regenerative response in heart tissue as well:
The adult mammalian heart is incapable of regeneration following cardiomyocyte loss, which underpins the devastating impact of cardiomyopathy. Recently, it has become clear that the mammalian heart is not a post-mitotic organ. For example, the neonatal heart is capable of regenerating lost myocardium, and the adult heart is capable of modest self-renewal. In both these scenarios, cardiomyocyte renewal occurs through proliferation of pre-existing cardiomyocytes, and is regulated by aerobic respiration-mediated oxidative DNA damage. Therefore, we reasoned that systemic hypoxemia inhibits aerobic respiration and alleviates oxidative DNA damage, thereby inducing cardiomyocyte proliferation in adult mammals.
Here we report that gradual exposure to severe systemic hypoxemia, where inspired oxygen is gradually decreased by 1% and maintained at 7% for two weeks, results in inhibition of oxidative metabolism, decreased reactive oxygen species (ROS) production and oxidative DNA damage, and reactivation of cardiomyocyte mitosis. Intriguingly, we found that exposure to hypoxemia 1 week after induction of myocardial infarction induces a robust regenerative response with decreased myocardial fibrosis and improvement of left ventricular systolic function. Finally, genetic fate mapping confirmed that the newly formed myocardium is derived from pre-existing cardiomyocytes. These results demonstrate that the endogenous regenerative properties of the adult mammalian heart can be reactivated by exposure to gradual systemic hypoxemia, and highlight the potential therapeutic role of hypoxia in regenerative medicine.
Aging, Just Another Disease
Aging is nothing more than a medical condition, and one that should be treated. There is a considerable amount of residual inertia on this topic, however, many people yet to be convinced that aging is anything other than set in stone, or that it is desirable to prevent the suffering and death caused by aging. At the large scale and over the long term, funding for medical research and pace of progress is determined by public support for the goals of that research. This is why we need advocacy, fundraising, and continued public discussion on the plausibility and desirability of building therapies capable of treating the causes of aging.
The concept of aging is undergoing a rapid transformation in medicine. The question has long been asked: Is aging a natural process that should be accepted as inevitable, or is it pathologic, a disease that should be prevented and treated? For the vast majority of medicine's history, the former position was considered a self-evident truth. So futile was any attempt to resist the ravages of aging that the matter was relegated to works of fantasy and fiction. But today, the biomedical community is rethinking its answer to this question. The controversy has been fanned, to a great extent, by one Aubrey de Grey, a Cambridge University-trained computer scientist and a self-taught biologist and gerontologist. Over the past decade, de Grey has undertaken an energetic campaign to reframe aging as a pathologic process, one that merits the same level of attention as, say, cancer or diabetes. Although many of de Grey's claims remain controversial - notably, that the first person who will live to 1,000 years old is already among us - I agree that we can and should pathologize aging. In fact, it seems we already have.
The human body comprises a number of different systems that each develop at its own pace. The nervous system seems to reach full maturity in our 20s, for instance, while the skeletal system may peak a decade later. Of course, this physiologic natural history is subject to environmental influence. Nevertheless, these environmental factors ultimately act on a foundation that, beyond a certain age, is inexorably deteriorating. There is a finite limit beyond which environmental factors cannot save us. The changes of aging vary in their specifics from one system to another, but common mechanisms are at work. For instance, wear-and-tear of joints results from depletion of articular cartilage, just as the thinning of skin is due to a loss of elastic connective tissue. Other age-related changes arise from errors in cellular activity or the accumulation of metabolic by-products, the probabilities of which rise over time. As these natural changes proceed, they lead to readily recognizable disease. The accumulation of fat in blood vessel walls provides a particularly good demonstration of this. Lipids are an essential part of our diet, but as processed lipids continue to accumulate in vessel walls, these vessels harden and narrow, eventually failing to supply the heart with enough blood. If the narrowing blocks vessels entirely, the heart is starved of blood, causing heart muscle death, or heart attack. This simplified example illustrates that perfectly normal processes that are critical to survival will quite naturally lead to disease. In a biological sense, the mere passage of time is pathological. Importantly, most of the early changes in this progression, such as high cholesterol, are symptomless. Yet they are precursors to life-threatening illness and are therefore considered pathologic entities in their own right, to be prevented and treated. The same can be argued of the more subtle and gradual damages of aging.
We can and should view these diseases, whose prevention and treatment are standard medical practice, as the clinical manifestations of natural age-related changes. Doctors have long targeted such changes to prevent disease. For instance, by recommending their patients limit the fat and carbohydrate content of their diets or take statin medications, doctors have strived to stave off heart disease. In so doing they unknowingly have been battling aging itself. Yet there are those who find this view of aging contentious, a reaction that likely stems from the misperception that the terms "natural" and "pathologic" are conflicting. There's a common yet unwarranted sense that these two terms are mutually exclusive; that what is natural can only be right, and what is pathologic cannot be natural. This is untrue. Because "natural" typically describes what conforms to the usual course of events, and "pathologic" describes what is harmful, the question posed in the opening paragraph presents a false dichotomy. Both "natural" and "pathologic" describe aging fairly. Thus, the controversy is largely semantic. If I were to replace the call for a "fight against aging" with an invitation to "combat age-related changes," I would expect a far more positive response. A call to "prevent the early stages of disease" would surely receive virtually unanimous support. I contend that the three phrasings are synonymous.
Continued Efforts to Alter the Behavior of Senescent Cells Without Destroying Them
Cellular senescence is an evolutionary adaptation of a mechanism of embryonic development that serves to to suppress cancer incidence. Cells that become senescent in response to damage or a toxic environment cease to divide, and usually go on to self-destruct or be destroyed by the immune system, which serves to remove from the picture those cells most at risk of becoming cancerous. Unfortunately, that isn't all they do, and not all are destroyed. Some fraction of senescent cells linger and accumulate to cause widespread harm in the body, despite their small numbers, through the secretion of various signal molecules. These signals produce chronic inflammation, damage the fine structure of tissue by remodeling the extracellular matrix, and alter the behavior of surrounding cells for the worse. They are one of the root causes of aging and age-related disease. While the primary, and I think most effective, approach to dealing with senescent cells as a cause of aging is to destroy them, a sizable contingent of researchers are more interested in finding ways to alter the behavior of these cells. This includes cancer researchers who would like to see more cellular senescence rather than less as a way to combat cancers. These researchers believe that by modulating senescent signaling, senescent cells can in principle be rendered largely harmless. This, however, is a long road in comparison to simply destroying the unwanted cells. Senescent cell signaling is by no means fully mapped or understood, and considerable effort to damp one type of signal would still leave all of the rest. Meanwhile, senescent cell destruction is forging ahead to towards clinical translation quite rapidly.
Cellular senescence is a state in which normal healthy cells do not have the ability to divide. Senescence can occur when cancer-causing genes are activated in normal cells or when chemotherapy is used on cancer cells. Thus, senescence induces a mechanism that halts the growth of rapidly dividing cells. Once thought to only be beneficial to halt cancer progression, work has shown that during senescence there is an increase in secreted factors called cytokines and chemokines (small proteins important in immune responses) that may have detrimental, pro-tumorigenic side effects. Researchers have identified a protein that plays a critical role in the expression of cytokines and chemokines, and that decreasing this protein suppresses the expression of these secreted factors. This suggests that there may be ways of promoting the positive effects of senescence while suppressing its negative effects.
The researchers focused on chromatin, a cellular structure responsible for holding the DNA in our cells together. During senescence, some of the chromatin is reorganized into senescence-associated heterochromatin foci (SAHF). When this happens, genes that are responsible for promoting proliferation are silenced. However, the expression of cytokine and chemokine genes - known collectively as the senescence-associated secretory phenotype (SASP) - is increased. "When senescence happens, you have two closely linked phenomena occurring, yet one of these helps to halt tumor progression while the other causes an increase in potentially harmful inflammatory cytokines and chemokines. We pinpointed the architecture of chromatin and the proteins that influence chromatin organization as the proper place to start to try and solve this paradox."
The scientists looked at a set of proteins known as high mobility group proteins, which are responsible for altering chromatin architecture in order to regulate gene transcription. One such protein called high mobility group box 2 (HMGB2) binds to DNA to increase chromatin's accessibility to transcription factors. They showed that HMGB2 promotes SASP gene expression by preventing the spreading of heterochromatin and therefore preventing SAHF from silencing SASP genes. When the researchers silenced HMGB2, SASP genes were successfully silenced by SAHF, suggesting that the detrimental effects of senescence might be negated by inhibiting HMGB2. "Understanding senescence is critical for understanding how tumor growth can be successfully suppressed. With the information from this study, we may be able to increase the effectiveness of chemotherapeutic agents that are able to induce senescence by silencing HMGB2 and decreasing the expression of unwanted secreted factors."
A Discussion with the KrioRus Founders
KrioRus is a Russian cryonics provider, and only the third such organization in the world after Alcor and the Cryonics Institute in the US. A number of other groups have for some years been inching towards launch, in Canada, Australia, and Switzerland, and there are numerous for-profit and non-profit companies involved in providing services to the cryonics industry, but the folk at KrioRus are to be commended for managing to make the leap. As is the case in the US, the Russian cryonics community has a large overlap with transhumanist and longevity science organizations, such as the Science for Life Extension Foundation. Cryonics is in essence the backup plan for those who will age to death prior to the advent of working rejuvenation therapies, and is the only other approach to offer any chance at a much longer life in the future.
The only obvious sign this is the office of a cryonics company sits on the windowsill: a stainless-steel vacuum vessel about the size of a lobster pot. It's meant to transport a human brain, and if used for its true purpose and not as a decoration, it would deliver that brain to a larger storage container filled with liquid nitrogen. The brain would be preserved there - the liquid nitrogen topped off once in a while - for however long the science and technology community takes to solve some vexing problems. First, how to repair the tissue damage caused by freezing. Second, and more important, how to gain access to the data inside - the neurons and connections and impulses that constitute a person's memories, emotions, and personality - and bring it all back to life, either in another, healthier body or uploaded into a computer. Otherwise, the office looks like a small apartment, and it is also that. It's the pied-a-terre of Danila Medvedev and Valerija Pride, life partners and co-founders of Moscow-based KrioRus, as well as a crash pad for eager young transhumanists who need a place to stay while working on projects intended to expedite the quest for immortality.
They're discussing the fate of a brain in Spain - the brain of a man described by Medvedev as "Spain's leading cryonicist," who's just died. Despite running a Spanish-language site dedicated to cryonics, the man had no plans in place to actually be frozen upon his death. His wife has managed to get his body put on ice, and now Medvedev and Pride are trying to figure out how to have his brain removed and stored in a way that will allow it to be transferred into KrioRus's care. These are the kinds of logistical challenges Medvedev is trying to iron out as he and Pride work to make KrioRus the leading cryonics company for Europe and Asia. The best way to cryopreserve is to replace all the water in the body with a chemical that essentially turns the tissue into glass as it freezes. Vitrification, as the process is known, prevents the damage caused by ice crystals when a body is frozen in its natural state. But vitrification has its own flaw: No one knows how to reverse it. Medvedev describes this as a minor challenge. The important thing, he says, quoting American nanotechnologist Ralph Merkle, is that "information is not destroyed" by freezing. They'll work it out later.
"Of course, the goal is to have the perfect preservation, but it depends on the situation," Medvedev says. "You can have the best technology in the world, but if it's not available in Barcelona it doesn't help you much." And any preservation, cryonicists say, is better than none. Truly, it's all just a best guess. Cryonics was first proposed by the physicist Robert Ettinger in his 1964 book, The Prospect of Immortality. Five years later, the first human was frozen, and a small, devoted community of cryonicists (almost all of them in America) have been debating best practices ever since. Today, the world leader is Alcor Life Extension Foundation, started in 1972 and based in Scottsdale, Ariz. Alcor has 148 patients stashed in tanks filled with liquid nitrogen. Then there's the Cryonics Institute, established in 1976. It has 114 patients in storage in a suburb of Detroit and is known for being cheaper than Alcor and for having a strong preference for freezing heads over full bodies.
Unlike its American rivals, KrioRus doesn't use stainless steel for its dewars. Instead, it uses a fiberglass and resin composite made by a company that builds racing yachts from the same material. The dewars stand inside a 2,000-square-foot hangar, but they don't really need to. "The walls of the building are actually weaker than the walls of the dewars," Medvedev says. "People tend to think that patients should be stored in buildings. There are few technical reasons behind it, just tradition and irrationality." "First you need everything functional," adds Dmitry Kvasnikov, who's been listening quietly. "Then once it is functional, you can make it look pretty." The company has big plans. It will soon move to a permanent home at an agricultural college outside Tver, a few hours west of Moscow. And KrioRus's principals and clients all make clear that the cryonics operation is merely the opening salvo of a far larger campaign, the quest for immortality. Medvedev and Pride are also co-directors of the Russian Transhumanist Movement (RTM), an activist organization and incubator for ideas to advance the cause of extending the human life span until we've achieved immortality. Generally speaking, transhumanists believe that technology is advancing at an exponential rate and that sometime in the future, death will be overcome. They like to speak of aging as a disease that can be cured, and depending on the transhumanist you're speaking with, she probably believes either that new bodies will be engineered and hooked up to our heads or that our minds and memories will live forever inside a machine. In either case, all you need is your brain, which is why most transhumanists, Medvedev and Pride included, think it's unnecessary to freeze your entire body.
KrioRus was born out of their enthusiasm for the transhumanist cause. Cryonics is the starting point. "It is Plan B," Medvedev admits. No one wants to be frozen. But dying is worse. As Mikhail Batin, an entrepreneur, transhumanist, and KrioRus client says: "It's the only alternative we have at the moment to death. It is definitely better to be frozen than buried or burned. Cryonics is the best action in the worst circumstances."
Heat Shock Protein Hsp60 Involved in Regeneration and Wound Healing
Heat shock proteins are involved in the cellular response to stresses, including heat, hence the name. They assist in protein quality control and correct function, one important part of the larger panoply of cellular maintenance activities. Here, researchers find that the heat shock protein Hsp60 also influences the role that the immune system plays in wound healing, and can be used to spur greater regeneration:
Researchers have identified a novel role for a gene known as heat shock protein 60 (Hsp60), finding that it is critical in tissue regeneration and wound healing. The study found that topical treatment of an Hsp60-containing gel dramatically accelerates wound closure in a diabetic mouse model. The study also describes the mechanism by which this works, finding that Hsp60 protein is released at the site of injury, signaling wound healing to initiate. The findings may help in the development of effective therapeutics for accelerating wound closure in diabetic patients, as well as for normal wound healing and scar reduction. "This study proposes an unusual role for a well-known gene. This gene is found in every organism from bacteria to man. We have shown that in vertebrates, it has a surprising role in immunity that is essential for wound healing."
Protein products of the Hsp60 gene are known primarily for their role in ensuring that other proteins are folded correctly. The Hsp60 protein has also been reported to serve as a signaling molecule that induces an inflammatory response to bacterial infection from a cut. Based on previous findings that the Hsp60 protein was necessary for an inflammatory response, the researchers hypothesized that the molecule might also be involved in an organisms' ability to regenerate. Using zebrafish - an ideal model for this work because fish can regenerate many tissues, including fins - the researchers used targeted mutagenesis, making specific and intentional changes to the DNA sequence of a gene, to "knock out" Hsp60 from the genome. The mutant fish appeared to develop normally, but when the researchers wounded them by injuring the cells involved in hearing or amputating a caudal fin, the fish were unable to regenerate their cells and fins, respectively. Using fluorescently tagged leukocytes (immune cells that flock to the site of injury as part of the inflammatory response under normal conditions), the researchers demonstrated that without the Hsp60 gene, there were significantly reduced numbers of leukocytes at the injury site. This suggested that the Hsp60 protein was somehow acting as an attractant that promoted inflammation, a necessary component of wound healing. "When we injected Hsp60 directly to the site of injury, the tissue surrounding the wound started to regenerate faster. That's when we got really excited."
However, the most striking finding from the study was that actually applying a topical treatment of the Hsp60 protein to a puncture wound in diabetic mice stimulated complete healing after only 21 days. Mice without the treatment did not show improvement over the same time frame. Although promising, this finding has only been shown in mice and is yet to be tested in humans. "We hope that topical treatment with Hsp60 will act the same way in humans. And we believe it will, but more work is needed. We also want to know if it will help any wound heal, not just wounds encountered by people with diabetes. Will it reduce scarring and increase the speed of healing?"
BACE1 Inhibition as an Alzheimer's Treatment
BACE1 is involved in the production of amyloid-β, the protein aggregates implicated in the pathology of Alzheimer's disease. Levels of amyloid in the brain are actually quite dynamic, so any method that safely increases clearance or reduces creation of amyloid will likely prove beneficial. As reported here, inhibition of BACE1 seems to achieve that goal, and is making progress towards human clinical trials. That said, Alzheimer's appears to be at least as much caused by aggregation of altered tau protein as by amyloid, so it is likely that both forms of metabolic waste will need to be cleared.
Researchers have reported results of early human and animal trials of a drug called verubecestat, which targets the production of protein plaques associated with the disease. Definitive conclusions will have to await the results of larger, ongoing phase III clinical trials to assess their efficacy, effectiveness and safety, but the results are promising, experts say. Verubecestat is a so-called BACE1 inhibitor. BACE1 (for Beta-site Amyloid precursor protein Cleaving Enzyme 1, aka beta-secretase 1) is an enzyme involved in producing amyloid beta, a protein that clumps together, eventually forming the plaques surrounding neurons that are the disease's key hallmark. The amyloid hypothesis of Alzheimer's proposes that the accumulation of amyloid beta aggregates in the brain drives a cascade of biological events leading to neurodegeneration. By blocking BACE1, the hope is this approach could prevent the buildup of these clumps in the first place. But until now, development of these drugs has been hindered by problems finding molecules with the right characteristics, and concerns over theoretical and actual side effects.
Amyloid is formed when amyloid precursor protein (APP) is cleaved into pieces by BACE1 and another enzyme called gamma-secretase. APP protrudes from cell membranes into the space between cells, where the enzymes can cut it. Production of amyloid beta involves two snips. First, BACE1 cleaves it some distance from the cell (producing fragments called sAPP beta) then gamma-secretase cuts the remaining stub off at the cell membrane. The fragment released by this cut is amyloid beta. BACE1 inhibitors work by attaching to the enzyme and preventing it from cleaving APP, thereby decreasing production of amyloid. Researchers have been studying its function using mice engineered to lack the BACE1 gene, and these studies have revealed numerous consequences including problems with insulation and guidance of neural wiring, retinal pathology and neurodegeneration, raising concerns that BACE1 inhibitor drugs might have side effects. Another challenge was developing molecules big enough to attach to BACE1 but still able to cross the blood-brain barrier. Several candidate drugs have now been developed, but a recent clinical trial was halted due to evidence of liver toxicity.
Researchers developed a molecule that appears to overcome these challenges. They tested the drug on animals and found it significantly reduced levels of both amyloid and sAPP beta in the blood, cerebrospinal fluid and brain in a dose-dependent manner. There were no signs of toxicity, even after treatment of up to six months in rats and nine months in monkeys. The only obvious side effect was reduced fur pigmentation in mice and rabbits, although this wasn't seen in monkeys. The researchers then moved on to small, early-stage human trials to assess safety and tolerability and inform the choice of suitable doses for later trials. Verubecestat reduced amyloid and sAPP beta in the cerebrospinal fluid of healthy adults who took the drug for two weeks and patients with mild to moderate Alzheimer's who took it for one week. "This is the first detailed report of what a BACE inhibitor does in humans. The good news is they didn't see evidence so far of any of the side effects we're concerned about with BACE inhibition." This is probably because the doses used did not fully inhibit BACE1 activity. "It might be you only need a little bit of BACE active in the brain and body to prevent side effects." Another possibility is that some of the consequences for mice lacking BACE1 from birth are developmental effects that don't apply when the enzyme's activity is lowered in adults.
Senescent Cells May Enhance Viral Replication, Making Infections More Dangerous
An accumulation of senescent cells is one of the causes of degenerative aging. These cells secrete a mix of inflammatory and other signal molecules, producing numerous detrimental changes in surrounding tissues. As the number of senescent cells grows with advancing age, their presence causes dysfunction and pathology that contributes significantly to the progression of age-related disease. Researchers here provide evidence to suggest that, in addition to the range of harmful outcomes that are already fairly well known, the presence of senescent cells may also make viral infections worse, though the degree to which this is the case is a question mark:
Aging is suggested to be promoted by cellular senescence because senescent cells accumulate in tissues and organs with age. Replicative senescence refers to a stage which normal cells undergo growth arrest after proliferating for a limited number of population doublings. Influenza virus (IFV) and Varicella Zoster Virus (VZV) are the pathogens that cause the most common infectious diseases worldwide and the elderly populations are most vulnerable to IFV and VZV infections. The efficacy and effectiveness of influenza vaccines decrease with age, due to the negative impact of aging on the development of the immune system and its ability to function. The detailed role and mechanisms of senescence that underlie the increase in the levels of susceptibility to influenza infection have not been well elucidated.
Previous work has highlighted the age or senescence-associated decline of innate immune receptor function. For example, decreased toll-like receptor (TLR) function in dendritic cells, dysregulated signaling cascades, and decreased cytokine production have been shown to contribute to impaired innate immune responses. Similarly, age-associated defects in retinoic acid inducible gene-I (RIG-I) signaling specifically impairs interferon (IFN) signaling. In addition to gene expression changes in receptors, senescence is known to cause inflammaging, characterized by the up-regulation of the inflammatory response that occurs with advancing age. Altered secretion levels of pro-inflammatory cytokines and chemokines, such as interleukin-8 (IL-8) and tumor necrosis factor-α (TNF-α), were observed in elderly mice. These aberrant cytokine responses are thought to contribute to the inability of the elderly to mount appropriate immune responses to pathogens, vaccines, and self-antigens.
Human sirtuins are composed of a family of seven nicotinamide adenosine dinucleotide (NAD)-dependent deacetylases that removes acetyl groups from wide ranges of essential proteins. SIRT1 has a broad range of physiological and biological functions, which play an important role in controlling gene expression, metabolism and aging. At cellular level, overexpression of SIRT1 was shown to prevent replicative senescence. Recent studies identified SIRT1 as an ancient antiviral defense factor. They showed that siRNA-mediated inhibition of each of the seven sirtuins could enhance the virus plaque formation for human cytomegalovirus (HCMV) and influenza A virus. The detailed mechanisms of SIRT1-mediated antiviral activities remain to be fully determined. In the present study, we used a replication-induced senescence in vitro model to illustrate the role and the mechanisms of senescence on viral replication and host response during viral infection.
In our study, we used two different virus infection models to examine the impact of replication-induced senescence and anti-senescence gene, SIRT1, on viral replication efficiency and host innate immune signaling pathways. A significant increase in viral replication efficiency was detected by replicative senescence during IFV and VZV infection. Furthermore, we confirmed that SIRT1 is an important antiviral factor, and SIRT inhibitor treatment or knockdown of SIRT1 resulted in the enhancement of virus plaque formation. As one of possible mechanisms for the increase in viral replication in senescent cells, a reduction in interferon (IFN) response after viral infection may account for it. Although DNA damage response caused by senescence-induced cell growth arrest can lead to increased basal expression levels of IFN and IFN-associated genes, our data suggests that virus-mediated induction of IFN and IFN-associated genes are down-regulated in senescent cells. Another possibility for the enhanced viral replication associated with senescence may largely attributed to the disruption of mitochondrial dynamics in that a defect in mitochondrial dynamics in senescent cells may contribute to down-regulation of early interferon response by inactivating the fission factor dynamin-related protein 1 (DRP1) in favor of viral replication. Further studies are required to test this hypothesis.
Among senescence-associated genes, SIRT1 is the best studied and currently considered to be the most important controlling factor involved in senescence and aging. Nicotinamide (NAM) is a well-known SIRT1 inhibitor and we wanted to assess whether NAM-mediated inhibition of deacetylase activity of SIRT1 was able to modulate viral replication. As expected, SIRT1 inhibition led to increased viral plaque formation. Recent studies also indicate that human SIRT1 shows a broad range antiviral function against DNA and RNA viruses, suggesting that sirtuin-modulating drugs can be used to treat viral diseases. Thus, sirtuin-modulating drugs can have a significant impact on the potential therapeutic approach for influenza infection. Considering that SIRT1 can be induced by viral infection and potentially affect the host immune response, further studies on the in vivo role of SIRT1 in determining susceptibility to viral infection may shed light on the function of SIRT1 in the amelioration of viral infection-associated symptoms.
In conclusion, our data demonstrate that cellular replicative senescence can contribute to increased viral replication. Furthermore, we provide the evidence that replicative senescence-associated changes could affect IFN expression, but not IFN-mediated antiviral response, which could result in an increased susceptibility of senescent cells to viral infection. A better understanding of immunosenescence during viral infection will greatly improve our knowledge of the pathogenesis of IFV and VZV and provide insight for therapeutic improvements in the response to IFV and VZV infection treatment in the elderly.