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.
This content is published under the Creative Commons Attribution 3.0 license. You are encouraged to republish and rewrite it in any way you see fit, the only requirements being that you provide attribution and a link to Fight Aging!
To subscribe or unsubscribe please visit: https://www.fightaging.org/newsletter/
- A Reminder that Fight Aging! has a Bus Factor of 1
- Implanting Liver Organoids to Generate Functional Liver Tissue
- An Immunotherapy Clears Amyloid from the Brains of Alzheimer's Patients
- A Method of Intermittently Increasing Neurogenesis in the Aging Mouse Brain is Shown to Improve Memory Function
- An Investigation of How Telomerase Cancers can Switch to Become ALT Cancers
- Latest Headlines from Fight Aging!
- The Moral Evil of Aging to Death
- Demonstrating Mitochondrial DNA Deletions to Cause Loss of Muscle Fibers
- The Potential Use of Cell Therapies to Treat Immunosenescence
- Vesicles and Amyloid in Alzheimer's Disease
- Increased AMPK Activity Reduces Cancer-Related Loss of Muscle
- Exercise Associated with a Halved Risk of Cardiovascular Mortality in Older People
- Gene Therapy for Mutation Repair as a Cancer Treatment Strategy
- A Review of Heavy Isotopes and Slowed Aging
- Alzheimer's Disease has the Look of a Condition Built of Multiple Causes
- An Example of Poor Correlation Between Telomere Length and Health
A Reminder that Fight Aging! has a Bus Factor of 1
Modern advocacy for longevity science, and indeed the entire longevity science community, is comparatively young and comparatively small when viewed in the grand scheme of things. Some single sports teams have a larger footprint in the world, measured in people and money. The importance of work on longevity science for the future of humanity is enormous, and enormously underappreciated, but that importance must be realized through growth. It is near all a potential yet to be realized. As of now our community includes many quite small organizations and initiatives which, while doing something valuable, are very vulnerable to happenstance and accident because of their small size. Many of the advocacy efforts that have arisen from the community, like Fight Aging!, have a bus factor of 1. If anything happened to me, that would be the end of Fight Aging! Not everyone is in that boat, of course. If you survey some of the organizations that are running research programs relevant to the medical control of aging rather than just talking about research and longevity, you'll find that their bus factors are in a more respectable range for their size of 2 to 4. That represents an organization far less likely to be rendered unable to continue through a normal rate of attrition of essential personnel.
Still, these are low numbers when considered against the bigger picture. They are a outcome of small organizations, areas of cutting edge research without a large number of experts, and the fact that the community of longevity science supporters is not large. If you look at larger institutions, those further from rejuvenation biotechnology but still within the field of aging research and interested in intervention, you might see that losing four people from, say, the Buck Institute - ten times the size of the SENS Research Foundation - would be unfortunate, but the organization would continue much as it is today without missing a step. On the other hand losing four people from the very select group of scientists who carry out research into glucosepane cross-links would probably set back that line of research for years - there are only a couple of labs with good experience, and little funding for the very important goal of clearing these cross-links from old tissues. Senescent cell clearance doesn't have this problem, given the growth in interest and the greater breadth of knowledge to start with: half of the researchers could decide tomorrow to take up a different line of work, and there would still be plenty of hands left to get the job done. Most of the lines of research relevant to the SENS vision for human rejuvenation fall somewhere between these two extremes.
Advocacy for research is a job for small groups of people - it is hard to justify spending enormous amounts on education and outreach when early stage research costs so very little. The biotechnology revolution has completely changed the economic calculus for near all of the life sciences. Fortunately writing doesn't take much effort, and one of the points of the exercise is to encourage more people to do exactly the same thing. In theory, the sooner you make yourself obsolete the better the job you are doing. So it shouldn't much matter than any one initiative has a low bus factor, because all initiatives have their start and their end, and it is the broader tapestry that is the important thing. One shouldn't lose sight of the forest for the trees. With that in mind, it has been encouraging to see more people trying their hand at this advocacy for longevity science business in the past few years. A number of quite promising attempts have come and gone, some of which are still in the sidebar links on the Fight Aging! home page, but I think it noteworthy that we're starting to see initiatives with a bus factor that is higher than 1. I might point out the Longevity Reporter, for example, that has good number of people involved.
Whether talking about advocacy or the actual work of making progress in rejuvenation biotechnology, growth in the community and the funding solves all concerns about the fragility of organizations and initiatives. The ideal world is one in which there are so many contributors and so much funding that the failure of a company or a laboratory group is not going to cause any significant delay in the pace of progress. The stem cell or cancer research fields are examples to aspire to in this regard. Longevity science is a way removed from that level of funding and participation, but I think it only a matter of time. There is no danger that treating aging as a medical condition will find itself in the same place that the cryonics industry has occupied for the past four decades, struggling to grow both support and funding. The dynamics are very different: I find it hard to envisage a scenario in which a working prototype of a narrowly focused rejuvenation therapy is ignored for decades. Approaches to rejuvenation that are demonstrated to work will be adopted by the biotechnology and medical industry, and after the first couple of these therapies the major players of that industry will stop waiting to be handed the technologies and start in on early stage development of the remainder themselves. It is all a matter of bootstrapping, as always. Just how long it will take is the big question mark, and the number we hope to influence through our actions.
I would hope it to be a matter of great irrelevance as to whether Fight Aging! itself is still around ten years from now or next year or tomorrow. I would be more comfortable saying that with a few more organizations working at advocacy in much the same way, and a five to tenfold growth in the size of this community, however.
Implanting Liver Organoids to Generate Functional Liver Tissue
In the research linked here, publicity materials and open access paper (PDF only, alas), the authors report on the generation of liver organoids that spur the growth of functional liver tissue when implanted into mice. The degree of functional gain is small, but this is one step upon a longer road. This is very much the age of organoids, a period of tissue engineering in which researchers are successfully establishing the methodologies needed to grow functional organ tissue, but are still very limited by the inability to reliably generate blood vessel networks. Thus the created tissues largely work as they are intended to, but are tiny in size: any bigger and the inner cells could not be supplied with sufficient oxygen and nutrients.
Organoids are useful in research, as a much more cost effective way of performing drug assessments, for example, or a way to generate dysfunctional tissues that mimic disease processes more accurately than animal models. The utility doesn't stop there, however. For those organs that operate largely as filters or chemical factories, and where the present large-scale structure and shape is not strictly necessary for correct function, it is a very plausible near-term goal to grow organoids from the patient's own cells and implant them inside or alongside the existing organ. Either the implanted organoids contribute to organ function, helping to rescue the patient from organ damage, or in the best of scenarios they will encourage regrowth and regeneration as well - a sort of hybrid half-way point between a cell therapy and an organ transplant. I predict that we'll be seeing ever more of this sort of use of organoids, and that usage will accelerate as the blood vessel challenge continues to go unsolved.
The liver is the most regenerative of organs in mammals. Even we humans are capable of regrowing lost sections of liver under favorable circumstances. Further, many of the liver's activities are independent of its location and shape - a selection of biochemical and cellular factory processes such as detoxification that only require access to the bloodstream. These points make the liver an excellent place to start building regenerative therapies, given the present state of biotechnology. There is certainly a need for these therapies: at the present time comparatively little can be done to compensate for the loss of the liver's activities as the organ fails with age.
Functional Human Tissue-Engineered Liver Generated from Stem and Progenitor Cells
Liver transplantation is the only effective treatment for end-stage liver disease, but scarcity of available organs and the need for lifelong immunosuppressive medication make this treatment challenging. Alternate approaches that have been investigated include significant limitations. For example, conventional liver cell transplantation requires scarce donor liver and a perfusion protocol that wastes many cells. This type of cell transplant typically lasts less than one year, with most patients ultimately requiring a liver transplant. Human-induced pluripotent stem (iPS) cells are another possibility but, so far, iPS cells have remained immature rather than developing into functional and proliferative liver cells, called hepatocytes. There continues to be a need for a durable treatment, particularly one that could eliminate the need for immunosuppression.
"Based on the success in my lab generating tissue-engineered intestine and other cell types, we hypothesized that by modifying the protocol used to generate intestine, we would be able to develop liver organoid units that could generate functional tissue-engineered liver when transplanted." The research team generated liver organoid units (LOU) from human and mouse liver and implanted both varieties of LOU into murine models. Tissue-engineered liver developed from the human and mouse LOU, with key cell types required for hepatic function including bile ducts and blood vessels, hepatocytes, stellate cells and endothelial cells. However, the cellular organization differed from native liver tissue. Human albumin, the main type of protein in the blood, was detected in the host mouse serum, indicating in vivo secretory function from the human-derived tissue-engineered liver. In a mouse model of liver failure, tissue-engineered liver was able to provide some hepatic function. In addition, the hepatocytes proliferated in the tissue-engineered liver.
Functional Human and Murine Tissue-Engineered Liver is Generated from Adult Stem/Progenitor Cells
Liver disease affects large numbers of patients, yet there are limited treatments available to replace absent or ineffective cellular function of this crucial organ. Donor scarcity and the necessity for immunosuppression limit one effective therapy, orthotopic liver transplantation. But in some conditions such as inborn errors of metabolism or transient states of liver insufficiency, patients may be salvaged by providing partial quantities of functional liver tissue. After transplanting multicellular liver organoid units composed of a heterogeneous cellular population that includes adult stem and progenitor cells, both mouse and human tissue-engineered liver (TELi) form in vivo.
TELi contains normal liver components such as hepatocytes with albumin expression, CK19-expressing bile ducts and vascular structures with α-smooth muscle actin expression, desmin-expressing stellate cells, and CD31-expressing endothelial cells. At 4 weeks, TELi contains proliferating albumin-expressing cells and identification of β2-microglobulin-expressing cells demonstrates that the majority of human TELi is composed of transplanted human cells. Human albumin is detected in the host mouse serum, indicating in vivo secretory function. Analysis of mouse serum after debrisoquine administration is followed by a significant increase in the level of the human metabolite, 4-OH-debrisoquine, which supports the metabolic and xenobiotic capability of human TELi in vivo. Thus implanted TELi grew in a mouse model of inducible liver failure.
An Immunotherapy Clears Amyloid from the Brains of Alzheimer's Patients
Alzheimer's disease research is perhaps the largest single theme in the aging research community, with the majority of National Institute on Aging funding going towards Alzheimer's programs. The most advanced of efforts in Alzheimer's research are those that seek to clear the accumulation of amyloid-β in the brain through the use of immunotherapies, enlisting the immune system to break down and remove the unwanted amyloid. To date, however, this has proven to be a road of great expense characterized by disappointment and slow progress, to the point at which it was possible to question whether amyloid was the right target. Other theories and lines of research have begun to prosper due to the lack of tangible human results for anti-amyloid immunotherapies, in particular that neurofibrillary tangles of misfolded tau protein are just as much a target for clearance as is amyloid-β, and that perhaps it is time to focus on the decline of known clearance mechanisms rather than the amyloid itself.
Still, over the past couple of years, one of the latest entries to the class of anti-amyloid immunotherapies has lived up to some of the promise first seen in animal studies of amyloid clearance. It may well be that the light at the end of the tunnel is in sight. In a human trial that has now lasted a year, this new immunotherapy cleared near all detectable amyloid-β from patients, and the patients showed improvement in the sense that their decline appeared to slow significantly. The caveat here is that a year is not long enough to declare a slowing of the condition in certainty given the number of people treated in the trial, 165 individuals. Certainty will arrive given time and more patients. Regardless, simply through the demonstrated clearance of amyloid in human patients this is a big step forward for the field. If this holds up over the next few years of larger trials it should become very clear as to the degree to which amyloid-β is or is not in fact the primary cause of pathology in Alzheimer's disease.
I have long said that the best way to answer these questions of cause and contribution is to remove the mechanism in question and see what happens. As an approach that is much, much faster - and thus more cost-effective - than trying to infer the answer by analyzing the enormously complex workings of cellular biochemistry. It is an important point when arguing for more funding for SENS rejuvenation therapies: fix the damage, and see whether it works, because that is cheap and fast in comparison to all of the other options. This principle is well demonstrated here in the matter of amyloid, I think, given the past decade of theorizing on the degree to which the harm of Alzheimer's is due to amyloid, tau, or other causes, and the lack of progress on that front from theorizing alone. As soon as a treatment can reliably and safely remove the amyloid from a sizable number of Alzheimer's patients, we will have the answer.
Antibody reduces harmful brain amyloid plaques in Alzheimer's patients
Although the causes of Alzheimer's disease are still unknown, it is clear that the disease commences with progressive amyloid deposition in the brains of affected persons between ten and fifteen years before the emergence of initial clinical symptoms such as memory loss. Researchers have now been able to show that Aducanumab, a human monoclonal antibody, selectively binds brain amyloid plaques, thus enabling microglial cells to remove the plaques. A one-year treatment with the antibody, as part of a phase Ib study, resulted in almost complete clearance of the brain amyloid plaques in the study group patients. "The results of this clinical study make us optimistic that we can potentially make a great step forward in treating Alzheimer's disease. The effect of the antibody is very impressive. And the outcome is dependent on the dosage and length of treatment."
The antibody was developed with the help of a technology platform from Neurimmune. Using blood collected from elderly persons aged up to one hundred and demonstrating no cognitive impairment, the researchers isolated precisely those immune cells whose antibodies are able to identify toxic beta-amyloid plaques but not the amyloid precursor protein that is present throughout the human body and that presumably plays an important role in the growth of nerve cells. The good safety profile of Aducanumab in patients may well be attributed to the antibody's specific capacity to bond with the abnormally folded beta-amyloid protein fragment as well as the fact that the antibody is of human origin.
165 patients with early-stage Alzheimer's disease were treated in the phase 1b clinical trial. Although not initially planned as a primary study objective, the good results encouraged researchers to additionally investigate how the treatment affected the symptoms of disease. This was evaluated via standardized questionnaires to assess the cognitive abilities and everyday activities of the patients. "Aducanumab also showed positive effects on clinical symptoms. While patients in the placebo group exhibited significant cognitive decline, cognitive ability remained distinctly more stable in patients receiving the antibody."
Alzheimer's treatment appears to alleviate memory loss in small trial
The trial mainly tested the safety of the drug in people, and so the final word on whether aducanumab works to ameliorate the memory and cognitive losses associated with Alzheimer's will have to wait until the completion of two larger phase III trials. They are now in progress, and planned to run until at least 2020. Patients in the groups that got the drug were given one of four different doses of aducanumab. Individuals who received the highest doses also saw the highest reductions in plaques. And a group of 91 patients treated for 54 weeks saw slower cognitive declines than did those who received placebo infusions. Scientists have debated for years whether the build-up of amyloid-β causes the memory loss and other symptoms of Alzheimer's. This trial is a point in favour of the "amyloid hypothesis", which suggests that elimination of the protein itself might alleviate the disease's symptoms. Still, the trial is too small to prove that the drug actually works. Numerous other Alzheimer's drugs have looked promising in early-stage trials, yet ended in failure.
The antibody aducanumab reduces Aβ plaques in Alzheimer's disease
Alzheimer's disease (AD) is characterized by deposition of amyloid-β (Aβ) plaques and neurofibrillary tangles in the brain, accompanied by synaptic dysfunction and neurodegeneration. Antibody-based immunotherapy against Aβ to trigger its clearance or mitigate its neurotoxicity has so far been unsuccessful. Here we report the generation of aducanumab, a human monoclonal antibody that selectively targets aggregated Aβ. In a transgenic mouse model of AD, aducanumab is shown to enter the brain, bind parenchymal Aβ, and reduce soluble and insoluble Aβ in a dose-dependent manner. In patients with prodromal or mild AD, one year of monthly intravenous infusions of aducanumab reduces brain Aβ in a dose- and time-dependent manner. This is accompanied by a slowing of clinical decline measured by Clinical Dementia Rating-Sum of Boxes and Mini Mental State Examination scores. These results justify further development of aducanumab for the treatment of AD. Should the slowing of clinical decline be confirmed in ongoing phase 3 clinical trials, it would provide compelling support for the amyloid hypothesis.
A Method of Intermittently Increasing Neurogenesis in the Aging Mouse Brain is Shown to Improve Memory Function
In the paper I'll point out today, researchers use an intriguing method to transiently spur greater neurogenesis and integration of new neurons into neural circuits in older mice. Mice undergoing the procedure exhibited better memory function than those that did not. The interesting part of their approach is that it involves disrupting some fraction of the established neural connections between older neurons, a feat accomplished in a reversible way. During the period of time in which these connections between older neurons are somewhat disrupted, the surrounding tissue reacts by dialing up both the pace at which new neurons are created and also their integration into neural circuits. When the disruption is removed, the connections between older neurons reestablish themselves. So in this fashion the researchers get to have their cake and eat it too: the existing neural circuitry is preserved, but also expanded and strengthened by the newly created neurons.
This approach suggests it is possible that any method of temporarily interrupting neural connections might lead to the same outcome. Equally, the reaction observed may be very dependent on the specific part of the structure of the synapse that is suppressed, and thus on the specific few proteins involved. Hard to say at this point: there is still a great deal to be accomplished in terms of mapping the biochemistry of structures associated with neural function, and how that biochemistry relates to specific functions such as memory retrieval and discrimination. What is clear based on the past few decades of research is that a higher level of neurogenesis is beneficial across the board: it increases the ability of the adult and aging brain to heal, adapt, and learn. It most likely modestly postpones the progression and impact of age-related neurodegeneration, but beyond that it has the look of an enhancement that, if it could be achieved safely, every human being should undergo, leading to improved cognitive function at all ages. Just like artificially increased autophagy and calorie restriction and exercise mimetics, therapies to meaningfully increase neurogenesis are definitely on the to-do list for the research community, but nowhere near any form of practical clinical realization despite the many and varied demonstrations in laboratory animals that have taken place in past years.
Making memories stronger and more precise during aging
"The hippocampus allows us to form new memories of 'what, when and where' that help us navigate our lives, and neurogenesis - the generation of new neurons from stem cells - is critical for keeping similar memories separate." As the human brain matures, the connections between older neurons become stronger, more numerous, and more intertwined, making integration for the newly formed neurons more difficult. Neural stem cells become less productive, leading to a decline in neurogenesis. With fewer new neurons to help sort memories, the aging brain can become less efficient at keeping separate and faithfully retrieving memories.
The research team selectively overexpressed a transcription factor, Klf9, only in older neurons in mice, which eliminated more than one-fifth of their dendritic spines, increased the number of new neurons that integrated into the hippocampus circuitry by two-fold, and activated neural stem cells. When the researchers returned the expression of Klf9 back to normal, the old dendritic spines reformed, restoring competition. However, the previously integrated neurons remained. "Because we can do this reversibly, at any point in the animals life we can rejuvenate the hippocampus with extra, new, encoding units." The authors employed a complementary strategy in which they deleted a protein important for dendritic spines, Rac1, only in the old neurons and achieved a similar outcome, increasing the survival of the new neurons.
In order to keep two similar memories separate, the hippocampus activates two different populations of neurons to encode each memory in a process called pattern separation. When there is overlap between these two populations, researchers believe it is more difficult for an individual to distinguish between two similar memories formed in two different contexts. If the memories are encoded in overlapping populations of neurons, the hippocampus may inappropriately retrieve either. If the memories are encoded in non-overlapping populations of neurons, the hippocampus stores them separately and retrieves them only when appropriate. Mice with increased neurogenesis had less overlap between the two populations of neurons and had more precise and stronger memories, which, according to the researchers, demonstrates improved pattern separation. Mice with increased neurogenesis in middle age and aging exhibited better memory precision.
Modulating Neuronal Competition Dynamics in the Dentate Gyrus to Rejuvenate Aging Memory Circuits
The neural circuit mechanisms underlying the integration and functions of adult-born dentate granule cell (DGCs) are poorly understood. Adult-born DGCs are thought to compete with mature DGCs for inputs to integrate. Transient genetic overexpression of a negative regulator of dendritic spines, Kruppel-like factor 9 (Klf9), in mature DGCs enhanced integration of adult-born DGCs and increased neural stem cell activation. Reversal of Klf9 overexpression in mature DGCs restored spines and activity and reset neuronal competition dynamics and neural stem cell activation, leaving the dentate gyrus modified by a functionally integrated, expanded cohort of age-matched adult-born DGCs. Spine elimination by inducible deletion of Rac1 in mature DGCs increased survival of adult-born DGCs without affecting proliferation or DGC activity. Enhanced integration of adult-born DGCs transiently reorganized adult-born DGC local afferent connectivity and promoted global remapping in the dentate gyrus. Rejuvenation of the dentate gyrus by enhancing integration of adult-born DGCs in adulthood, middle age, and aging enhanced memory precision.
An Investigation of How Telomerase Cancers can Switch to Become ALT Cancers
The paper I'll point out today is a timely one, given that the SENS Research Foundation's fundraiser for early stage work on a therapy for alternative lengthening of telomeres (ALT) cancers is nearing its close. There are still thousands left in the matching fund, so give it some thought if you haven't yet donated. The search for ways to safely sabotage ALT is a useful, important line of research because (1) blocking telomere lengthening is a path to a universal cancer therapy, (2) those research groups presently working on it are all looking to achieve this goal by interfering in the activities of telomerase, (3) cancers can switch from using telomerase to using ALT, and (4) next to no-one is working on ways to suppress ALT mechanisms. It seems fairly clear based on the evidence to date that the universal cancer therapy that lies ahead, built by inhibiting telomere lengthening, must involve a blockade of both telomerase and ALT. The open access paper below reinforces this point, the authors investigating how exactly cancers switch from telomerase to ALT to maintain their dangerous growth.
Cancer research today has a grand strategy problem. There is only so much funding and only so many researchers, but hundreds of subtypes of cancer. Therapies tend to be highly specific to the peculiarities of one type of cancer or a small class of cancers, meaning that great expense and time leads to a treatment that is only applicable for a fraction of cancer patients, all too often a tiny fraction. Further, since tumors evolve at great speed, any one individual patient's cancer may find its way out from under the hammer by changing its signature and mode of operation. All is not doom and gloom, however. Consider that the research community could build a therapy applicable to all cancers with little to no modification, where the cost of development would be no greater than any one of the highly specific therapies presently in use and under development. That therapy would be, of course, based on the blockade of telomere lengthening. The act of telomere lengthening is fundamental to all cancers, and without it tumors can neither grow nor sustain themselves: every cell loses a little of its telomeres with each division, and those with short telomeres self-destruct or become senescent. There is no expectation that any cancer would be able to evolve a way around a loss of telomere lengthening: these are core cellular mechanisms, not amenable to radical change or reinvention by simple mutational damage. The promise here is that the economics of cancer research and development could be entirely changed for the better, and that every cancer would become tractable, open to effective treatment.
The SENS Research Foundation cancer program staff propose to use an assay for ALT activity to assess the contents of the standard drug library for anti-ALT capabilities. The hope is that this will turn up potential candidates for further development, as well as shed more light on the most promising molecular mechanisms and targets to consider for the goal of shutting down ALT entirely, and further lend support for other groups to join in and help speed progress. In many ways ALT is a much easier target than telomerase. No normal adult cell uses ALT, so it is possible to take an indiscriminate, and therefore less costly approach to treatment without harming the patient. Telomerase is essential to stem cells, however, and so forms of targeting will be essential for that side of the future of cancer therapies. The paper linked here adds to the weight of evidence indicating that anti-ALT therapies are a necessary complement to the anti-telomerase therapies that are presently in the early stages of development.
Switch telomerase to ALT mechanism by inducing telomeric DNA damages and dysfunction of ATRX and DAXX
Continuous telomere loss which derives from DNA replication, drives the fusion of chromosome ends, leads to cell cycle arrest and induces cell senescence. However, tumour cells can maintain telomere length and proliferation through telomerase reactivation or the alternative lengthening of telomeres (ALT) mechanism. It is reported that approximately 85-90% of cancer types are telomerase-positive, which use its RNA subunit (termed TR or TERC) as a template and its telomerase reverse transcriptase (TERT) to maintain chromosomal ends. Due to lack of telomerase activity in human somatic cells, telomerase is considered as a potential target of cancer therapy. However, this strategy would be ineffective in several human cancers, which are lack of detectable telomerase activity and utilize the ALT mechanism relying on recombination-mediated telomere elongation. Previous studies have shown that anti-telomerase therapy provoked a switch from telomerase activity to the ALT mechanism in mice. Furthermore, it has been shown that the ALT is an alternative mechanism for telomere maintenance during oncogenesis, which would ultimately decrease the effectiveness of anti-telomerase treatment. Therefore, identifying the mechanism of ALT induction and the telomerase-ALT switch is beneficial in resolving the bottlenecks of anti-telomerase therapy.
ALT-positive cells typically contain abnormally heterogeneous telomeres, ALT-associated promyelocytic leukaemia bodies (APBs) and extrachromosomal TTAGGG repeats (ECTRs). Despite understanding the hallmarks of ALT, the mechanism of ALT induction remains unknown. The study of ALT activation which transformed a telomerase-positive cell line into an ALT-positive cell line in vitro is rare. Recently, several factors have been shown to contribute to ALT formation. It has been reported that the depletion of a histone chaperon ASF1 resulted in ALT cells induction and long telomeres elongation concomitant with inhibition of telomerase activity. Since the ALT mechanism is a recombination-mediated lengthening mechanism, the clustering of telomeres caused by DNA damage response (DDR) promotes homology-directed telomere synthesis, suggesting that DDR may play an important role in ALT induction. Further, somatic mutations of the histone variant H3.3, alpha-thalassemia X-linked syndrome protein (ATRX) and death associated protein (DAXX) have been found in ALT cancers. They are chromatin remodeling factors at telomeres, which are responsible for ALT activity. Furthermore, it has been shown that ATRX inhibits ALT and relates to telomerase assembly and depositing. Although single and double deletion of ATRX and DAXX could not initiate the ALT mechanism, histone management dysfunction and chromatin structure disorder might provide a suitable genomic environment for ALT induction. Lastly, telomerase activity plays very important role in ALT repression. Inhibition of telomerase activity might promote ALT induction. It has been shown that genetic extinction of telomerase in T cells of ATM knockout mice results in tumor emergence, concomitant with the increase of APB and C-circles.
To determine the mechanism by which telomerase-positive cancer cells switch to ALT and to elucidate the mechanism of ALT induction, we induced telomere-specific DNA damage, disrupted the function of the ATRX/DAXX complex and inhibited telomerase activity in telomerase positive cancer cells, which successfully transformed a telomerase-positive cell line into a ALT-positive cell line.
Latest Headlines from Fight Aging!
The Moral Evil of Aging to Death
The author quoted here has written a number of interesting posts on aspects of philosophical thinking pertinent to rejuvenation biotechnology and the goal of bringing an end to the pain and suffering caused by aging. While from my position I see that no more justification is needed for working to greatly lengthen healthy life spans than the fact that some of us want to do it, and that it will make the world a better place for all if successful, there are always those who want more of a story than that. There is of course a small mountain of literature that does indeed go far beyond my brief motivations, but I suspect that this is the case because writing and thinking is easy. Building new technology is much harder, and so, inevitably, there is far more discussion than action for rejuvenation research, just as is the case for every challenging form of human endeavor.
A friend recently recommended a paper by Davide Sisto entitled "Moral Evil or Sculptor of the Living? Death and the Identity of the Subject". Unfortunately I was slightly underwhelmed. While it does contain an interesting metaphor - namely: that we should view death as a valuable 'sculptor' of our identities - it presents this metaphor in a way that bothers me. It presents it as part of critique of the contemporary (transhumanist) view of death as a biological problem that can be solved with the right the technological fix. Indeed, it tries to suggest that those who favour radical life extension are beholden to an absurd metaphysics of death. Now, to the extent that certain transhumanists believe we can achieve a genuine immortality - i.e. an existence free from all prospect of death - I might be inclined to agree that there is something absurd in their views. But I'm not convinced that this fairly represents the views of anti-ageing gurus like Aubrey de Grey. I think they have a much more modest, and I would suggest sensible, view: that human life can be prolonged far beyond the current limits without thereby causing us to lose something of tremendous value to our sense of self.
Ostensibly, Sisto's paper attempts to contrast two views of death. The first view of death is the one that has now started to dominate in the secular, medicalised world. It is the view of death as something that is part of the current natural order. When Christianity dominated the western world, death was viewed as a consequence of original sin. As the Christian view slowly receded into the background, it was replaced by a biological and medical view of death. Death was a consequence of the current natural order - an unfortunate result of biological decay. Our cells slowly degrade and denature themselves. The degradation eventually reaches a critical point at which our metabolically maintained homeostasis breaks down. This results in our deaths (though the precise markers of biological death are somewhat disputed - 'brain death' is the currently preferred view). This naturalised view of death is very different from the old Christian ideal, closely joined to something that the bioethicist Daniel Callahan calls 'technological monism', the belief that everything in the world is, in principle if not in fact, within the reach of our technology. Technological monism suggests that death is not a fixed and immutable feature of our existence. It is something we can - with the right kind of intervention - prevent. We can slow down and reverse our biological ageing. We can preserve our identities for longer than we previously hoped. This 'technologised' view of the world lends support to the belief that death is a moral evil: it is something within our power to fix, and hence we are, morally speaking, on the hook for allowing it to continue.
There is much more in Sisto's discussion of the 'death as moral evil' view, but I think the preceding summary captures the gist. The main argumentative thrust of Sisto's paper comes from the contrast he draws between this view and his own preferred view of 'death as a sculptor'. The essence of this view is that death is not separable from life contrary to what the technological monists want to believe. They want to have a life without death. But this is not possible. Death is a necessary part of life as a whole. It is what gives shape, direction and, above all else, a sense of identity to life. Sisto explains this symbolic idea by reference to the biological process of apoptosis, or programmed cell death. This is a highly regulated biological process whereby cells within an organisms body will kill themselves off when they are no longer necessary for some particular tissue. Sisto makes this example do a lot of work. He argues that the apoptotic process is essential to biological life; that it is what gives the organism its unique identity. He believes that this supports his contention that life and death are inseparable. Death is built into the biological process of being alive. Once you die, your life becomes characterised by the path you took through the space of possible choices. This path contains all your accomplishments and failures, all your loves and losses, all your aspirations and fears. It effectively constitutes your identity. Without death, this lifeline would lose its unique identity. If you had infinite time to play around in, you could travel back down some other paths; take routes through life that you hadn't taken before. Death - the end of choice-making - is what sculpts you from the void of possibilities. I find this metaphor to be very evocative. It really does give you an interesting perspective on the nature of death. But I don't think it is as interesting and useful as Sisto supposes.
Demonstrating Mitochondrial DNA Deletions to Cause Loss of Muscle Fibers
Researchers here demonstrate that mice with a larger number of mitochondrial deletion mutations exhibit a greater age-related loss of muscle fibers, a study that you might compare with past results showing reduced life span resulting from increased mitochondrial mutations. Mitochondria are the power plants of the cell, responsible for generating chemical energy store molecules, descended from symbiotic bacteria, and still bearing the leftover remnant of their original DNA. Mitochondrial dysfunction is implicated in the progression of aging and age-related disease, both from fairly high level measures of age-related changes in mitochondrial function and dynamics in specific tissues, and from an examination of mitochondrial DNA damage and its consequences. Further, differences in the composition of mitochondria correlate strongly with species life span across many types of organism: the more resistant mitochondria are to oxidative damage, the longer the life span.
The evidence to date makes a compelling argument for work on mitochondrial repair of one sort or another as the basis for a rejuvenation therapy, a way to remove this contribution to the aging process. The favored approach for the SENS Research Foundation is to insert suitably edited copies of mitochondrial genes into the cell nucleus as a form of backup, something that is, gene by gene, slowly advancing into commercial development. Deletions in mitochondrial DNA cause problems because they prevent the creation of necessary proteins required for correct function, but if the proteins are also created and supplied from the nucleus, then the expected outcome is that no harm will come from mitochondrial DNA damage.
With age, somatically derived mitochondrial DNA (mtDNA) deletion mutations arise in many tissues and species. In skeletal muscle, deletion mutations clonally accumulate along the length of individual fibers. At high intrafiber abundances, these mutations disrupt individual cell respiration - the electron transport chain (ETC) mechanisms - and are linked to the activation of apoptosis, intrafiber atrophy, breakage, and necrosis, contributing to fiber loss. This sequence of molecular and cellular events suggests a putative mechanism for the permanent loss of muscle fibers with age.
To test whether mtDNA deletion mutation accumulation is a significant contributor to the fiber loss observed in aging muscle, we pharmacologically induced deletion mutation accumulation. Beta-guanidinopropionic acid (GPA), a creatine analogue, induces mitochondrial biogenesis primarily in skeletal muscle. Previous experiments demonstrated that a 7 weeks GPA treatment of 27-month-old rats resulted in an increased incidence (3.7-fold) of ETC abnormal fibers, but did not result in measureable fiber loss. Clonally expanded mtDNA deletion mutations first appear as ETC abnormal fibers at approximately 28 months of age in the hybrid rat. We hypothesized that inducing mitochondrial biogenesis at older ages, when deletion mutation frequency is higher, would explicitly test the role of these mutations in muscle fiber loss. Four months of GPA treatment in 30-month-old rats resulted in a 12-fold increase in ETC abnormal fibers, accelerating cell death, fiber loss and fibrosis, leading to a 22% loss of muscle mass.
In muscle aging, activation of apoptosis and necrosis predominantly occurs in ETC abnormal muscle fibers. The ETC abnormality results from the focal accumulation of mtDNA deletion mutations. As GPA treatment promotes sarcopenic changes through an increase in ETC abnormal fiber abundance, treatment should also accelerate the mitochondrial genotypic changes observed with muscle aging. To test this relationship, we quantitated mtDNA deletion mutation abundances in both muscle tissue homogenates and single muscle fibers. The mtDNA deletion frequency (20%) in tissue homogenates mirrored the increased abundance of ETC abnormal fibers. Similarly, in single fibers, GPA treatment resulted in deletion mutation abundances that exceed the 90% phenotypic threshold for presentation of a respiration deficiency. These data strengthen the causal link between mtDNA deletion mutation and fiber loss and underscore the significance of latent mtDNA deletion mutations.
The Potential Use of Cell Therapies to Treat Immunosenescence
Immunosenescence is the name given to the decline of immune system effectiveness with aging, a large component of the frailty that arises in later life. This decline is partially a result of a failing supply of new immune cells, and partially a result of a growing misconfiguration of the immune system as a whole, driven by life-long exposure to infections. On this second front, persistent infection by herpesviruses such as cytomegalovirus appears to be particularly problematic, the cause of large fractions of the immune cell population in an old individual becoming specialized and unable to react to new threats. This open access paper considers the potential role for cell therapies in reversing immunosenescence, with possibilities that go beyond merely generating and delivering new immune cells to the patient on a regular basis:
Human life expectancy has increased from 40 to 80 years of age just over the past 2 centuries largely due to medical advances. However, it is likely that the human immune system did not evolve to protect the host over such an extended lifespan. Immunosenescence is a term that describes the changes in the immune system that are seen in the aging population. The hallmarks of immunosenescence include a reduced capability to respond to new antigens, increased memory responses, and a lingering level of low-grade inflammation that has been termed "inflamm-aging." Decline of the immune system is associated with increased incidence of infection, immune disease, and cancer in the elderly. While immunosenescence is often described as a decline in the number and function of immune cells, myeloid cells have been shown to increase in the aged population and some secreted peptides are also expressed in greater amounts. Therefore, it is important to keep in mind that immunosenescence is more appropriately conceptualized as a change in the actions of the immune system, rather than an overall decline of all functions and constituents.
The immune system is generated and maintained by asymmetric division of multipotent haematopoietic stem cells (HSCs) in the bone marrow. The immune system has 2 arms, the innate and the adaptive systems, which work together to eliminate pathogens and neoplastic cells, respond to vaccination, and regulate processes such as tissue turn over and wound healing. Increasing evidence shows that HSCs themselves undergo age-related changes and have a limited replicative lifespan. HSC aging was demonstrated by serial transplantation of whole bone marrow, which only supported 4-6 rounds of transplantation, suggesting the possibility of stem cell exhaustion or replicative senescence. In addition, accumulation of DNA damage has a profound impact on HSCs, leading to loss of proliferation, diminished self-renewal, increased apoptosis, and subsequent exhaustion. Differentiation of the HSCs is also affected by aging, where HSCs committed to the myeloid lineage outnumber lymphoid cells in both mice and men.
Rejuvenating the HSCs might improve some of the dysfunction of both macrophages and T-cells, as well as many other cell types, observed in aging. Bone marrow transplantation from a young donor to an elderly patient could be used to rejuvenate the exhausted, aged progenitor pool. However, imperfect tissue matches often lead to rejection and even graft-vs.-host disease, a major hurdle to overcome in many fields of study. Induced pluripotent stem cells (iPSCs) could theoretically be used to generate HSCs from a patient's own cells, thereby eliminating donor-recipient mismatch. Techniques to differentiate HSCs from iPS cells exist, but efficiency and safety are major hurdles that this technology must yet overcome. In addition, genetic reprogramming will likely need to take place ex vivo to prevent collapse of organ function in the intermediate, undifferentiated cell state, so repopulation of tissue resident macrophages and lymphocytes will take several weeks or months from a single bone marrow transplantation. Also, effectiveness of rejuvenated HSCs would be limited by thymic output for T-cells and would likely not replace tissue resident macrophages, which are self-sustaining. However, repopulating the bone marrow with autologous iPSC-derived HSCs is a promising approach to rejuvenating the majority of immune system, especially the innate effector response.
The thymus begins to significantly deteriorate around 10 years of age in humans, and likely plays a role in the decline of the immune system, especially the diversity of the T-cell repertoire, during aging. Rejuvenating or somehow regulating thymic output is an intriguing approach to combat age-related decline of T-cells. Approaches to replacing or regenerating the thymus include tissue and cell transplantation. Transplantation of cultured thymic tissue from human cadavers into the kidney capsule of patients with DiGeorge syndrome successfully restored immune function for up to 10 years. However there are limitations to this approach for treating the aging population due to lack of donated tissue, invasive surgery, and tissue rejection. Regenerative medicine, including tissue engineering and cell and gene therapy, offer alternative approaches to replacing the thymus. Many groups have identified multipotent progenitors, termed thymic epithelial cells (TEC), that can grow into a 3-dimensional thymus and support normal T-cell development when transplanted into the kidney capsule. Human TECs have yet to be isolated in sufficient numbers, however protocols to push human embryonic stem cells toward TEC lineage are becoming consistently more efficient.
Vesicles and Amyloid in Alzheimer's Disease
Researchers have uncovered another way in which growing amounts of amyloid, aggregates of a misfolded protein, can cause dysfunctional cellular behavior in the brain. As presented, this is actually a good example of the way in which research to explore exactly how a disease state progresses tends to focus on the novel mechanisms rather than the known root causes, to the detriment of building better therapies. The right approach is to tackle the root causes, and with greater support for that approach provided by the new knowledge as to why those root causes are in fact damaging. Instead research institutions chase after ways to manipulate newly discovered secondary effects because they are novel and therefore open to patent protection or other forms of ownership:
Vesicles, fluid-filled sacs that brain cells make to trap amyloid, a hallmark of Alzheimer's, appear to also contribute to the disease. Reducing the production of these vesicles, called exosomes, could help reduce the amount of amyloid and lipid that accumulates, slow disease progression and help protect cognition. When confronted with amyloid, astrocytes, plentiful brain cells that support neurons, start making exosomes, to capture and neutralize it. Not unlike a landfill, the real problems begin when the biological sacs get piled too high. In such volume and close proximity to neurons, exosomes begin to interfere with communication and nutrition, neurons stop functioning well and eventually begin to die, a scenario that fits with disease progression.
Scientists followed the process in an animal model with several genetic mutations found in types of Alzheimer's that tend to run in families and make brain plaques early in life. One mouse group also was genetically programmed to make a nonfunctional form of the enzyme neutral sphingomyelinase-2. Amyloid also activates this enzyme, which converts another lipid, called sphingomyelin, into ceramide, a component of the brain cell membrane known to be significantly elevated in Alzheimer's. In fact, with disease, the brain has two to three times more of the lipid. The scientists found exosomes made by astrocytes accelerated the formation of beta amyloid and blocked its clearance in their animal model of Alzheimer's. Male mice, which were also sphingomyelinase-deficient, developed fewer plaques and exosomes, produced less ceramide and performed better in cognitive testing. For reasons that are unclear, female mice did not reap similar benefits; Alzheimer's tends to be more aggressive in women. Earlier work has shown that female mice have higher levels of antibodies in response to the elevated ceramide levels that further contribute to the disease.
The new work is the first evidence that mice whose brain cells don't make as many exosomes are somewhat protected from the excessive plaque accumulation that is the hallmark of Alzheimer's. It is also an indicator that drugs that inhibit exosome secretion may be an effective Alzheimer's therapy. The team is already testing different drugs given to patients for reasons other than Alzheimer's that may also inhibit sphingomyelinase and ultimately ceramide and exosome production.
Increased AMPK Activity Reduces Cancer-Related Loss of Muscle
Researchers here identify AMP-activated protein kinase (AMPK) as important in the loss of muscle that occurs in cancer patients, a wasting syndrome known as cachexia. They manage to reduce cachexia in mice. AMPK shows up in many considerations of metabolism and aging; to pick just a few, it can be used to extend life in flies, and appears to be involved in the mechanisms by which exercise improves health. Its role in these matters may be related to mitochondrial activity and cellular quality control, but like so many of these proteins it is involved in a large number of processes. An open question as a result of this research is the degree to which altered activity of AMPK might be involved in the loss of muscle mass and strength that occurs with aging, known as sarcopenia, or in other wasting conditions.
Healthy fat tissue is essential for extended survival in the event of tumor-induced wasting syndrome (cachexia). Cancer often results in weight loss due to unwanted metabolic complications. This so-called cancer cachexia is accompanied by a poor prognosis with regard to disease progression, quality of life, and mortality. After sepsis, cachexia is the most frequent cause of death in cancer patients. It is not entirely clear which biochemical mechanisms play a role. To date there have also not been any pharmacological possibilities for selectively influencing tumor-associated wasting syndrome.
Researchers have identified the AMP-activated protein kinase (AMPK) as the central enzyme in cancer cachexia. AMPK is normally responsible for protecting cells from energy deficiency. In the case of cancer cachexia, however, AMPK activity is inhibited due to the illness, resulting in a pointless waste of the body's own energy store. Selective AMPK reactivation was successfully carried out in tumor models. The therapeutic manipulation took place through a specific peptide which prevents the interaction between AMPK and the lipid droplet-associated protein Cidea, and which consequently can stop the increased fat breakdown (lipolysis) found in tumor diseases. "Our data suggest that the preservation of "healthy" adipose tissue can promote not only the quality of life, but also the response to treatment and the survival of cancer patients. The interaction between AMPK and Cidea can be taken as a starting point for developing new lipolysis inhibitors which could then prevent the breakdown of energy stores in the fat of tumor patients."
Exercise Associated with a Halved Risk of Cardiovascular Mortality in Older People
This study is a good example of the degree to which the choice to remain active in later life makes a difference. That implies a range of other choices over the decades in order to raise the odds that you can in fact choose to remain active when older, such as avoiding weight gain.
Moderate physical activity is associated with a greater than 50% reduction in cardiovascular death in over-65s. The 12 year study in nearly 2500 adults aged 65 to 74 years found that moderate physical activity reduced the risk of an acute cardiovascular event by more than 30%. High levels of physical activity led to greater risk reductions. The present study assessed the association between leisure time physical activity and cardiovascular disease (CVD) risk and mortality in 2456 men and women aged 65 to 74 years who were enrolled into the National FINRISK Study between 1997 and 2007. Baseline data collection included self-administered questionnaires on physical activity and other health related behaviour, clinical measurements (blood pressure, weight and height), and laboratory measurements including serum cholesterol. Participants were followed up until the end of 2013. Deaths were recorded from the National Causes of Death Register and incident CVD events (coronary heart disease and stroke) were collected from the National Hospital Discharge register.
During a median follow-up of 11.8 years, 197 participants died from CVD and 416 had a first CVD event. When the researchers assessed the link between physical activity and outcome they adjusted for other cardiovascular risk factors (blood pressure, smoking and cholesterol) and social factors (marital status and education). To minimise reverse causality, where worse health leads to less physical activity, patients with coronary heart disease, heart failure, cancer, or prior stroke at baseline were excluded from the analysis. The investigators found that moderate and high leisure time physical activity were associated with a 31% and 45% reduced risk of an acute CVD event, respectively. Moderate and high leisure time physical activity were associated with a 54% and 66% reduction in CVD mortality. "Our study provides further evidence that older adults who are physically active have a lower risk of coronary heart disease, stroke, and death from cardiovascular disease. The protective effect of leisure time physical activity is dose dependent - in other words, the more you do, the better. Activity is protective even if you have other risk factors for cardiovascular disease such as high cholesterol."
Gene Therapy for Mutation Repair as a Cancer Treatment Strategy
The advent of CRISPR/Cas9 is making gene therapy so much cheaper and easier that uses previously rendered impractical are now more plausible to attempt. For example, cancers are driven by a very wide range of mutations, such as those disabling cancer suppression genes. A possible approach is to develop a stable of gene therapies that repair those mutations when they are present, starting with the most common, and thus shutting down cancer cells and halting their growth. The large number of different genes and mutations to target has meant that this strategy would make little sense without the large reduction in the cost of building and deploying gene therapies that CRISPR has created. The challenge of uptake of a gene therapy into cells, how to guarantee that near all cells in a tissue have their genes modified, is still not yet solved, but that will come in the next few years - everyone in the field needs a solution to that problem in order to proceed, and so all eyes are upon it.
CRISPR/Cas9 is likely one of the most revolutionary tools in biotechnology, with tremendous implications for a broad range of biological and medical disciplines. As programmable scissors this technology allows cleavage of DNA at predefined sites in the genome of cells. Now researchers have found a way to utilize the technology to diagnose and inactivate cancer mutations, thereby accelerating cancer research. "Mutations in cancer cells are identified at increasing speed through next generation sequencing, but we mostly do not know, which of these mutations are actually driving the disease and which ones are rather benign." The authors first analyzed how many of the more than 500,000 reported cancer mutations could theoretically be targeted and found that more than 80% of the mutations could be cleaved with the currently most popular CRISPR/Cas9 system. The research group then demonstrated that they could specifically cleave a panel of common cancer mutations without significantly targeting the healthy, wildtype alleles.
Moreover, expression of Cas9 together with the cancer-specific guide (g)RNAs was able to unmask mutations that drive cell growth and viability in cancer cell lines. "This is an important advance, because we can now rapidly separate driver from passenger mutations. This is currently a bottleneck in cancer research. Because each cancer shows a specific combination of many mutations, this scientific approach could improve cancer diagnostics as mutations that promote cancer growth could be specifically identified. Based on the obtained results an individualized therapy could be initiated.
A Review of Heavy Isotopes and Slowed Aging
Heavy isotopes are variants of atoms with one or more extra neutrons. Only some configurations are stable, such as the deuterium in heavy water, hydrogen with an extra neutron, or carbon-14, containing two more neutrons than the standard carbon atom. The chemical properties of a heavy isotope are slightly different, usually too slight to matter: heavy water is the exception to the rule, as it is toxic in large amounts, while heavy carbon isotopes appear to have little to no effect on living organisms. In recent years it has been shown that raising short-lived species, those with quite plastic life spans, on a low dosage of heavy water appears to modestly slow aging. This may be because it grants greater resistance to oxidative damage for some important parts of cell's molecular machinery, but may also simply be a matter of hormesis, in that a low level of damage or toxicity triggers greater levels of cell maintenance and repair, leading to a net benefit. From a practical point of view, this, like all ways to modestly slow aging, is probably only of interest as a tool for those researchers attempting to map the biochemistry of aging. It isn't a path to rejuvenation.
In a recent effort to look for the intrinsic factors that cause aging, we have discovered a potential candidate. By examining the intracellular small-molecule metabolites in yeast cells undergoing aging, we found that as yeast cells age, the overall heavy isotopic content, such as that of carbon-13, nitrogen-15, and hydrogen-2 (deuterium) declines in the amino acids, an essential group of metabolites that serve as building blocks in protein biosynthesis and precursors in all living organisms. Moreover, supplementing heavy isotopes through nutritional uptake extends the lifespan of yeast by more than 80% in aging assays, likely via eliciting a dietary-restriction-like effect. If this observed trend represents a wide-spread phenomenon in the isotopic composition of the metabolome, proteome, and genome in other organisms as well, new perspectives on understanding aging and retarding the end of life may open up.
Before our observation of heavy isotope decline during organismal aging, deuterium-bearing heavy water has been shown to promote longevity or improve certain health aspects in several organisms, including fruit flies, rodents, and humans. In fruit flies, transient exposure to heavy water at juvenile stages extends lifespan, and the exposure does not affect the health and reproduction. However, a dosage of 50% heavy water shortens the lifespan, and the relative lifespan shortening by heavy water was ameliorated by temperature elevation from 10 to 30°C, suggesting a protective effect of heavy water on fruit fly survival in hot conditions where accelerated metabolic rate normally reduces longevity. Improved thermoresistance was indeed observed at the protein, cell, and organism levels in fruit flies upon heavy water treatment. Similarly, a driving factor in temperature-compensated effects by heavy water was observed to alter the phase relation in circadian oscillation. The heavy water effect is increasingly more pronounced with rising temperature. However, the mechanism is still unknown. The similarity in the biological responses between heavy water and low temperature also correlate well with the general observation that fruit flies and worms have longer lifespan, and retarded brain degeneration when maintained at low temperature.
Several functional studies have shown that deuterated polyunsaturated fatty acids, even supplied in a minor fraction (20-50%), can protect yeast and mammalian cells from reactive oxygen species (ROS) damage to mitochondria. In whole animals, 25% heavy water was able to normalize high blood pressure induced by high salt diet in rats, possibly through suppressing hypertension-related elevation in calcium uptake. These effects would surely extend lifespan. In yeast, we also showed that heavy water extends chronological lifespan in a dosage-dependent manner. This pro-longevity effect could be essentially abrogated by mild dietary restriction or mitochondrion removal. Heavy water also suppresses the endogenous ROS generation, which could ameliorate the background chemical damages from ROS and lead to long-term improvement in fitness and survival rate. All these protective effects indicate that heavy water functions as a metabolism modifier to promote longevity, a feature that could be amenable to implementation in the context of other well-known anti-aging interventions.
Alzheimer's Disease has the Look of a Condition Built of Multiple Causes
As a companion piece to the news of amyloid clearance in Alzheimer's patients from earlier this week, in which the outcome was not enough of an improvement to suggest that amyloid accumulation is the only issue, this article looks at a range of recent evidence for Alzheimer's disease to be a condition with multiple significant causes, some of which may be fairly independent of one another.
When pursuing an elusive beast, hunters look for the traces it leaves behind as clues to its whereabouts. Geneticists are employing a similar method to hunt variants linked to Alzheimer's disease (AD), with changes in the brain representing the variants' traces. By correlating biomarker changes with genetic factors, researchers gain clues to the mechanism of action of these genes. A common theme emerged when various groups reported finding distinct sets of factors that influenced amyloidosis versus tau degeneration. The findings imply that these processes have different underlying causes. Other research homed in on specific genes involved in atrophy, in some cases analyzing known AD genes for associations. To many researchers, the data reinforce that to prevent the progression of AD it will be important to treat not only factors that affect amyloid, but also those that affect neurodegeneration.
Previous data have long identified a disconnect between amyloid and atrophy. The regions affected by each form distinct, though overlapping, patterns in the brain. In addition, many older people have brain atrophy without amyloid accumulation. Researchers wondered if amyloid and atrophy might involve distinct risk and protective factors. To test this idea, they analyzed data from Mayo Clinic Study of Aging participants aged 70-90. The cohort comprised 713 cognitively healthy controls, 148 people with mild cognitive impairment, and 12 with AD dementia. For amyloidosis, as expected, older age and the presence of an ApoE4 allele heightened risk. Being a man, or having ApoE2, protected against plaques. However, little else affected amyloid deposition. In contrast, many factors contributed to atrophy. Lifestyle choices such as smoking associated with brain shrinkage, as did numerous chronic diseases of aging, such as hypertension and diabetes.
The data argue that Alzheimer's progression is more complex than simply amyloidosis driving tangles that in turn drive atrophy. Instead, different factors affect each process. The researchers tweaked the common AD analogy that amyloid acts as the gun and tau the bullet by saying that amyloid is the gun and degeneration the bullet. The speed of the bullet varies, they believe, based on risk factors that have nothing to do with amyloid. How do tau tangles fit in? Neurodegeneration has often been thought of as synonymous with tangles, but tau PET imaging data has now made clear that the brain can shrink without any tangles present. To specifically compare risk factors for amyloidosis, for tangles, and for atrophy, researchers analyzed a smaller cohort of 326 cognitively normal participants who had undergone tau imaging. They found that amyloidosis was the main factor driving tau pathology, in agreement with recent imaging studies. In turn, tangles drove some atrophy. However, here, too, the researchers calculated that many other factors affected neurodegeneration independently of amyloid or tau deposits.
An Example of Poor Correlation Between Telomere Length and Health
Telomeres are lengths of repeated DNA at the ends of chromosomes. Telomeres shorten with each cell division, and when they get too short cells self-destruct or become senescent. Thus their average length in any particular tissue, in our species at least, where other factors are less important, is a function of how often cells divide and how often the stem cells supporting that tissue deliver replacement cells with long telomeres. Telomere length is presently measured in immune cells from a blood sample, and this introduces a whole range of other influences based on the current status of the immune system. Average telomere length is fairly dynamic for any individual in response to circumstance and illness, and when measured across large populations tends to trend downwards with aging - which one might expect given the decline in both immune system and stem cell function that occurs in later life. Variation is large between individuals, however, and when looking at any specific individual it really isn't clear that measurement of telomere length is of much practical use in medicine: it is a terrible candidate for a biomarker of aging and health in that respect.
Telomeres are nucleoprotein complexes that cap the ends of linear chromosomes. Telomeric DNA decreases with age and shows considerable heterogeneity in the wider population. There is interest in the application of telomere length measures as a biomarker of general health or "biological age," and the possibility of using mean telomere length to gauge individual disease risk, and to promote lifestyle changes to improve health. This study examined the effectiveness of telomere length as a biomarker for an individual's current overall health status by assessing several measures of general health including SF-36v2 score, current smoking status and a comprehensive obesity phenotype. Participants were from the Canterbury Health, Ageing and Lifecourse (CHALICE) cohort, a New Zealand population based multidisciplinary study of aging. Telomere length measurements were obtained on DNA from 351 peripheral blood samples at age 49-51, using a quantitative polymerase chain reaction assay.
No associations were found between telomere length measured at age 49-51 and any measures of current health status. The only significant association observed was between telomere length and gender, with females having longer telomere length than men. Our results suggest that telomere length measurements are unlikely to provide information of much predictive significance for an individual's health status.