Fight Aging! Newsletter, October 17th 2016

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

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  • A Newfound Interest in Mapping the Signs of Cellular Senescence
  • The Prospect of Regenerative Heart Therapies Using Immune-Matched Donor Cells
  • Application of Ultrasound Appears to Slow Age-Related Changes in Neural Structure
  • Interfering in a Later Stage Mechanism of Tauopathy Can Restore Some Lost Cognitive and Memory Function
  • A Calorie Restricted Medical Diet, to be Filed Next to Selling Ice to Eskimos
  • Latest Headlines from Fight Aging!
    • Investigating Declines in Speech Processing with Age
    • The Development of Targeted DNA Methylation Editing
    • Suggesting that Vascular Dementia Accounts for Alzheimer's Trial Failures
    • MIF as a Path to Reduce Cell Death Following Stroke
    • Are Lifespan and Healthspan Strongly Coupled?
    • Suppressing ANGPTL2 Slows the Progression of Heart Failure
    • Recent Progress on Senescent Cell Clearance at SIWA Therapeutics
    • More Evidence for Transthyretin Amyloid to Associate with Osteoarthritis
    • Can Rejuvenation Biotechnologies Stop Cancer from Developing in the First Place?
    • Further Assessment of the Effects of Young Ovaries Transplanted into Old Mice

A Newfound Interest in Mapping the Signs of Cellular Senescence

Now that selectively clearing senescent cells from aged animals has been proven to produce benefits to health, tissue function, and life span, and its role in aging is well appreciated, there is a lot more interest in the research community in mapping out the biochemistry of these cells. Up until about five years ago, it was a real challenge to generate both this interest and the funding to sustain it, but better late than never. Below I'll point out a few recently published items in that theme, representative of much more work that is presently taking place. Researchers not actively working on methods of senescent cell destruction are looking for better definitions of what exactly constitutes cellular senescence, better biomarkers for these cells, and a better understanding of how exactly a comparatively small number of these cells can cause such harm to the rest of the tissue that contains them. This is all largely irrelevant to the first generation of senescent cell clearance therapies under development in companies like Oisin Biotechnologies and UNITY Biotechnology - the existing targets and methodologies are good enough for a first pass. When the second generation of therapies are under construction, however, the burning question will be the degree to which they are improvements over what already exists.

Cells become senescent in response to damage, the consequence of toxic and cancer-prone environments, or once they reach the Hayflick limit imposed on cell divisions for ordinary somatic cells. Senescent cells also transiently arise as a part of the wound healing process, and further are involved in shaping the body during embryonic development. Senescence predisposes a cell to self-destruction, and most destroy themselves via apoptosis. Those that do not self-destruct still remove themselves from the cell cycle of replication and begin to secrete a potent mix of molecules that spur inflammation, restructure the nearby extracellular matrix, and encourage surrounding cells to change their behaviors in a range of ways, few of them good in the long term. The immune system is attracted to these cells and destroys those that do not self-destruct, but nonetheless some senescent cells linger. That number grows with age, to the point at which a few percent of all the cells in a tissue or organ might be senescent. These cells collectively cause significant harm, by destroying functional structures in complex tissue, by secreting signals that alter and degrade function in healthy cells, and by producing enough chronic inflammation to meaningfully speed progression of age-related disease.

Given sufficiently comprehensive clearance of senescent cells, all of these contributions to the process of aging will go away, and we'll be healthier and longer-lived as a result. The first generation therapies are at present clearing as many as half of the identified senescent cells in a single treatment in laboratory mice. It remains to be seen how much that can be improved through longer treatment programs and tweaking the present treatment methods. It is interesting to ask whether the currently identified cells represent the full count of senescent cells, and whether or not they represent multiple different types of senescence, some better or worse for health than others. The answers to that will come in time, but the research and development community will still produce pretty good therapies in advance of those lines of further inquiry reaching their conclusions.

New method to detect ageing cells - and aid rejuvenation therapies - developed by researchers

Scientists have discovered a new way to look for ageing cells across a wide range of biological materials; the new method will boost understanding of cellular development and ageing as well as the causes of diverse diseases. Frustrated by the limitations of commercially available biomarkers the researchers have developed a universally applicable method to assess senescence across biomedicine, from cancer research to gerontology. Cellular senescence is a fundamental biological process involved in every day embryonic and adult life, both good - for normal human development - and, more importantly to researchers, dangerous by triggering disease conditions. Up to now available senescence detecting biomarkers have very limited and burdensome application. Therefore, a more effective, precise and easy-to-use biomarker would have considerable benefits for research and clinical practice. "The method we have developed provides unprecedented advantages over any other available senescence detection products - it is straight-forward, sensitive, specific and widely applicable, even by non-experienced users. In addition to helping researchers make significant new breakthroughs into the causes of diseases - including cancer - through more effective understanding of senescence in cells, the new process will also aid the impact of emerging cellular rejuvenation therapies. By the better identification - and subsequently elimination of - senescent cells, tissues can be rejuvenated and the health span extended."

Genes that control cellular senescence identified - Potential applications for cancer treatment and development of anti-aging products

The research group had previously discovered that cell senescence was effectively induced by using low concentrations of anticancer drugs on cancerous cells. In anticancer treatment, drugs are carried to the cancerous tissue via the bloodstream. The researchers predicted that differences in concentrations of the anticancer drugs would arise based on the distance of the cells from the blood vessels, and so even in the normal cancer treatment process senescent cells would emerge. Therefore, if we simultaneously administer a medicine that inhibits cell senescence during standard cancer treatment, there is the potential for a dramatic increase in treatment effectiveness. Previously the research group found that if cancerous cells are treated with a low concentration (10 μM) of the anticancer drug etoposide this induces cell senescence, and if they are treated with a high concentration of the drug (100 μM) this induces apoptosis. For this research, they treated cancerous cells under three different conditions: A) with no etoposide; B) with a low dose of etoposide (10 μM); and C) with a high dose of etoposide (100 μM). They then used DNA microarrays to identify the genes in which a rise in transcription levels could be observed.

They predicted that genes which showed increased expression in response to treatment B were mainly related to cell senescence, genes expressed in response to C were mainly those involved in apoptosis, and among the genes which specifically showed increased expression in B compared to C would be genes that play an important role in implementing cell senescence. There were 126 genes where three times as much expression was recorded under treatment B compared to A, and 25 genes that showed twice as much expression in B compared to C. These 25 genes are expected to express specifically in senescent cells since the other factors caused by DNA damage are removed, and researchers confirmed that the genes involved in causing cell senescence were among them. If we can develop a drug that targets and regulates the activity of the genes that control senescence identified in this research, by administering it together with conventional anticancer treatment we can limit the emergence of senescent cells and potentially increase the effectiveness of cancer treatment. Additionally, it has been reported that one of the causes of individual aging is the accumulation of senescent cells. This means that drugs which control cell senescence could have potentially large benefits for the development of anti-aging medication products.

CellAge Database of Cell Senescence Genes

Cell senescence can be defined as the irreversible cessation of cell division of normally proliferating cells. Human cells become senescent from progressive shortening of telomeres as cells divide, stress or oncogenes. Primarily an anti-tumour mechanism, senescent cells accumulate with age in tissues and have been associated with degeneration and ageing of whole organisms. Many proteins have been linked to cell senescence as biomarkers and as causal drivers. To facilitate studies focused on cell senescence, we developed CellAge, a database of genes associated with cell senescence. Our manually-curated data is based on gene manipulation experiments in different human cell types. A gene expression signature of cellular senescence will also be made available in due course. CellAge is in the beta phase of development and therefore still being improved and expanded. Collaborations and contributions are welcomed, please contact us if you wish to be involved.

The Prospect of Regenerative Heart Therapies Using Immune-Matched Donor Cells

Cell therapies involving transplantation from immune-matched donors go a long way back; think of the bone marrow transplants used in a variety of circumstances, for example. These were a way to ferry across stem cells before it was possible to extract and manage those stem cells in a clinical setting, and the approach is sufficiently advantageous and practiced to remain in use, even as cell based regenerative medicine is reaching the clinic. In the research I'll point out today, scientists take a little of that older world of patient matching to avoid immune rejection and a little of the new world of using small, easily obtained cell samples from a donor, such as blood or skin, to reprogram and culture a large number of cells of the desired type for transplantation. In this case they turn this mixed approach to heart regeneration, and demonstrate the ability to produce benefits following heart attack in monkeys.

The heart is not a very regenerative organ in mammals. Mammalian tissues span a range of willingness to heal, from the liver at one extreme, capable of regrowing lost sections, to the brain and the heart at the other, both of which exhibit little ability to recover from injury. Both ends of the range make for interesting targets for regenerative research: the liver because it seems like an easier starting point, and the brain and the heart because any improvement is significant given the present situation. Cell therapies for the heart have been underway within and outside the formal regulated system of trials for more than fifteen years, but at this point the effectiveness of the various strategies that have arisen is still something of a question mark. Better than nothing, but how much better? A wider range of approaches is available via medical tourism than has been rigorously tested, and the rigorous tests in trials and animal models have exhibited a sizable variation in outcomes. It seems clear that the methodology used is a very important determination of the outcome given the present state of the field: you can't just throw stem cells into a patient and hope for the best. That said, that strategy actually does seem to work fairly well when well-established and well-characterized cell types are used and the goal is reduction of chronic inflammation, which is why there is a high expectation of benefits to result from mesenchymal stem cell therapies for age-related joint pain and similar issues. Regenerative therapies for organs like the heart are a whole other ball game, however, and still a work in progress.

Stem cells regenerate damaged monkey heart

Cardiac muscle cells grown from the stem cells of one macaque monkey can be used to regenerate the hearts of other macaques. The transplanted cells improved the heart's ability to contract after an induced heart attack and integrated with no sign of rejection by the recipient's immune system. However, the recipient's heart did suffer from an irregular heart beat in the first four weeks after the transplant, but this passed and was non-lethal. Researchers used cardiac muscle cells derived from induced pluripotent stem cells (iPSC-CMs) from a donor instead of the patient's own cells. Donor cells are considerably easier to manufacture but increase the risk of being rejected by the recipient's immune systems. The scientists overcame this by matching a surface protein on the donor and recipient's cells that is used by the immune system to recognize foreign cells.

"We found that monkey iPSC-CMs or cardiac muscle cells derived from induced pluripotent stem cells survived in the damaged monkey heart and electrically coupled with the host heart. In addition, the heart's ability to contract was partially recovered by the transplantation. We had a hard time handling monkey iPS cells. Unlike human iPS cells, they are somewhat tricky. The condition of iPS cells are critical for generating high purity cardiac muscle cells. Also, it took a long time to get grafted cardiac muscle cells to survive in the recipients. In addition to daily treatments of immunosuppressant drugs, we made sure the surface protein major histocompatibility complex (MHC), which is used by the immune system to recognize foreign cells, was carefully matched on the donor and recipient's cells. Human embryonic stem cell-derived cardiac muscle cells have already been used in clinic as a new therapy for post myocardial infarction (MI) heart failure. But I think it will take at least a couple of years for this treatment to become more widely-used."

Allogeneic transplantation of iPS cell-derived cardiomyocytes regenerates primate hearts

Induced pluripotent stem cells (iPSCs) constitute a potential source of autologous patient-specific cardiomyocytes for cardiac repair, providing a major benefit over other sources of cells in terms of immune rejection. However, autologous transplantation has substantial challenges related to manufacturing and regulation. Although major histocompatibility complex (MHC)-matched allogeneic transplantation is a promising alternative strategy, few immunological studies have been carried out with iPSCs. Here we describe an allogeneic transplantation model established using the cynomolgus monkey (Macaca fascicularis), the MHC structure of which is identical to that of humans. Fibroblast-derived iPSCs were generated from a MHC haplotype (HT4) homozygous animal and subsequently differentiated into cardiomyocytes (iPSC-CMs). Five HT4 heterozygous monkeys were subjected to myocardial infarction followed by direct intra-myocardial injection of iPSC-CMs.

The grafted cardiomyocytes survived for 12 weeks with no evidence of immune rejection in monkeys treated with clinically relevant doses of methylprednisolone and tacrolimus, and showed electrical coupling with host cardiomyocytes. Additionally, transplantation of the iPSC-CMs improved cardiac contractile function at 4 and 12 weeks after transplantation; however, the incidence of ventricular tachycardia was transiently, but significantly, increased when compared to controls. Collectively, our data demonstrate that allogeneic iPSC-CM transplantation is sufficient to regenerate the infarcted non-human primate heart; however, further research to control post-transplant arrhythmias is necessary.

Application of Ultrasound Appears to Slow Age-Related Changes in Neural Structure

Use of ultrasound as a tool is commonplace in medicine these days, with applications ranging from tissue imaging to breaking up dental plaque to destruction of kidney stones. Many of the effects, actual and potential, at the cellular level are still being explored, however, and they range from the merely intriguing to the very promising. For example, ultrasound appears to speed wound healing in aged skin. More relevant to the research presented here, ultrasound applied to the brain makes the blood-brain barrier leak a little, enough to spur the immune system into greater productive activity. In mice this has been shown to improve cognitive function as well as produce some clearance of the metabolic waste known as β-amyloid that is associated with Alzheimer's disease.

There are lengthy and poorly mapped chains of cause and effect spanning the gap between the application of ultrasound and end results such as amyloid clearance. Which mechanisms are relevant, and how exactly the ultrasound produces the end results of interest, is a line of work that remains very open to hypothesis, competing evidence, and debate. If we consider the effects on the blood brain barrier noted above, it is worth bearing in mind that growing age-related dysfunction and leakage in this structure is thought by many in the field to be a part of the problem in the aging brain. The purpose of the barrier, which lines blood vessels in the brain, is to keep the environment of the brain insulated from that of the rest of the body. Leakage encourages greater levels of neural inflammation and contributes to early development of Alzheimer's disease. So how is it that brief disruption can be as beneficial as long-term disruption is harmful? Nothing is simple when it comes to cellular biochemistry and the progression of aging.

The question of mechanisms is particular pronounced in the research linked below, in which researchers examine the fine structures of dendrites in one area of the brain and how those structures change over time. Dendrites are a part of the structure of the synapses that link neurons into networks. They are decorated with spines that some research suggests are the form in which the data of memory is encoded in the brain. Synapses, dendrites, and spines all change over time, and in characteristic ways with aging. With the application of ultrasound, this age-related change appears to be reduced, but there is no shortage of places to start fishing for the reasons why that might be the case. One could build a career simply trying to fill in the gaps in this picture.

Research finds that ultrasound slows brain ageing

Research shows that scanning ultrasound prevented degeneration of cells in the brains of healthy mice. "We found that, far from causing any damage to the healthy brain, ultrasound treatments may in fact have potential beneficial effects for healthy ageing brains. In a normal brain the structure of neuronal cells in the hippocampus, a brain area extremely important for learning and memory, is reduced with age. What we found is that treating mice with scanning ultrasound prevents this reduction in structure, which suggests that by using this approach we can keep the structure of the brain younger as we get older. We are currently conducting experiments to see if this preservation of the brain cell structure will ameliorate reductions in learning and memory that occur with ageing." In the next stage of research, the team will test the effect of ultrasound on the brain structure and function of older mice.

Scanning Ultrasound (SUS) Causes No Changes to Neuronal Excitability and Prevents Age-Related Reductions in Hippocampal CA1 Dendritic Structure in Wild-Type Mice

Recently, our group has reported that repeated scanning ultrasound (SUS) treatments reduced the amyloid plaque pathology in a transgenic mouse model of Alzheimer's disease (AD) and improved hippocampal-dependent spatial memory performance by activating brain-resident microglia. In this approach, ultrasound was combined with microbubbles to disrupt the blood-brain barrier (BBB) which is achieved by mechanical interactions between the microbubbles and the blood vessel wall as pulsed focused ultrasound is applied, resulting in cycles of compression and rarefaction of the microbubbles. This leads to a transient disruption of tight junctions and the uptake of blood-borne factors by the brain, which are likely to have a role in the activation of microglia that were found to take up amyloid into their lysosomes.

However, the short- and long-term effects of SUS treatment on individual neuronal action potential (AP) firing and dendritic morphology have not been investigated. To address this issue, we evaluated the physiological effects of both a single and multiple SUS treatments on short- and long-term neuronal excitability, dendritic morphology and dendritic spine densities in the CA1 region of the hippocampus of wild-type mice. This allowed us to determine the effect of different SUS treatments in a non-disease state system before eventually moving to a more complicated disease model, where alterations in neuronal function are already present at an early age. For example, reductions in dendritic spine density, AP firing, synaptic activity and long-term potentiation (LTP) have all been reported to occur in amyloid-depositing mouse models of AD.

In our study using wild-type mice, we found that the different SUS treatment regimes had no deleterious effect on neuronal function or morphology. In addition to this we made the interesting observation that repeated SUS treatments prevented reductions in the dendritic complexity and length of CA1 pyramidal neurons that occur in age-matched sham-treated wild-type mice over the course of three months, while a reduction in dendritic spine density was not halted. Taken together, these findings suggest that multiple SUS treatments ameliorate a reduction in the total number of dendritic spines per neuron. A more extensive follow-up study will determine, whether SUS treatments improves cognition in aging mice and what the underlying mechanism is of such an effect.

Age-associated reductions in the structure of neuronal dendritic trees have previously been reported in a range of brain areas and species. However, our understanding of changes in dendritic tree arborization in the hippocampus is less advanced, where both increases and decreases in CA1 pyramidal dendritic length and complexity have previously been reported. While a number of differences exist between these reports and the current work, perhaps the most important is the duration of ageing over which changes in dendritic tree structure was quantified (approximately 1.5 years versus 3 months in the current study). This is a limitation of the current study when evaluating changes in dendritic structure associated with ageing. Further experimentation will be required to assess changes in dendritic tree structure over longer time periods. Despite this, it is evident that multiple SUS treatments are able to prevent reductions in dendritic structure.

Also, the question of how SUS preserves dendritic structure remains to be determined. One possibility is that microglia may play a role, because SUS treatment has previously been reported to activate this cell-type in mouse models as well as in wild-type mice. Microglia constantly probe their local environment and secrete factors that alter neuronal signalling. During activation they can also modify synaptic connections, the key mediators of learning and memory, by increasing the expression of neurotrophins such as brain-derived neurotrophic factor (BDNF). In fact, a recent study has reported that microglia mediate synapse loss at an early time-point in Alzheimer's disease mouse models. One possible mechanism for the neurotrophic effect of SUS may therefore be the delivery of endogenously circulating neurotrophic factors from the blood to the brain. Furthermore, ultrasound waves by themselves, without the need for BBB opening, may also contribute to the observed preservation of dendritic structure, as increased BDNF expression has been reported following ultrasound application. Other neurotrophic factors such as glial cell-derived neurotrophic factor (GDNF) and vascular endothelial growth factor (VEGF) have also been linked to improve memory performance in rats following ultrasound treatment.

Interfering in a Later Stage Mechanism of Tauopathy Can Restore Some Lost Cognitive and Memory Function

In the research linked below, scientists describe a potentially beneficial point of interference in a tau-related mechanism of neurodegeneration: targeted sabotage of this mechanism can restore lost cognitive function and otherwise turn back some of the effects of a tauopathy, at least in the engineered mouse lineages used. Tauopathies are neurodegenerative conditions characterized by an accumulation of altered forms of tau protein, forming solid fibrils and tangles in brain tissue. Alzheimer's disease is perhaps the most familiar of these conditions, and there is still considerable debate over the degree to which the harm to brain cells and cognitive function is caused by amyloid-β versus tau in that case. For both proteins the situation is somewhat similar: a lot of work focused on how the deposited solid aggregates relate to mechanisms of cell death and dysfunction, as well as why it is that older people have more of these aggregates, and so far frustratingly limited progress towards therapies capable of clearing out these forms of metabolic waste, despite years of large-scale investment. Many researchers are, however, focused less on clearance than on altering the operation of brain biochemistry in the presence of tau and amyloid: finding ways to short-circuit the worst consequences rather than finding ways to remove the root causes. I can't say I think that this is a wise high-level strategy, but it is very prevalent in the research community.

Why does the presence of the insoluble form of tau increase with age? One possibility is shared with amyloid, that the clearance and filtration mechanisms operating on cerebrospinal fluid decline in later life. That might include dysfunction in the choroid plexus, responsible for filtration, or dysfunction in the drainage system of small fluid passageways behind the nose. The creation and removal of these aggregates is actually fairly dynamic, and the outcome only looks like a slow and steadily increase because the imbalance between that creation and removal grows slowly and steadily. Another possible cause of growing levels of tau is the age-related decline in immune function, just as apparent in the brain as elsewhere in the body. Immune cells are responsible for clearing out waste, among many other tasks, and when they are less efficient we might expect levels of all forms of waste between cells to increase. At the detail level of biochemistry and mechanisms, however, a great deal of uncertainty remains. There is considerable debate and a great deal of published research covering efforts to catalog how and why the presence of tau increases with age, and how and why it does so to a larger degree in only some people. It is a complex field, still in progress towards definitive answers.

In the ideal world, this lack of knowledge could be treated as a Gordian Knot and cut with some form of therapy that efficiently removed tau aggregates. That would very quickly and clearly pin down the importance of the role of tau in neurodegenerative disease and cell death. It isn't the chosen strategy for much of the research community, however, and there is typically more of a focus on the class of approach illustrated below, in which downstream mechanisms in a disease brain are mapped and then manipulated. The root cause remains, able to cause harm via any of the other, yet to be mapped consequences: keeping a damaged machine running without repairing that damage is typically much harder than just focusing on repair. It is possible to achieve beneficial outcomes by following this strategy, as is the case here, but they will typically only deal with a fraction of the issue or only slow the progression of the condition. Still, within the context of the strategy chosen here, and with the caveat that work in mouse models for amyloid and tau pathologies has a poor record of success when it comes to making the leap to human medicine, this seems promising. Those in the audience who have followed research into Alzheimer's and amyloid-β over the past decade might find that there are a number of parallels in the results presented here and some of the discoveries made of how amyloid gives rise to harmful effects on cells - also quite indirect in its relationship with the aggregrated solid form of the protein.

Untangling a cause of memory loss in neurodegenerative diseases

Using a mouse model of tauopathy that produces a mutated form of human tau protein, researchers correlated memory deficits with the presence of a fragment of the tau protein. The tau fragment, which is produced when caspase-2 cuts the full-length tau protein at a specific location, was also found at higher levels in the brains of Alzheimer's disease patients compared to healthy individuals of the same age. While the standard hallmark of tauopathies is the appearance in brain tissue of large tangles of abnormal tau protein, it has recently become less clear whether the tangles of tau are actually causing cognitive decline. "In the past, many studies focused on the accumulation of tangles and their connection to memory loss, but the more we learn, the less likely it seems that they are the cause of disease symptoms. The pathological fragment of tau that we have identified resists forming tangles and can instead move freely throughout the cell. Therefore, we decided to look for other mechanisms that could affect synaptic function."

The researchers used fluorescent labeling to track and compare the behavior of normal and mutated tau in cultured neurons from the rat hippocampus, the brain region most associated with learning and memory. Unlike normal tau, both mutated tau and the short fragment produced when caspase-2 cuts tau were primarily found within structures called dendritic spines, where neurons receive inputs from neighboring cells. The overabundance of mutated tau, including the caspase-2-produced fragment, caused disruptions in synaptic function in the spines. The impact on synapses was specific, with no observed effects on the overall structure or survival of the neurons. "It appears that abnormally processed tau is disrupting the ability of neurons to properly respond to the signals that they receive, producing memory deficits independent of tangle formation. Because this effect is occurring without cell death or a loss of synapses, we have a better chance of intervening in the process and hopefully reversing symptoms of the disease."

Caspase-2 cleavage of tau reversibly impairs memory

In Alzheimer's disease (AD) and other tauopathies, the tau protein forms fibrils, which are believed to be neurotoxic. However, fibrillar tau has been dissociated from neuron death and network dysfunction, suggesting the involvement of nonfibrillar species. Here we describe a novel pathological process in which caspase-2 cleavage of tau at Asp314 impairs cognitive and synaptic function in animal and cellular models of tauopathies by promoting the missorting of tau to dendritic spines. The truncation product, Δtau314, resists fibrillation and is present at higher levels in brains from cognitively impaired mice and humans with AD. The expression of tau mutants that resisted caspase-2 cleavage prevented tau from infiltrating spines, dislocating glutamate receptors and impairing synaptic function in cultured neurons, and it prevented memory deficits and neurodegeneration in mice. Decreasing the levels of caspase-2 restored long-term memory in mice that had existing deficits. Our results suggest an overall treatment strategy for re-establishing synaptic function and restoring memory in patients with AD by preventing tau from accumulating in dendritic spines.

A Calorie Restricted Medical Diet, to be Filed Next to Selling Ice to Eskimos

One of the more recent innovations in calorie restriction research has nothing to do with the science, and everything to do with figuring out how to pull more funding into the field. There is never enough funding for research in any field: going by how funds flow through our societies, it is easy to say that to a first approximation no-one really cares about progress in medicine. Bread and circuses, yes. Better technologies, better understanding of biology, and less disease, no. There is also a large difference between the funds available for non-commercial research versus money available and interested in investment in for-profit ventures. The latter is at least ten times the former, and much more easily arranged as well. Writing grants and raising philanthropic funding is a considerably harder job than pitching angels and venture firms; more effort for less money at the end of the day. But without the funding for non-profit research initiatives, there will be no new technologies ready to be carried forward in for-profit companies. It is one of the great frustrations of patient advocacy to know that the owners of countless millions in potential funding are sitting on their hands, waiting for viable biotech companies, while the important research projects that will generate those companies struggle to raise hundreds of thousands to sustain shoestring budgets.

Calorie restriction is a particular challenge in this context. It is a lifestyle choice, not a drug or an antibody or something else that the medical industry understands how to package, market, and sell. It is nothing more than eating sensibly and eating less. Anyone can choose to do it. It is free and straightforward and well-documented. Yet the effects on long-term health and aging in ordinary individuals are much larger than anything that can be generated by the presently available panoply of drugs and other interventions. That, I should say, is more a statement on the poor quality of present medicine when it comes to treating aging as a medical condition than it is on the benefits of calorie restriction. It is a case of something being better than nothing: no presently available medicine deliberately addresses the root causes of aging, for all that the first therapies that will do that are in development at various stages. The nature of calorie restriction means that there has been little to no for-profit investment aiming to better characterize its benefits. Rather, all that funding was directed towards mapping the biochemistry and haphazardly testing the established drug libraries to find something that triggered any of the same effects. The search for such calorie restriction mimetics is well documented elsewhere, so I won't dwell on that, beyond noting that the outcome of ten to fifteen years of work and a great deal of money is, so far, nothing of any practical use.

So to calorie restriction itself, and how to obtain for-profit funding for research into eating less, and eating less in an effective way. The innovators here are Valter Longo and colleagues, who have achieved the goal of pulling in for-profit funding on the backs of turning specific implementations of fasting and low-calorie diets into FDA-approved therapies, such as an adjuvant in cancer treatment. The magic of regulation means that companies can manufacture a medical diet on the basis of research, and then use the barriers set up via intellectual property and regulatory pronouncements to charge an inordinate amount for what is, basically, a little bit of food that anyone could throw together after reading the papers to obtain the target calories, protein, micronutrient levels, and so on. That in turn means that the principals of these companies are willing to pay for the supporting research. On the one hand it's a depressing example of the distorted priorities that emerge from regulation of medicine, on the other one feels a certain admiration for Longo et al for having successfully hacked the system to fund the useful results they have produced these past few years. Quantifying the degree to which fasting alters the immune system, and quantifying the degree to which low-calorie diets and fasting are effectively equivalent in altering metabolism, are both helpful new information for those who practice forms of calorie restriction and intermittent fasting. In any case, here is a pointer to the less useful outcome from all of this, which is to say the medical diet. It comes across as a bad parody of itself, but that seems fairly true of most medical diet products.

Introducing ProLon

Industry leading nutritechnology company L-Nutra has announced the release of ProLon, a groundbreaking 5 days per month only natural plant based meal program that nourishes the body while convincing it that it is fully fasting. This is the first time in history that 'Fasting with Food' is possible and is therefore called the Fasting Mimicking Diet (FMD). Developed at the Longevity Institute of the University of Southern California (USC) and under the sponsorship of the National Institute for Aging and the National Institute of Health, ProLon induces the body to protect itself and rejuvenate in response to 5 consecutive days of fasting.

In the latest clinical trial conducted at USC's Longevity Institute, 100 participants on 3 cycles of ProLon (5 days only per month over a 3-month period) showed statistically significant improvements on various health metrics: decrease in body fat; decrease in body weight; preservation of bone density; reduction in fasting glucose and insulin resistance; optimization of cholesterol and triglyceride levels; decrease in IGF-1 (aging marker); decrease in C-reactive protein; elevated mesenchymal/progenitor cells (rejuvenation marker). This 'fasting with food' program features meals ranging from 770 to 1,100 calories per day.

Needless to say you can do all of this yourself, and whether or not you happen to have cancer at the time. It isn't hard to construct and follow a diet to a specific target of calories and nutrients: it just takes the willingness to do it. When presented with the above, and there's more along the same lines if you want to explore the ProLon website, it has to be said that it is more of a challenge than usual to remain optimistic that the first generation of rejuvenation therapies after the SENS model, such as senescent cell clearance, will be able do without the ridiculous marketing language that characterizes present day efforts such as the one above.

Latest Headlines from Fight Aging!

Investigating Declines in Speech Processing with Age

Cognitive decline with aging is a complex process with many facets. Different classes of task suffer loss of function at different rates and vary between individuals. Researchers use these differences to map the brain and the neurodegeneration that accompanies aging. Here, researchers investigate speech processing:

Researchers have found clues to the causes of age-related hearing loss. The ability to track and understand speech in both quiet and noisy environments deteriorates due in part to speech processing declines in both the midbrain and cortex in older adults. Thirty-two native English-speaking volunteers with clinically normal hearing were assigned to two groups: younger adults (average age, 22) and older adults (average age, 65). The research team measured the volunteers' speech comprehension using the Quick Speech-in-Noise (QuickSIN) test. The researchers also gave the volunteers an electroencephalogram, which measured mid-brain activity, and a magnetocephalogram to measure cortical activity. For both groups, the researchers calculated the listeners' ability to comprehend speech in quiet settings and environments with more than one person talking. Background noise was delivered in four distinct signal-to-noise ratios (SNR), which measures signal strength (i.e., the primary talker) relative to background noise (i.e., the competing reader).

The researchers found that the older group had more trouble tracking speech than the younger group in both quiet and noisy environments across all SNRs. The older adults took more time to process several acoustic cues, such as accuracy of speech, and also scored lower on the QuickSIN test for speech comprehension in noise. Deficits from aging were also seen neurally, both in midbrain and cortex, according to the researchers. These results suggest that age-related problems with understanding speech are not only due to the inability to hear at certain volumes but also occur because the aging brain is not able to correctly interpret the meaning of sound signals.

The older adults gained significant benefit in focusing on and understanding speech if the background is spoken by a talker in a language that is not comprehensible to them (i.e. a foreign language). The results suggest that neural processing is strongly affected by the informational content of noise. Specifically, older listeners' cortical responses to the attended speech signal are less deteriorated when the competing speech signal is an incomprehensible language than when it is their native language. Conversely, temporal processing in the midbrain is affected by different backgrounds only during rapid changes in speech, and only in younger listeners. Additionally, cognitive decline is associated with an increase in cortical envelope tracking, suggesting an age-related over (or inefficient) use of cognitive resources that may explain difficulty in processing speech targets while trying to ignore interfering noise.

The Development of Targeted DNA Methylation Editing

Given the ability edit genes, why not also work on the ability to edit the epigenetic decorations such as DNA methylation, those that control the rate of gene expression, the production of proteins from the genetic blueprint? All cellular behavior is governed by the pace of production of specific proteins - these are the switches and dials of the cellular machine. So there are countless ways in which such an editing capability might prove useful. Perhaps the most interesting for this community is that efficient epigenetic editing should enable the production of compelling tests to disprove programmed aging theories that claim changes in gene expression to be the root cause of aging. Given that aging looks to be caused instead by accumulating molecular damage, with gene expression changes as a downstream reaction to that damage and its consequences, adjustments to gene expression should be of only marginal benefit, just like most of today's drug-based medicine for age-related disease. The ability to directly and precisely edit gene expression on a gene by gene basis without the use of a drug and its side-effects should make that very clear.

Mammalian DNA methylation is a critical epigenetic mechanism orchestrating gene expression networks in many biological processes. However, investigation of the functions of specific methylation events remains challenging. Here, we demonstrate that fusion of Tet1 or Dnmt3a with a catalytically inactive Cas9 (dCas9) enables targeted DNA methylation editing.

Targeting of the dCas9-Tet1 or -Dnmt3a fusion protein to methylated or unmethylated promoter sequences caused activation or silencing, respectively, of an endogenous reporter. Targeted demethylation of the BDNF promoter IV or the MyoD distal enhancer by dCas9-Tet1 induced BDNF expression in post-mitotic neurons or activated MyoD facilitating reprogramming of fibroblasts into myoblasts, respectively. Targeted de novo methylation of a CTCF loop anchor site by dCas9-Dnmt3a blocked CTCF binding and interfered with DNA looping, causing altered gene expression in the neighboring loop. Finally, we show that these tools can edit DNA methylation in mice, demonstrating their wide utility for functional studies of epigenetic regulation.

Suggesting that Vascular Dementia Accounts for Alzheimer's Trial Failures

Researchers here claim that the high degree of overlap between Alzheimer's disease and vascular dementia could account for the difficulty in translating promising research results into successful clinical trials for Alzheimer's therapies. If patient cognitive decline is largely due to the vascular dementia in a sizable proportion of cases, that would be enough to tip the trial into failure when the benefits for Alzheimer's symptoms were modest. If large benefits could be produced, however, if the pathology of Alzheimer's could be cleared away, then it would be clear as to whether the therapy worked even if only half the patients saw a meaningful reduction in symptoms. Much of the difficulty in modern medicine exists precisely because most therapies for age-related disease are only producing small benefits, and thus trials results can be prone to misinterpretation due to any number of confounding factors.

Because Alzheimer's disease (AD) is the leading cause of dementia, many people use the two terms interchangeably. But inadequate blood flow to the brain due to microinfarcts, mini-strokes, or strokes is a hallmark of a disease called Vascular Cognitive Impairment and Dementia (VCID). VCID is the second most common cause of dementia, and the two are not mutually exclusive - researchers estimate that 40-60% of Alzheimer's disease patients also have VCID. A paper recently published reports that a certain form of immunotherapy targeted to Alzheimer's patients may be ineffective when that patient also has VCID. "These findings are important in that they provide a possible explanation for why clinical trials of anti-Aβ immunotherapy for Alzheimer's disease have been historically unsuccessful. If up to 40 percent of people with Alzheimer's also have VCID, treatment candidates that target only the AD physiology won't be effective in those patients. It's like treating only half the disease."

Most researchers agree that the formation of brain plaques containing amyloid β (Aβ) peptides is an initial step in the development of Alzheimer's disease, which has led to a race to identify and test treatments that reduce the levels of these plaques. Anti-Aβ immunotherapy, which uses antibodies against Aβ to clear it from the brain, has been a leading approach. While these drugs showed promise in animal studies, clinical trials have failed to show similar benefits in human patients. Without a suitable animal model, testing the vascular dementia hypothesis would not have been possible. Fortunately, the research team had already developed an innovative model of combined AD and VCID. Using this mouse model, together with its parent model of AD without VCID, scientists evaluated the ability of an anti-Aβ antibody to enhance cognitive capabilities in both models. While Aβ levels were reduced in both groups, cognitive function was not improved in the groups with combined AD and VCID. "The failure of anti-Aβ immunotherapy in the mixed AD-VCID model suggests that both disease processes have to be treated to have a successful outcome. The missing link has been that our animal models usually possess the hallmarks of only one disease, which has led to failure of successful translation to clinic."

MIF as a Path to Reduce Cell Death Following Stroke

A number of genes and proteins are turning out to be important in the processes of cell death that occur following a stroke or similar injury involving ischemia followed by reperfusion of tissue. It is the return of blood supply that leads directly to cell death, not the initial loss of blood supply. To pick one example from past research, absence of PHD1 has been shown to greatly reduce damage following stroke. Here, researchers investigate a similar functional role for macrophage migration inhibitory factor, MIF, representative of a range of other work along the same lines. These various genes and mechanisms are all windows onto the same core processes of programmed cell death in response to circumstances:

One particular protein is the final executioner of events that result in the death of brain cells during stroke, researchers report. This finding could ultimately lead to new ways to protect against brain damage. Researchers discovered that the protein, macrophage migration inhibitory factor (MIF), breaks the cell's DNA, resulting in brain cell death. The study outlines three possible ways to manipulate MIF to protect brain tissue during a stroke - and possibly in other brain-damaging conditions such as Alzheimer's, Parkinson's, and Huntington's diseases, although this study examined only stroke. Researchers screened thousands of human proteins to find 160 that could be the culprits behind stroke-induced cell death. Eventually, the researchers were able to narrow the field to just one - MIF, a protein long known for its roles in immunity and inflammation.

The MIF finding is the final piece in a puzzle that researchers have been carefully assembling for years to reveal the process by which brain cells die. Despite their very different causes and symptoms, brain injury, stroke, and Alzheimer's, Parkinson's, and Huntington's diseases have a shared mechanism involving a distinct form of "programmed" brain cell death called parthanatos, researchers said. The name comes from the personification of death in Greek mythology, and PARP, an enzyme involved in the cell death process. "I can't overemphasize what an important form of cell death it is; it plays a role in almost all forms of cellular injury." The researchers are working to identify chemical compounds that could block MIF's actions and possibly protect brain cells from damage.

Are Lifespan and Healthspan Strongly Coupled?

Lifespan is length of life, while healthspan is length of healthy life. Are they strongly coupled? Is it possible to arrive at treatments that greatly alter one without much altering the other? A related concept is something that many researchers believe (or at least claim in public) that they are aiming for: compression of morbidity, in which healthspan is extended without lifespan being extended. It is hard to say how much of that is driven by the desire to avoid talking about life extension in the context of research, however, versus an earnest belief in the plausibility of the outcome. On the other side of that coin, it does seems plausible that the present bad strategy of trying to compensate for outcomes or ameliorate proximate causes of age-related disease - rather than address their root causes, the cell and tissue damage that causes aging - could be acting to marginally extend lifespan without extending healthspan. These are approaches that, at best, make suffering a chronic age-related condition a somewhat slower, somewhat less damaging process. It is a very expensive path to small gains, however. Keeping a damaged machine running without repairing that damage is a challenging undertaking, and far from the best approach to the problem.

Interventions that extend longevity in model laboratory organisms have proliferated. Traditionally, such interventions have been assumed to retard aging itself based on their ability to increase mean and maximum lifespan. The emphasis on longevity metrics alone made some sense in that longevity seemingly provides an unambiguous endpoint that has been assumed to be necessarily correlated with a general age-related physiological decline. While this may often be the case, it is not necessarily so. Indeed, human females live longer lives than males, but also suffer greater age-related morbidity by a number of measures. In laboratory species, long-lived worm genotypes are often outcompeted by shorter-lived genotypes and some evidence suggests that by a number of measures some long-lived worm genotypes are less healthy than the standard genotype even relatively early in life. As a major goal of basic aging research is to develop interventions that will enhance and prolong health in humans, it would be beneficial to the field to determine for all model organisms, which interventions extend health and which extend only life.

Because efforts to develop a cognate battery of tests to assess healthspan in mice and other model organisms have met with varying degrees of success we have taken a different approach. We feel that important indicators of health that can be commonly addressed in humans and in mice can be roughly categorized as those associated with age-related decreasing strength and mobility and those associated with decreasing cognitive capabilities. To this end, we present here an analysis of age-related change in commonly measured, noninvasive parameters associated with age-related changes in energetics, strength and mobility in the commonly used C57BL/6 mouse strain, and we determined to what extent these health parameters were associated with premature death. We measured age-related changes in healthspan in male and female mice assessed at 4 distinct ages (4 months, 20 months, 28 months and 32 months). Correlations between health parameters and age varied. Some parameters show consistent patterns with age across studies and in both sexes, others changed in one sex only and others showed no significant differences in mice of different ages. Few correlations existed among health assays, suggesting that physiological function in domains we assessed change independently in aging mice. With one exception, health parameters were not significantly associated with an increased probability of premature death. Our results show the need for more robust measures of murine health and suggest a potential disconnect between health and lifespan in mice.

Suppressing ANGPTL2 Slows the Progression of Heart Failure

Researchers here present a potential way to slow the progression of heart failure. They have identified one of the proximate causes of pathology, a change in the gene expression of ANGPTL2 that accompanies aging or damage in heart tissue. Suppressing this signal improves function and slows the decline. This, like many of today's potential therapeutic approaches, is compensatory in nature. It doesn't address the underlying reasons for the identified change, but seeks to adjust the behavior of damaged tissues to be more youthful despite that damage. It cannot fix the problem, it can only slow down the inevitable; arguably other approaches that do address the root cause damage should have a higher priority.

Heart failure occurs when heart function is reduced making it no longer able to pump enough blood to body. Patients with severe heart failure have a very poor prognosis, with a five-year survival rate of 50-60% despite advances in modern medicine and medical technology. Researchers found that cardiac muscle cells that were from heart failure patients, were aged cells, or were under the stress of high blood pressure had increased production and secretion of the protein ANGPTL2. The research team previously reported that excessive secretion of the ANGPTL2 protein by aged or stressed cells causes chronic inflammation and promotes the development of lifestyle-related diseases such as atherosclerotic disease, obesity, diabetes, or cancer. ANGPTL2 is also related to heart failure. Excessive ANGPTL2 secretions by cardiac muscle cells impair important functions, such as intracellular calcium concentration regulation and energy production, that help maintain the contractile force of the heart. On the other hand, moderate exercise reduces the production of ANGPTL2 in cardiac muscle cells which helps keep the heart healthy.

"We found that ANGPLT2 is significantly involved in heart failure. Among knockout mice that could not produce the protein, the development of heart failure was suppressed in a manner similar to moderate exercise. Furthermore, we genetically engineered a non-pathogenic virus which was designed to infect cardiac muscle cells and reproduce a special RNA molecule that inhibited the production of the ANGPTL2 protein." This new gene therapy in the heart failure mouse model was successful in suppressing ANGPTL2 production in cardiac muscle cells thereby reducing the pathological progression of heart failure. Additionally, in cardiac muscle cells that were differentiated from human induced pluripotent stem cells, the suppression of ANGPYL2 promoted calcium concentration regulation and enhanced energy production. It is considered that the newly developed gene therapy may also be effective for human heart failure patients. Current treatment for heart failure is mainly symptomatic. The gene therapy developed here is expected to become a fundamental treatment that corrects the mechanism of reduced heart function itself.

Recent Progress on Senescent Cell Clearance at SIWA Therapeutics

SIWA Therapeutics is one of a number of companies that have been around for some years, working away at the problem of senescent cells and their contribution to age-related disease at a slow pace. It is probably the case that some of these initiatives will raise new funding and be invigorated as a result of Oisin Biotechnologies and UNITY Biotechnology entering this area, as well as the recent research results showing life extension and other benefits in mice as a result of senescent cell clearance. The principals at SIWA, however, are in this release emphasizing cancer treatment rather than rejuvenation or slowing the pace of aging. This makes sense from a business perspective if you consider where most of the money is in medical research and development. Aging research has always been the poor cousin in comparison to the better established institutions. While effective treatments for aging will be massively more lucrative than effective treatments for cancer, as the target market is pretty much every individual over the age of 30, it requires investment to build those treatments. That is easier to obtain if cancer is involved.

SIWA Therapeutics today reports results of its recent in vivo preclinical study which showed that its monoclonal antibody for removing senescent cells, SIWA 318, significantly inhibited tumor metastasis. Importantly, there were no observable adverse effects from the treatment and no increase in tumor growth over the control group. "These results suggest that the removal of senescent cells may become a therapeutic approach against metastatic cancers. Based on data we and the rest of the scientific community have generated over the last several years, the evidence is clearly mounting that senescent cells are causally implicated in the manifestation and progression of many diseases including cancer metastasis."

The study was done in a BALBc 4T1 metastatic breast cancer mouse model. Mice were grouped to receive 5 ug/g, 10 ug/g, or saline injections two times daily for three weeks. A fourth group received no treatment. At 23 days, when the study ended, the 10ug/g group showed 30% fewer metastatic lung foci compared to the control. The new data are consistent with earlier results in which we showed that SIWA 318 significantly increased muscle mass in normally aged CD-1 mice as well as significantly reducing the level of p16INK4a expression, a validated biomarker of senescent cells. Based on the results SIWA has generated to date, the company is optimizing a humanized form of SIWA 318, and planning additional preclinical studies.

More Evidence for Transthyretin Amyloid to Associate with Osteoarthritis

There is some evidence for the deposition of misfolded proteins into solid structures known as amyloid to contribute to the development of arthritis. Amyloid is better known for its role in Alzheimer's disease, but there are a number of types of amyloid, each a different misfolded protein, and for many of these the the relationships to age-related disease are still tentative or only partially explored. In recent years transthyretin amyloid has been recognized as important in heart disease and a range of other conditions, for example, but these are quite new discoveries despite the fact that the existence of this type of amyloid has been recognized for a long time. Still, amyloids are one of the characteristic differences between old tissue and young tissue: the research community should be aiming at the development of safe methods of removal for all of them, even in advance of a comprehensive understanding of how exactly they cause harm.

Amyloidosis is a protein conformational disorder in which amyloid fibrils accumulate in the extracellular space and induce organ dysfunction. Recently, two different amyloidogenic proteins, transthyretin (TTR) and apolipoprotein A-I (Apo A-I), were identified in amyloid deposits in knee joints in patients with knee osteoarthritis (OA). However, clinicopathological differences related to those two kinds of amyloid deposits in the knee joint remain to be clarified. Here, we investigated the clinicopathological features related to these knee amyloid deposits associated with knee OA and the biochemical characteristics of the amyloid deposits.

We found that all of our patients with knee OA had amyloid deposits in the knee joints, especially in the meniscus, and those deposits were primarily derived from TTR and/or Apo A-I. Some patients with knee OA, however, had unclassified amyloid deposits. One of our interesting observations concerned the different effects of aging on each type of amyloid formed. The frequency of formation of ATTR deposits clearly increased with age, but that of AApo A-I deposits decreased. Furthermore, we found that ∼16% of patients with knee OA developed ATTR/AApo A-I double deposits in the meniscus. Amyloid deposition may therefore be a common histopathological feature associated with knee OA. Also, aging may induce ATTR formation in the knee joint in elderly patients with knee OA, whereas AApo A-I formation may be inversely correlated with age.

Can Rejuvenation Biotechnologies Stop Cancer from Developing in the First Place?

A supporter recently asked the SENS Research Foundation staff whether the implementation of rejuvenation therapies that follow the SENS model of damage repair would prevent the development of cancer, since cancer is predominantly an age-related disease. Would rejuvenation alone, without any progress towards a comprehensive and effective cure for cancer, be good enough to hold cancer at bay?

It's certainly a good bet that applying rejuvenation biotechnologies to remove, repair, and replace other kinds of aging damage will in some ways make us less vulnerable to cancer. Notably, ablating senescent cells would eliminate the "senescence-associated secretory phenotype" (SASP), which promotes the growth and invasiveness of cancers in several ways, including stimulating early-stage cancer cells to continue replicating, encouraging the growth of new blood vessels needed by cancer cells to supply themselves with fuel and oxygen, and breaking down the physical barriers that prevent them from metastasizing, which is when most cancers become deadly. Also, rejuvenating the aging immune system (by eliminating the dysfunctional T-cells that accumulate with age and rebuilding the atrophied thymus gland) will restore the body's ability to suss out and eliminate cancers as they emerge. But it's also clear that deploying these other rejuvenation biotechnologies won't be enough to eliminate cancer altogether, and that must be our ultimate goal.

First, we already know that cancers can evolve multiple mechanisms to avoid being hit or destroyed by antibodies and immunological factors, and the longer a person lives with proto-cancerous cells (even in the presence of a healthy, young immune system), the longer those cells have to develop ways to evade such an immune system. This is one of the reasons that cancer is an age-related disease, despite the fact that young people can and do certainly get cancer, and despite the fact that many late-life cancers originate with mutations that arise in the body decades earlier. More importantly, perhaps, there is good reason to worry that otherwise-rejuvenated tissues in a body that is still vulnerable to the core processes of cancer may actually become more vulnerable to cancer than they would be under "aging as usual." Consider the following contrasting scientific findings.

On the one hand, it has been shown in animal experiments that when you transplant a pre-formed cancer into an old host, it usually grows more quickly than the same cancer does when transplanted into a young one. This is as you'd expect from things that make the aged host more vulnerable to cancer: senescent cells make it easier for the implanted cancer to take root and spread, and a flagging immune system is less able to root out the invader. On the other hand, when you infect mice with a virus that can cause new cancers to form, it is actually less likely to happen in an old mouse than in a young one - and the tumors that do form grow more slowly, despite the weakened immune system and burden of senescent cells in the older animal. This strongly suggests that something about biological aging itself eventually makes our tissues less prone to forming cancers.

Consistent with this, consider the phenomenon of people (and mice) with mutations in DNA repair genes that cause them to accumulate mutations more rapidly than the rest of us. These people develop an "old" burden of potentially cancer-causing mutations in a body that is otherwise still young. This would be similar to having an otherwise-rejuvenated body in which the problem of age-associated mutations had not been solved by a specific rejuvenation biotechnology. Such people develop what are often very aggressive cancers at much younger ages than is typical in the general population. This suggests that once the mutations needed to form a cancer take hold, even an otherwise-young body is unable to hold the invasion back. Thus, rejuvenating the body will reduce the risk of some cancers (notably, by reversing immunosenescence, clearing out senescent cells, and restoring the structural integrity of the extracellular matrix of our tissues). In other ways, however, rejuvenation could restore the host tissues' intrinsic vulnerability to forming new cancers, and to that extent make cancer more of a risk: all those fresh, proliferation-competent cells, and a restored signaling environment full of growth factors.

Further Assessment of the Effects of Young Ovaries Transplanted into Old Mice

Not so very many years ago it was noted that transplanting young ovaries into old mice resulted in extended life. There is still no good understanding of why this happens, and which of the numerous changes produced by this transplantation are most important in determining life span, but researchers here focus on beneficial effects for the immune system. Age-related failure of the immune system negatively impacts a wide range of important functions, including wound healing, destruction of senescent and potentially cancerous cells, and maintenance and support of neural tissues. It also leads to increased levels of chronic inflammation, a factor that contributes to the development of all of the common age-related diseases. Immune system decline is an important component of frailty in old age, so it isn't unreasonable to think that meaningful benefits will be generated by immune system restoration.

As we age, our metabolism slows and our immune system runs out of steam. Older people are more likely to have severe cold and flu symptoms, probably because they have fewer fresh immune cells left. And a slower metabolism means that glucose stays in the blood stream for longer after eating a meal. Over time, high blood sugar levels can damage organs. But experiments in mice suggest that transplanting organs from a younger individual could reverse these changes. Researchers removed the ovaries of 10 mice that were 12 months old and had gone through oestropause, a transition similar to the human menopause. They replaced these with ovaries taken from 60-day old mice - roughly equivalent to people in their early 20s in terms of ageing.

Four months later, the researchers assessed the mouse immune systems. The numbers of immune cells that respond to new infections - called naive T-cells - tend to decline with age, and had already fallen in these mice before surgery. Between the ages of 6 months (before the operation) and 16 months, the number of naive cells in these mice rose by around 67 per cent. Cell counts fell by 80 per cent in untreated mice over the same period. To test metabolism, researchers injected the mice with glucose and measured how long it took for their blood sugar levels to return to normal. The mice with young ovaries removed glucose from their blood faster than untreated mice. The findings build on the team's previous work, which found that mice transplanted with young ovaries in middle age live about 40 per cent longer than their peers, and have healthier looking hearts too. How young ovaries might exert these benefits remains something of a mystery. One theory is that the hormones produced by the eggs inside these ovaries are responsible. But when researchers killed all the eggs inside young ovaries before transplanting them into another set of older mice, they still saw the same benefits. The researchers theorize that some other kind of cell inside the ovary might be responsible for the rejuvenation.


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