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Fight Aging! Newsletter, January 14th 2019

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Posted 13 January 2019 - 03:07 PM

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 4.0 International 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!

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  • A Selection of Recent News in Parkinson's Disease Research
  • The Harm Done by Senescent T Cells
  • Is it Safe to Greatly Reduce LDL Cholesterol, Far Below Normal Levels?
  • Wary of the Beautiful Fairy Tale of Near Term Rejuvenation
  • Old Tissues Have Many Mutations, Even Absent Cancer
  • The Prospects for Cell Therapy to Restore Lost Neurons in Parkinson's Disease
  • Results from a Pilot Human Trial of Senolytics versus Idiopathic Pulmonary Fibrosis
  • Claiming Cellular Senescence for the Hyperfunction Theory of Aging
  • Persistent Chronic Inflammation Raises the Risk of Neurodegenerative Disease
  • Protein Aggregation versus Infection Hypotheses of Alzheimer's Disease
  • More Evidence for Excess Fat Tissue to Contribute to Hypertension
  • Delivery of Extracellular Vesicles for Skin Repair and Rejuvenation
  • Age-Related Oxidative Stress Contributes to Excess Cholesterol in the Liver
  • Declining Autophagy Implicated in Tau Aggregation in the Aging Brain
  • More on TREM2 and Immune Function in Alzheimer's Disease

A Selection of Recent News in Parkinson's Disease Research

Today I'll note a selection of recent news from the Parkinson's disease research community. Alzheimer's disease may be where the lion's share of funding goes when it comes to research and development related to neurodegenerative conditions, but work on Parkinson's disease is nonetheless well funded and diverse. This condition is characterized by aggregation of α-synuclein and the death of a small but vital population of dopamine generating neurons. The loss of those neurons results in the loss of motor control observed in patients, but there is a great deal of other damage done to the operation of the brain as a result of abnormal biochemistry downstream of α-synuclein aggregation.

Setting aside the older pharmaceuticals that do little but slow the condition or mask the symptoms, the dominant approaches to development of new therapies involve replacement of the lost dopamine neurons and clearance of α-synuclein. However, there are plenty of other places in which researchers have sought to intervene, in mechanisms that may or may not be downstream of α-synuclein. For example, it was recently demonstrated that cellular senescence in glial cells in the brain contributes meaningfully to the progression of Parkinson's - and thus near future senolytic therapies may produce patient benefits here as in many other age-related conditions. It is also the case that age-related decline in mitochondrial function accelerates the loss of neurons in Parkinson's disease. Where Parkinson's is connected with mutations, such as in the parkin gene, these are mechanisms affecting the maintenance of mitochondria.

Parkinson's disease is similar at the high level to other major neurodegenerative conditions: aggregation of damaging proteins; abnormal inflammatory behavior of the immune system in the brain; faltering mitochondrial function. The lower level details are wildly different, but the theme is the same. To talk about curing any neurodegenerative condition is to talk about curing aging. These conditions are the result of forms of molecular damage and waste buildup that cause aging itself; they can only be effectively dealt with by repairing this damage, and preferably early enough to prevent it from ever reaching pathological levels.

A Proposed Roadmap for Parkinson's Disease Proof of Concept Clinical Trials Investigating Compounds Targeting Alpha-Synuclein

The convergence of human molecular genetics and Lewy pathology of Parkinson's disease (PD) have led to a robust, clinical-stage pipeline of alpha-synuclein (α-syn)-targeted therapies that have the potential to slow or stop the progression of PD and other synucleinopathies. To facilitate the development of these and earlier stage investigational molecules, the Michael J. Fox Foundation for Parkinson's Research convened a group of leaders in the field of PD research from academia and industry, the Alpha-Synuclein Clinical Path Working Group. This group set out to develop recommendations on preclinical and clinical research that can de-risk the development of α-syn targeting therapies.

This consensus white paper provides a translational framework, from the selection of animal models and associated endpoints to decision-driving biomarkers as well as considerations for the design of clinical proof-of-concept studies. It also identifies current gaps in our biomarker toolkit and the status of the discovery and validation of α-syn-associated biomarkers that could help fill these gaps. Further, it highlights the importance of the emerging digital technology to supplement the capture and monitoring of clinical outcomes. Although the development of disease-modifying therapies targeting α-syn face profound challenges, we remain optimistic that meaningful strides will be made soon toward the identification and approval of disease-modifying therapeutics targeting α-syn.

Improved stem cell approach could aid fight against Parkinson's

Scientists have taken a key step towards improving an emerging class of treatments for Parkinson's disease. It addresses limitations in the treatment in which, over time, transplanted tissue can acquire signs of disease from nearby cells. It could aid development of the promising treatment - known as cell replacement therapy - which was first used in a clinical trial this year. Experts hope the approach, which involves transplanting healthy cells into parts of the brain damaged by Parkinson's, could alleviate symptoms such as tremor and balance problems.

Researchers have created stem cells - which have the ability to transform into any cell type - that are resistant to developing Parkinson's. They snipped out sections of DNA from human cells in the lab using advanced technology known as CRISPR. In doing so, they removed a gene linked to the formation of toxic clumps, known as Lewy bodies, which are typical of Parkinson's brain cells. In lab tests, the stem cells were transformed into brain cells that produce dopamine - a key brain chemical that is lost in Parkinson's - in a dish. The cells were then treated with a chemical agent to induce Lewy bodies. Cells that had been gene-edited did not form the toxic clumps, compared with unedited cells, which developed signs of Parkinson's.

"We know that Parkinson's disease spreads from neuron-neuron, invading healthy cells. This could essentially put a shelf life on the potential of cell replacement therapy. Our exciting discovery has the potential to considerably improve these emerging treatments."

Parkinson's disease protein buys time for cell repair

Parkin is absent or faulty in half the cases of early onset Parkinson's disease, as well as in some other, sporadic cases. In a healthy brain, Parkin helps keep cells alive, and decreases the risk of harmful inflammation by repairing damage to mitochondria, which are responsible for supplying energy to cells. Damaged mitochondria could trigger the cell's internal death machinery, which removed unwanted cells by a cell death process termed apoptosis.

"We discovered that Parkin blocks cell death by inhibiting a protein called BAK. BAK and a related protein called BAX are activated in response to cell damage, and begin the process of destroying the cell - by dismantling mitochondria. This ultimately drives the cell to die, but low-level mitochondrial damage has the potential to trigger inflammation - warning nearby cells that there is potential danger."

The team showed that Parkin restrains BAK's activity when mitochondria are damaged. Parkin tags BAK with a tiny protein called ubiquitin. With normal Parkin, BAK is tagged and cell death is delayed. Parkin 'buys time' for the cell, allowing the cell's innate repair mechanisms to respond to the damage. Without Parkin - or with faulty variants of Parkin that are found in patients with early-onset Parkinson's disease - BAK is not tagged and excessive cell death can occur. This unrestrained cell death may contribute to the neuronal loss in Parkinson's disease.

The Harm Done by Senescent T Cells

Senescent cells accumulate with age in all tissues, and their presence is one of the root causes of aging. Cells become senescent in large numbers at all ages, and under a variety of circumstances: toxins, wound healing, ordinary somatic cells reaching the Hayflick limit, random mutational damage to important genes, and so forth. Senescence irreversibly shuts down cellular replication, making it a useful defense against cancer. Near all newly senescent cells are destroyed quickly. They either self-destruct or they are destroyed by the immune system, but both paths to a reliable natural clearance of senescent cells falter with the damage and dysfunction of aging.

Lingering senescent cells that have evaded destruction never rise to more than a few percent of all cells by number, even in very late life, but that is more than enough to produce major disruption to tissue function. Senescent cells secrete a potent mix of signals that remodel the extracellular matrix, encourage nearby cells to become senescent, produce chronic inflammation and immune system overactivation, and generally make a mess of things in many other ways. This is particularly disruptive for regenerative capacity, even though senescent cells are necessary for wound healing: their activity is generally useful in the short term for specific circumstances like this, it is when the signaling continues for the long term that the problems arise.

Immune cells, such as the T cells of the adaptive immune system, can also become senescent. Since these cells roam the body, the detrimental consequences can be broad and varied, unlike the case for senescent cells that reside in a given organ. Some of those consequences are examined in the open access review paper noted below. Roaming or not, it is the case that selective destruction of these cells via some form of senolytic therapy will provide benefits. We might think of the signals produced by senescent cells as a mechanism that actively maintains a more aged, damaged state of the body and brain. Destroying these cells is a narrow form of rejuvenation, turning back one of the causes of aging wherever it can be achieved.

The impact of senescence-associated T cells on immunosenescence and age-related disorders

Immunosenescence is age-associated changes in the immunological functions, including diminished acquired immunity against infection, pro-inflammatory traits, and increased risk of autoimmunity. The proportions of memory-phenotype T cells in the peripheral T cell population steadily increase with age, but the relationship between this change and immunosenescent phenotypes remains elusive. Recently, we identified a minor memory-phenotype CD4+ T cell subpopulation that constitutively expressed PD-1 and CD153 as a bona fide age-dependent T cell population; we termed these cells senescence-associated T (SA-T) cells. SA-T cells exhibit characteristic features of cellular senescence, with defective T cell receptor-mediated proliferation and T cell cytokine production.

The T cell receptor (TCR) responsiveness of the overall CD4+ T-cell population, in terms of proliferation and regular cytokine production, diminished gradually with age. Our careful studies, however, revealed that these effects were attributed primarily to the increase in the proportions of SA-T cells with age, given that the residual naïve and PD-1- (CD153-) MP CD4+ T cells in aged mice exhibited TCR responsiveness comparable to those from young mice. Senescent cells tend to resist apoptosis; consistent with this, SA-T cells were quite stable over long-term culture, probably accounting for the progressive accumulation of SA-T cells with age despite their defective proliferation capacity.

The age-dependent increase in SA-T cells could be due to CD4+ T cell-intrinsic effects or to the tissue environment of aged individuals. We found that the naïve CD4+ T cells transferred from young mice robustly proliferated in an aged host environment and underwent significant conversion to SA-T cells, whereas in young hosts, the same T cells barely proliferated and generated few SA-T cells. Thus, the aged, but not young, host environment plays a crucial role in the development of SA-T cells from naïve CD4+ T cells.

Accumulating evidence indicates that the SA-T cells are markedly increased in the tissues under persisted inflammation, often in association with the tertiary lymphoid tissues, of chronic inflammatory disorders. Recent evidence indicates that the selective elimination of tissue senescent cells leads to a significant improvement of age-associated tissue dysfunctions with prolonged lifespan. Consequently, tissue senescent cells are emerging as a crucial target for preventive and therapeutic intervention of age-related chronic disorders. Targeted elimination of SA-T cells represents a promising strategy for controlling chronic inflammatory disorders and possibly cancer.

Is it Safe to Greatly Reduce LDL Cholesterol, Far Below Normal Levels?

The dominant approach to slowing atherosclerosis remains a mix of pharmaceuticals that can, separately, reduce blood pressure and LDL cholesterol (LDL-C) in the bloodstream. In the latter case, new therapies such as PCSK9 inhibitors and improved combinations of statins are capable of doing far more than just return raised LDL-C to normal levels. It is in fact possible to reduce blood cholesterol to something like a half or quarter of normal levels, and this produces incrementally greater benefits in reduction of atherosclerosis risk. But is it safe over the long term? And if it is, why did we evolve to have the observed normal levels of cholesterol in blood?

Atherosclerosis is the build up of fatty plaques that narrow and weaken blood vessels, ultimately leading to a fatal rupture of some form. Raised blood pressure accelerates this process through mechanisms that are incompletely explored - but it is obviously the case that, at later stages, more pressure and weaker blood vessels combines to increase the risk of fatal structural failure. Cholesterol is another input, arriving from the bloodstream. The final input is the activity of the immune system, and local inflammatory signaling, as the immune cells called macrophages attempts to clean up cholesterol from blood vessel tissues and return it to the liver to be disposed of.

Atherosclerotic plaques start and grow due to the presence of damaged, oxidized cholesterol more than overall cholesterol, but the more cholesterol in total, the more oxidized cholesterol is mixed in. That proportion increases with age, as rising levels of oxidative molecules throughout the body lead to ever more oxidative damage to molecules. Macrophages respond to the presence of cholesterol, arrive, become overwhelmed by oxidized cholesterol, and become inflammatory foam cells or die. In either case they produce signaling that leads to a further influx of macrophages, a feedback loop that only worsens with time. The bulk of atherosclerotic deposits is made up of the debris of dead cells and the cholesterol they failed to clear away, a significant fraction of it oxidized cholesterol.

Thus lower blood cholesterol is good in the sense that it will slow down this process by reducing one of the inputs. Unfortunately it doesn't appear to significantly reverse atherosclerosis. Established atherosclerotic plaques remain, and the fatal end result is only put off to some degree, even for the very dramatic reductions in blood cholesterol discussed here. Better approaches are needed, such as ways to destroy oxidized cholesterol, or make macrophages resistant to oxidized cholesterol, or otherwise improve the process by which macrophages mine cholesterol from plaques and export it back to the liver. The past twenty years has seen a fair amount of innovation on the latter option, but sad to say that it has failed in human trials, even while producing as much as a 50% reversion of plaque in mice.

Is very low LDL-C harmful?

LDL-C is deposited in the arterial wall and promotes the inflammation process through the attraction of monocytes and macrophages at the site of cholesterol deposition, thus resulting in the development of atherosclerotic plaques and overt cardiovascular (CV) disease. An abundance of evidence has shown a linear relationship of LDL-C levels with the risk for CV events. Several lipid-lowering treatments such as statins, ezetimibe and the novel proprotein convertase subtilisin kexin 9 (PCSK9) inhibitors were found to offer significant benefits in the reduction in LDL-C and importantly in the amelioration of the overall CV risk of patients with hyperlipidemia with or without CV disease.

Towards this direction, the European Society of Cardiology and the European Society of Atherosclerosis recommend the reduction in LDL-C to lower than 70 mg/dl or a reduction of at least 50% if the baseline values are between 70 and 135 mg/dl in very high-risk patients, to lower than 100 mg/dl or a reduction of at least 50% from baseline values between 100 and 200 mg/dl in high-risk patients, and to less than 115 mg/dl in low to moderate risk patients. The 2017 American Association of Clinical Endocrinologists and American College of Endocrinology Guidelines for Management of Dyslipidemia and Prevention of Cardiovascular Disease suggest even lower LDL-C targets of <100 mg/dl, <70 mg/dl, and <55 mg/dl, in high, very high, or extreme risk diabetic patients.

The necessity for the reduction in LDL-C levels to provide significant CV beneficial effects has been shown and is recommended by all international guidelines. However, there are concerns for the optimal lower limit in which LDL-C can be reduced to achieve optimal CV benefit without causing potential adverse events. The purpose of this review is to present available data for the safety of reducing LDL-C to low or very low levels as it comes from studies of lipid-lowering drugs that achieved such levels.

In general, intensive lipid-lowering studies with statins showed that there is no increased risk of adverse events with reducing LDL-C to levels of approximately 40-50 mg/dl. The most important data for reducing LDL-C to such levels are provided from PCSK9 inhibitors studies where remarkable reductions in LDL-C levels were achieved and no increased rates of adverse events were noted with evolocumab. The slightly concerning findings with alirocumab in the ODYSSEY LONG TERM trial were not verified in the ODYSSEY OUTCOMES study. More importantly, the potential neurocognitive decline with low LDL-C was not observed in several post-hoc analyses and in the EBBINHAUS trial that was specifically designed to evaluate such events. However, it has to be noted that in most trials, the follow-up period and the exposure of the patients in low LDL-C was rather short and trials with longer study periods are needed to unveil potential harms.

Last, higher incidences of hemorrhagic stroke and cancer were not observed in these studies, even at very low LDL-C levels. In conclusion, reduction of LDL-C to less than 50 mg/dl seems safe and provides greater CV benefits compared with higher levels. Data for achieved LDL-C lower than 20-25 mg/dl is limited, although findings from the above mentioned studies are encouraging. However, further evaluation is needed for future studies and post-hoc analyses.

Wary of the Beautiful Fairy Tale of Near Term Rejuvenation

One might compare this interview with researcher Leonid Peshkin to last year's discussion with Vadim Gladyshev. There is a spectrum of caution and pessimism regarding near term progress towards rejuvenation; the pessimists in the research and development communities are not all alike in their viewpoints, and nor do they all have the same take on the complexity of cellular metabolism as a hurdle to progress.

If a researcher thinks that small molecule drugs or gene therapies to alter the operation of metabolism into a state in which aging is slowed are the only way forward, then yes, it is reasonable to consider that progress will be slow and incremental. Metabolism is far from fully mapped, and thus the detailed progression of aging is also full of unknowns. Yet why take the hard path when there is an easier way forward? The whole point of the SENS approach to aging, based upon repair of root cause damage, is to bypass this complexity and lack of knowledge. Remove the known and well-catalogued damage at the root of aging, and a sizable fraction of the consequences will be repaired by the normal processes of tissue maintenance; we know this because we have the example of youthful individuals and their metabolism to draw on.

Of course, it is then possible to debate whether or not the short-term repair projects that can be achieved in the next ten to twenty years will produce large enough gains in life expectancy to enable people to live to see success in the long-term, harder repair projects. Senolytics, breaking of glucosepane cross-links, clearance of protein aggregates, cell replacement therapies, and more, will all be going concerns in the 2020s. But projects such as repair of stochastic mutations in nuclear DNA or damaged nuclear pore molecules in long-lived and critical populations of neurons are well beyond present capabilities.

An Interview with Dr. Leonid Peshkin

As a way of introduction, I'd like to offer a caricature of the currently popular sensationalist view in the field of aging: "We are the chosen generation. Singularity is near. Rejuvenation therapy is almost here. Not one, several a-la-carte: stem cells, factors from young blood, senolytics, Skulachev's ions, NAD, etc. Companies backed up by luminaries from business and science are already sorting out the remaining details, helped by the formidable force of AI technology called 'deep learning'." This fairy tale is beautiful, and deep in my heart, I hope I am mistaken, but I think that at the moment, this positive mysticism is not justified and is rather counterproductive. The excessive optimism is, unfortunately, standing in the way of progress, as I will try to explain.

There are many proposed models of aging, such as the Hallmarks of Aging, SENS, and the deleteriome. Which, if any, of these models do you believe reflects the reality of aging?

I would not want to take part in religious wars. People get very passionate and clash about often vaguely defined terms. Which of the observed hallmarks of aging, from the molecular to the organism levels, are correlates and which are causes of aging is hard to say. Biology has not yet matured to become an exact science. Perhaps owing to my training in quantitative science I take a "model" to mean a level of quantitative understanding that allows for "modeling"; that is, forecasting and answering "what if" questions. Such a model might not be ultimately expressed by a set of crisp human-readable mathematical formulae but rather a large set of tuned parameters in an artificial neural net or some other representation that has not yet been invented. It must, however, provide a way to assess the current state of an organism and predict its lifespan and healthspan in a stable environment, outside of a major perturbation, and then go further to allow for perturbations and adjust the predictions.

Today, I can't even say that there is an agreement in the field of what is a useful definition of "aging". I like "increase of hazard rate (i.e. the probability of dying) with time", which is admittedly a very mathematical notion - precise and not terribly useful. Inverting this formula, we get a curious metaphor - a life without aging can be imagined as a life where, say, once a year, you undergo a treatment that rejuvenates you a year in biological age, or, with some small but non-negligible probability, kills you. Life is a game of chance.

Do you believe that aging is a one-way process or something that is flexible and amenable to intervention?

It is both. Imagine one dramatic intervention: one day, we invent a way to cryo-protect a warm-blooded organism like ours so that it can undergo a freeze-thaw cycle without damage. Now, you are faced with a challenge to design a schedule that determines when, and in what size fractions, you'd like to use up your lifespan. While you are frozen, time stops. While you are alive, you age: the "deleteriome" kicks in, ionizing radiation wrecks your DNA, your defrosted friends and family du jour stress you out, etc. That's what things would look like ad absurdum, illustrating the tradeoffs.

Now, back to the interventions: I imagine a process not unlike a beauty salon, in which you do your nails and hair and get an occasional facelift; all of these are tradeoffs, even if people do not recognize it. Beauty treatments make you look younger at the moment, but cosmetics products may poison your skin and accelerate actual aging. There is evidence of such tradeoffs across organisms in nature; extending lifespan in many species can be accomplished at the expense of reproduction, and in cold-blooded organisms, you can multiply the lifespan several-fold by just cooling the environment down or slowing down metabolic processes in other ways. I believe that the first results will be not so much in giving people free tickets to longer lives but in making the tradeoffs more explicit, educating people and putting them in control of decision making.

Do you consider epigenetic alterations as a cause of aging or a downstream consequence?

Neither cause nor downstream. There is no linear causal chain with the two links of "aging" and "epigenetic alterations"; instead, there are loops and amplifiers in the circuits of aging. Epigenetic alterations have to be caused by something else; these, in turn, control many things. On the other hand, DNA damage is clearly pretty early in the causal network but is hard to undo. There is more hope to proofread and fix "epigenetic alterations". I am very much interested in this direction of research, so much so that we are planning an experiment looking at changes in the distributions of cell types in cell populations that make up young and old individuals. The expectation is that epigenetic alterations lead to de-differentiation and mis-differentiation of cells in old organisms, which could be characterized and further used as end-points for aging interventions.

Old Tissues Have Many Mutations, Even Absent Cancer

Cancer is the result of random mutational damage to nuclear DNA, but most such damage has no real effect, not even to the behavior of the affected cell. Cells in old tissues are riddled with mutations, but it is an open question as to how much this accumulated damage contributes to aging beyond cancer risk. Does it produce sufficient disarray in tissue function to be measured? A mutation capable of meaningfully altering cell behavior (a small subset of all possible mutations) can only have a noticeable affect when it occurs in many cells, a significant fraction of those present in a tissue. One slightly defective cell is a drop in the ocean, provided it isn't actively cancerous.

Many researchers consider that the outcome of clonal expansion of mutations in adult tissue can be achieved when the original mutation occurs in a stem cell of some kind. The mutation can spread with the long-term delivery of a supply of daughter somatic cells and their descendants. Along these lines, the studies noted in the article below raise the possibility that cancer-associated mutations can also grant this ability to spread through excessive replication, yet without immediately resulting in the production of a tumor.

The field lacks definitive studies and models that would enable researchers to put numbers to the contribution of mutational damage to degenerative aging and age-related diseases other than cancer. Clearly the boundary between production of cancer and production of functional damage isn't sharply drawn if expansion of mutations is a feature of the pre-cancerous state. Fixing the damage is usually the best way to proceed when answering this sort of question, but that is very hard to achieve for random DNA damage in isolation of all the other aspects of aging. Every cell needs custom work. More practically, delivering newly created, undamaged stem cell populations to replace old stem cell populations is a feasible form of future therapy, but it certainly doesn't isolate DNA damage as the only altered variable.

Mutations differ in normal and cancer cells of the oesophagus

Errors in DNA replication can alter a cell's DNA sequence. If such alterations occur early enough in embryonic development, the changes are inherited by all of an organism's cells. But if the alterations arise later in adult life, it is more difficult to track such changes in a small number of cells in a specific tissue, so the extent of these alterations in normal tissues is poorly understood. It is thought that cancer is initiated when cells acquire a minimum compendium of genetic alterations needed to trigger tumour formation. Understanding when such initiating mutations occur in normal cells is crucial for enabling reconstruction of the early events that lead to cancer.

Researchers have analysed the extent of mutations in human epithelial tissue from the healthy oesophagus, and how this relates to the processes that drive cancer development. They sequenced 74 cancer-associated genes in 844 tissue samples taken from the upper oesophagus of 9 healthy donors who differed in gender, age and lifestyle. For 21 of these samples, the authors also determined whole-genome sequences. A previous study assessing mutations in healthy skin cells reported between two and six mutations per million nucleotides of DNA. By contrast, here the mutations in oesophageal cells arose at a roughly tenfold lower rate. This difference is unsurprising, because skin cells are exposed to more DNA-damaging agents, such as ultraviolet light, than are oesophageal cells.

Instead, the surprise is that, compared with healthy skin, the healthy oesophagus has more mutations in cancer-associated genes. Moreover, at least a subset of these altered genes was under strong positive selection, meaning that the genetic alterations promoted cell proliferation, leading to the formation of cell clones. Compared with the samples from younger people, the overall number of mutations, the number of mutations in cancer-associated genes and the size of the clones were all greater in the samples from older people. The authors found that the donors' samples had an average of about 120 different mutations in NOTCH1, a known cancer-associated gene, per square centimetre of normal oesophageal tissue.

The clonal expansion of normal oesophageal cells after cancer-promoting genes have mutated seems to be necessary, but not sufficient, to drive cancer, so something else must happen to the cells for tumours to form. For example, gaining a large-enough number of alterations in cancer-promoting genes might be needed. Few of the mutations were present in all the cells of the normal clones, and many of the cancer-promoting mutations were often found in spatially distinct subclones. This suggests that none of the normal cells had acquired enough cancer-promoting alterations to start cancer formation.

The Prospects for Cell Therapy to Restore Lost Neurons in Parkinson's Disease

Generating and transplanting dopamine-generating neurons into the brains of Parkinson's disease patients, to replace the cells destroyed by processes such as aggregation of α-synuclein, is one of the longer-running lines of development in modern cell therapy research. While the regenerative medicine community has advanced a long way past the first, mixed attempts at treating Parkinson's disease in this way, a great deal of work yet lies ahead in order to produce a reliable approach to the replacement of damaged cells. Most of the challenges are relevant to all attempts to introduce new, functional cell populations into the aging body: ensuring the cells survive; preventing the age-damaged environment from overwhelming any benefits that are produced; establishing cost-effective sources of cells, preferably derived from the patient's own tissues.

Current approaches to cell replacement therapy in Parkinson's disease (PD) are strongly focused on the dopamine system, with the view that restoring dopaminergic inputs in a localized and physiologic manner will provide superior benefits in terms of effect and longevity compared with oral medication. Experience using transplants of fetal tissue containing dopaminergic cell precursors has provided valuable proof that the approach is feasible, and that engrafted cells can survive and function over many years. However, multiple drawbacks and procedural complications are recognized in using fetal cells.

Recent strides in stem cell technology now make it possible to overcome some of the barriers associated with fetal tissue. The first generation of stem cell-derived dopaminergic neurons now in the pipeline is predicted to perform at least at an equivalent level to human fetal cells, but in a more robust and reproducible manner, providing a stable, expandable, and readily accessible cell source for transplantation. As such the therapy is expected to provide a better way of treating the dopamine responsive features of PD using a targeted, physiological delivery of dopamine to the striatum, but it is not a disease modifying treatment, nor a cure.

Many questions remain to be addressed. For example, PD pathology is not cell-autonomous, and the spread of pathology potentially affecting graft function is an oft-repeated although unsubstantiated objection to cell therapy. While current evidence supports absence of any major effect, it does raise the question of whether a combinatorial therapy comprising grafting and, for example, a biologic or small molecule to abrogate spread of alpha-synuclein pathology would be desirable.

In this article we have only discussed use of dopaminergic cells, whereas a stem cell source allows growth of any cell type. Other neural networks would be much more difficult to rebuild, but it is tempting to speculate that, for example, cholinergic neurons could be helpful in addressing cognitive function, or balance. There is a long road ahead in demonstrating how well stem cell-based reparative therapies will work, and much to understand about what, where, and how to deliver the cells, and to whom. But the massive strides in technology over recent years make it tempting to speculate that cell replacement may play an increasing role in alleviating at least the motor symptoms, if not others, in the decades to come.

Results from a Pilot Human Trial of Senolytics versus Idiopathic Pulmonary Fibrosis

Researchers here report on results from an initial pilot trial of the use of a senolytic therapy to treat idiopathic pulmonary fibrosis. The data is perhaps much as expected for a first pass at removing senescent cells associated with a specific condition, using the tools available today: a starting point, benefits observed, but definitely room for improvement. The particular senolytic combination used here is cheap and readily available and can remove as much as half of senescent cells in some tissues in mice, but the degree of clearance varies widely by tissue type, and the optimal human dose is yet to be determined. Typically the next trial following an initial feasibility study will test a range of doses.

The past few years of animal data have indicated that the inflammatory signaling of senescent cells, the senescence-associated secretory phenotype (SASP), plays an important role in producing and maintaining age-related fibrosis in multiple tissues, but may not be the only process involved. Fibrosis is an outcome of disarray in regenerative and tissue maintenance, in which scar-like connective tissue is laid down in place of correctly formed tissue. Organ function is degraded as a result. In the case of idiopathic pulmonary fibrosis death follows within a few years of diagnosis, as the lungs fail.

Cellular senescence is a key mechanism that drives age-related diseases, but has yet to be targeted therapeutically in humans. Idiopathic pulmonary fibrosis (IPF) is a progressive, fatal cellular senescence-associated disease. Selectively ablating senescent cells using dasatinib plus quercetin (DQ) alleviates IPF-related dysfunction in bleomycin-administered mice.

A two-center, open-label study of intermittent DQ (D:100 mg/day, Q:1250 mg/day, three-days/week over three-weeks) was conducted in 14 participants with IPF to evaluate feasibility of implementing a senolytic intervention. The primary endpoints were retention rates and completion rates for planned clinical assessments. Secondary endpoints were safety and change in functional and reported health measures. Associations with the senescence-associated secretory phenotype (SASP) were explored.

The retention rate was 100% with no DQ discontinuation; planned clinical assessments were complete in 13 of the 14 participants. One serious adverse event was reported. Non-serious events were primarily mild-moderate, with respiratory symptoms (16 events), skin irritation/bruising (14 events), and gastrointestinal discomfort (12 events) being most frequent. Physical function evaluated as 6-minute walk distance, 4-minute gait speed, and chair-stands time was significantly and clinically-meaningfully improved. Pulmonary function, clinical chemistries, frailty index (FI-LAB), and reported health were unchanged. DQ effects on circulating SASP factors were inconclusive, but correlations were observed between change in function and change in SASP-related matrix-remodeling proteins, microRNAs, and pro-inflammatory cytokines.

IPF appears to be relentlessly progressive: in large IPF drug trials, no improvements in 6-minute walk distance have been observed in the placebo-control arms. Pulmonary function in this IPF patient population did not change during the course of this preliminary study. It is likely that in this pilot exploration, the follow-up period is too short and the sample size too modest to assess effects on long-term trajectories, especially in a complex chronic disease such as IPF. If resolution of pulmonary scarring and fibrosis does indeed occur, it may take considerable time after clearance of senescent cells from the lung.

Claiming Cellular Senescence for the Hyperfunction Theory of Aging

This mildly infuriating commentary well illustrates just why it is that theories of aging are so very diverse. Even a mechanism as well understood as cellular senescence can be fairly convincingly argued into one camp or another. For those who see aging as damage accumulation, lingering senescent cells are clearly a form of damage, a byproduct of normal metabolism that grows slowly over time and produces tissue dysfunction in proportion to the number of such cells. For those who consider the hyperfunction theory of aging, in which aging is the result of developmental programs failing to shut down in adult life, it is fairly easy to argue that the prevalence of cellular senescence in old people is an embryonic development mechanism or wound healing mechanism run wild. Cellular senescence does indeed play important roles in those circumstances.

Senolytics are drugs that extend lifespan and delay some age-related diseases by killing senescent cells. I want to draw your attention to the paradoxes associated with senolytics, which argue against the dogma that says aging is a functional decline caused by molecular damage. This dogma predicts that senolytics should accelerate aging. If aging is caused by loss of function, then killing senescent cells would be expected to accelerate aging, given that dead cells have no functionality at all. Instead, however, senolytics slow aging, which highlights a contradiction in the prevailing dogma.

The theory of hyperfunctional aging addresses this paradox. Killing senescent cells is beneficial because senescent cells are hyperfunctional. The hypersecretory phenotype or Senescence-Associated Secretory Phenotype (SASP) is the best-known example of universal hyperfunction. Most such hyperfunctions are tissue-specific. For example, senescent beta cells overproduce insulin and thus activate mTOR in hepatocytes, adipocytes, and other cells, causing their hyperfunction, which in turn leads to metabolic syndrome and is also a risk factor for cancer. SASP, hyperinsulinemia and obesity, hypertension, hyperlipidemia and hyperglycemia are all examples of absolute hyperfunction (an increase in functionality).

In comparison, relative hyperfunction is an insufficient decrease of unneeded function. For example, protein synthesis decreases with aging, but that decrease is not sufficient. In analogy, a car moving on the highway at 65 mph is not "hyperfunctional." But if the car were to exit the highway and enter a residential driveway at only 60 mph it would be "hyperfunctional," and stopping that car would likely prevent damage to other objects. Similarly, killing hyperfunctional cells can prevent organismal damage. Senolytics eliminate hyperfunctional cells, which otherwise damage organs.

Persistent Chronic Inflammation Raises the Risk of Neurodegenerative Disease

In this open access paper, the authors present evidence for chronic inflammation to contribute to the development of neurodegenerative disease. A great deal of research into the late stage disease state robustly connects inflammation to pathology, and given the risk factors for neurodegeneration, such as excess visceral fat tissue, it is entirely reasonable to think that inflammation is important. It accelerates the development of many other age-related conditions, after all. Less work has been carried out on the early stages of development of neurodegenerative diseases in humans, however, due to the lack of good data sets that span the necessary decades of time. There are already many good reasons to minimize chronic inflammation throughout life, to as great a degree as is possible. This one can be added to the stack.

Although it has become clear over the last several decades that inflammation plays a role in the pathogenesis of Alzheimer's disease and other forms of dementia, the precise nature and temporal characteristics of the neurodegeneration-inflammation relationship have remained largely unknown. Several lines of research have identified inflammation, both within the brain and within the periphery, as a potential driver of neurodegenerative brain changes and cognitive decline. Chronic low-grade inflammation, in particular, has received considerable attention, as translational studies suggest that it may play a causal role in dementia, late-life cognitive decline, and a number of other age-related phenotypes.

Although evidence from animal models indicates that chronic inflammation can perpetuate, or even initiate, neurodegenerative changes, this hypothesis has been challenging to examine in human studies. This is largely due to a lack of longitudinal data on inflammatory biomarkers in cohort studies which examine neurocognitive outcomes in older adults. In a recently published study of participants from the Atherosclerosis Risk in Communities (ARIC) Cohort, we were able to clarify the relationship between long-term (21-year) patterns of systemic inflammation and late-life neurodegenerative changes.

In this study, we found that individuals who both demonstrated elevated inflammation before or during middle adulthood and maintained high levels of inflammation over the subsequent two decades had greater white matter hyperintensity volume and reduced white matter microstructural integrity as older adults, compared to those who maintained low levels of inflammation. These findings support the idea that systemic inflammation can initiate or perpetuate neurodegenerative brain changes which underlie cognitive impairment and dementia.

Protein Aggregation versus Infection Hypotheses of Alzheimer's Disease

The amyloid hypothesis has dominated the past twenty years of failed attempts to build therapies to treat Alzheimer's disease. However, it is only very recently that immunotherapies and other methods of reducing amyloid-β levels in the aging brain have started to show signs of working. As a consequence, the field is in a state of some upheaval when it comes to choice of strategy going forward. Alternative views of Alzheimer's and its development have emerged and gained enough support to raise sufficient funds to compete. In the long run, this is all to the good, I think. A diversity of approaches always beats out a top-down monoculture when it comes to finding viable paths forward. The open access paper noted here examines a few different hypotheses that have risen to prominence.

In this review, we focus on four Alzheimer's disease (AD) hypotheses currently relevant to AD onset: the prevailing amyloid cascade hypothesis, the well-recognized tau hypothesis, the increasingly popular pathogen (viral infection) hypothesis, and the infection-related antimicrobial protection hypothesis. In briefly reviewing the main evidence supporting each hypothesis and discussing the questions that need to be addressed, we hope to gain a better understanding of the complicated multi-layered interactions in potential causal and/or risk factors in AD pathogenesis.

As a defining feature of AD, the existence of amyloid deposits is likely fundamental to AD onset but is insufficient to wholly reproduce many complexities of the disorder. A similar belief is currently also applied to hyperphosphorylated tau aggregates within neurons, where tau has been postulated to drive neurodegeneration in the presence of pre-existing Aβ plaques in the brain.

Although infection of the central nervous system by pathogens such as viruses may increase AD risk, it is yet to be determined whether this phenomenon is applicable to all cases of sporadic AD and whether it is a primary trigger for AD onset. Lastly, the antimicrobial protection hypothesis provides insight into a potential physiological role for Aβ peptides, but how Aβ/microbial interactions affect AD pathogenesis during aging awaits further validation. Nevertheless, this hypothesis cautions potential adverse effects in Aβ-targeting therapies by hindering potential roles for Aβ in anti-viral protection.

Unlike familial AD, sporadic AD may evolve from a combination of various genetic and environmental factors. Neuroinflammation, tau pathogenesis, and viral infection have all been implicated to play important roles in AD; however, these factors do not appear to be pathogenic triggers that are specifically relevant to AD. Thus, specific causal mechanisms that drive AD onset have yet to be clearly defined, which may lead to the identification of new therapeutic targets. It is now widely accepted that sporadic AD is a complicated syndrome.

More Evidence for Excess Fat Tissue to Contribute to Hypertension

Hypertension, or increased blood pressure, is one of the more important ways in which the low-level molecular damage of aging is converted into high-level structural damage to tissues. Hypertension produces increased rupture of capillaries and other forms of pressure damage to delicate structures of the brain and other organs, resulting in loss of function and, ultimately, death. It also accelerates the progression of atherosclerosis, the creation of fatty plaques that weaken and narrow blood vessels, with the end result of stroke or heart attack as an important blood vessel suffers structural failure.

Being overweight or obese is strongly associated with risk and degree of hypertension. The underlying mechanisms are easy to speculate on: the chronic inflammation produced by visceral fat tissue causes dysfunction in the smooth muscle cells that control blood vessel dilation and constriction, for example. That breaks the feedback mechanisms controlling blood pressure, leading to hypertension. The diet needed to become overweight likely contributes to greater cross-link formation, stiffening blood vessel tissues to produce much the same outcome. And so forth through a laundry list of other low-level damage that manifests in blood vessel walls.

Among the cardiovascular disease (CVD) risk factors, age is considered as the most important predictor of CVD events and hypertension is a major cause of CVD mortality. Age-related increase in blood pressure (BP) is recognized as a universal feature of human aging. Previous epidemiological surveys have shown a progressive increase in systolic blood pressure (SBP) with age, whereas diastolic blood pressure (DBP) also initially increases with age but falls at latter ages. Thus, effective control of BP is essential for improving population health.

Studies of BP associated with adiposity-related genetic variants and controlled trials of weight loss interventions have established the causal relationship between adiposity and BP. Regardless of age and other unmodifiable CVD risk factors such as sex and race, there are many risk factors that are manageable and can be controlled through lifestyle modification, including reduction of obesity. However, there are inconsistencies as to whether a general or central adiposity is more strongly associated with BP and different opinions about which variable is the strongest predictor of BP.

The present study aimed to investigate how BP and body composition change within different age groups and their correlation across the adult age span. We also investigated the contribution of body composition measures (including body mass index (BMI), lean mass percent (LM%), and visceral fat rating (VFR) to the age-related alteration of BP across ten 5-year age groups ranging from 18-79 years in a sample of healthy Chinese adults. We demonstrated that mean SBP showed an age-related increase and mean DBP showed an inverted U-shape across the age span, and this trend was closely associated with the age-related body composition changes. Furthermore, we found that the association between BP and body composition indices was weaker in the elderly compared to the younger subjects.

As demonstrated in our study, all measures of general obesity, central obesity, and LM% were correlated to BP at the whole population level, and among them the relationships with BP were similar across most of the body composition indices. Some studies have suggested that general adiposity was more strongly correlated with BP, while other studies suggested central or visceral adiposity was more strongly correlated with BP than general adiposity. In this study, we didn't find significant differences between these two kinds of obesity indices.

To examine whether body composition was a factor influencing BP throughout the whole adult age span, we further analyzed the association of BP with BMI, LM% and VFR in each specific age-group (at 5-year ranges). After adjustment for education level, smoking status, alcohol consumption, and residential location, BMI and VFR were positively associated with BP in each age group, suggesting that adiposity was an important risk factor for the increased BP, whereas LM% was negatively associated with BP, the latter indicating its protective effect on BP. The correlation between BP and all these three measures (BMI, LM%, and VFR) was weaker in the elderly than younger adults. Thus, as demonstrated by our study, we may infer that factors associated with increased BP may be more complicated in the elderly compared to the younger age groups.

Delivery of Extracellular Vesicles for Skin Repair and Rejuvenation

To what degree can skin be restored to a more youthful state just by changing cell behavior? That question will be explored comprehensively in the years ahead, and not just for skin. Many research groups are taking the approach of harvesting extracellular vesicles from stem cells and delivering them into tissues, a potential form of therapy that appears to produce many of the same benefits as first generation stem cell transplants, and with less expense and complexity.

What fraction of these benefits are a matter of overriding unfortunate cellular reactions to damage, or putting damaged cells back to work, hopefully without reaching the threshold at which this would produce an increased cancer risk? How much is a genuine clean-up of metabolic waste or damaged components in cells? That remains to be determined, but it is worth bearing in mind that there are forms of metabolic waste and cell damage that our biochemistry cannot deal with, no matter how fired up it might be. Ultimately, the research community must do better than simply instructing our cells to work harder. Tools must be provided to break down that waste, irreparably damaged stem cells replaced, and more.

Stem cells have attracted great interest from the scientific community since their discovery. Their capacity to differentiate into various cell types and hence provide tissue repair made them promising tools in the treatment of such pathologies as neurodegenerative disorders, organ failure, and tissue damage. However, stem cells such as mesenchymal stem/stromal cells (MSCs) exert their functions via paracrine effects and not by the replacement of dead cells.

The term secretome refers to the complex mixture of factors released by virtually all cell types, including stem cells, to the extracellular space. Once released by stem cells, this combination of different classes of molecules can modify microenvironments by controlling inflammation as well as inducing selective protein activation and transcription. This secreted milieu of molecules may culminate in tissue regeneration. Recent evidence about this paracrine mechanism has opened up a new paradigm in stem cell therapy and stimulated the search for strategies that explore the concept of "cell therapy without cells."

The most well-studied and dynamic part of the growing field of secretomics is extracellular vesicles (EVs). EVs represent an important fraction of virtually any cell type's secretome. Extensive research is currently being conducted to elucidate the healing potential of stem cell EVs in numerous disease processes. EVs released by stem cells to the extracellular space have been shown to improve vascularization, immunomodulation, and cardiac and central nervous system regeneration.

Stem cell-conditioned media from endothelial precursor cells differentiated from human embryonic stem cells have been used in skin rejuvenating research with interesting results. The injection of conditioned media from those cells improved the aspect of skin wrinkles and skin aspect in women. UV light damage and aging affect extracellular matrix collagen and elastin depots, both of which are key in the prevention of skin dehydration as well as in firmness and elasticity preservation. The beneficial effects of stem cell EVs for cellular matrix maintenance and collagen production as described previously could contribute to this effect, considering that vesicles are important components of stem cell-conditioned media.

Furthermore, reports have suggested that purified stem cell EVs could play a role in rejuvenating skin cells. A report indicated that EVs from induced pluripotent stem cells (iPSCs) could restore the function of aged human dermal fibroblasts. The authors reported that dermal fibroblasts pretreated with iPSC EVs resisted photoaging with UVB and did not overexpress matrix-degrading enzymes MMP-1/3 but, on the contrary, displayed a high expression of collagen I, as young fibroblasts do. Other researchers studied the capacity of human umbilical cord stem cell EVs to rejuvenate skin by modulating collagen production and permeation. They also investigated whether EVs acceptance could accelerate fibroblast proliferation. Not only did skin cells proliferate more after EVs endocytosis, but a better production of collagen and elastin in human skin models was also observed in their study. Altogether, these studies indicate that stem cell EVs could be good candidates for therapeutic strategies against aging.

Age-Related Oxidative Stress Contributes to Excess Cholesterol in the Liver

The presence of oxidative molecules in our biochemistry rises with aging, and cells react to this in many different ways. Internally to cells, this sort of damage can be rapidly repaired and brief bursts of oxidative molecule creation even serve as a signal for many necessary processes, such as the beneficial reactions to the stresses of exercise. Chronic oxidative stress produces dysfunction, however, whether that is via the production of toxic oxidized lipids or through through more direct means of causing cells to act in a harmful manner.

Chronic inflammation and mitochondrial dysfunction are two of the upstream causes of increased numbers of oxidative molecules. Among the downstream consequences can be found all sorts of detrimental cellular reactions, many of which are only poorly explored at best. The open access paper here is an example of the type. The best solution to this class of age-related problem is to go after the upstream causes, though mitochondrially targeted antioxidants appear to provide a beneficial suppression of oxidative stress in at least some situations.

The production of reactive oxygen species (ROS) is progressively increased in aging and is one of the key factors in cellular damage. It is known that ROS, including free radicals and peroxides, adversely affects cells and tissues and causes an imbalance in the biological system, contributing to the development of many aging-related diseases. In addition, oxidative stress plays an important role in hepatic disease. Aging increases fibrotic responses and is also associated with the development of a variety of liver diseases including nonalcoholic fatty liver disease and alcoholic liver disease. In particular, the prevalence of nonalcoholic fatty liver disease tends to increase with age, and thus, aging and lipid metabolism in the liver may be closely related. In addition, evidence suggests that increased oxidative stress due to various factors leads to increased lipid accumulation in the liver, while decreased oxidative stress has a lipid-lowering effect in hepatocytes.

Lipid supply to liver tissue consists of three main pathways: dietary intake, peripheral lipolysis, and de novo lipogenesis. Fatty liver occurs when the lipid supply exceeds the hepatic lipid removal. In many previous studies, triglyceride and cholesterol metabolism disorders and accumulation have been reported to be closely related to aging. For example, in the senescent-associated mouse, the cholesterol content in the liver was increased compared with control mice. In this study, we investigated the mechanisms for the increase in cholesterol accumulation during aging. We found that the increased ROS in aging plays an important role for the accumulation of cholesterol in the liver by increasing cholesterol uptake and cholesterol synthesis via increasing glucose uptake.

The mRNA expression of GLUT2, GK, SREBP2, HMGCR, and HMGCS, genes for cholesterol synthesis, was gradually increased in liver tissues during aging. When we treated HepG2 cells and primary hepatocytes with the ROS inducer, H2O2, lipid accumulation increased significantly compared to the case for untreated HepG2 cells. H2O2 treatment significantly increased glucose uptake and acetyl-CoA production, which results in glycolysis and lipid synthesis. Treatment with H2O2 significantly increased the expression of mRNA for genes related to cholesterol synthesis and uptake. These results suggest that ROS play an important role in altering cholesterol metabolism and consequently contribute to the accumulation of cholesterol in the liver during the aging process.

Declining Autophagy Implicated in Tau Aggregation in the Aging Brain

Tau aggregation, the formation of solid deposits of altered tau protein called neurofibrillary tangles, is thought to be the most damaging of the processes underlying Alzheimer's disease. The earlier accumulation of amyloid-β only sets the stage for the later accumulation of altered tau. When looking at why protein aggregates such as amyloid-β and tau accumulate only in later life, one of many candidate mechanisms is the decline of autophagy that takes place with aging. Autophagy is the name given to a collection of cellular maintenance processes responsible for clearing out damaged structures and other unwanted waste, such as protein aggregates. A range of interventions shown to slow aging in laboratory species involve raised levels of autophagy: if cells are more aggressively maintained, there is less of a chance for damage and dysfunction in cellular processes to spread and cause further harm. The other side of the coin is that lower levels of autophagy mean more metabolic waste, more damaged components, and more downstream consequences.

Early in the course of Alzheimer's disease, neurons in the brain become clogged with toxic tau proteins that impair and eventually kill the neurons. A new study found that tau accumulates in certain types of neurons, probably because the cellular housekeeping system of autophagy is less effective in these neurons. Researchers have long known that neurodegenerative diseases like Alzheimer's affect some neurons but not others, even leaving neighboring neurons unharmed. But the reasons for this selectivity have been difficult to identify.

The new study was only possible because of new techniques that allow researchers to probe individual cells in the brain. Researchers detected signs that the components of a cellular cleaning system were less abundant in the neurons that accumulate tau proteins. To confirm the connection between the cleaning system and tau buildup, the researchers manipulated BAG3, a regulatory protein in autophagy, in mouse neurons. When the researchers decreased BAG3 levels in mouse neurons, tau piled up. But when BAG3 expression was enhanced, the neurons were able to rid themselves of excess tau.

The researchers have tantalizing, still unpublished data that the same housekeeping deficiencies found in vulnerable neurons occur with aging, which might explain the link between advanced age and Alzheimer's disease. "If we can develop therapies to support these natural defense mechanisms and stop tau from accumulating, then we might be able to prevent, or at least slow, the development of Alzheimer's and other tau-related neurodegenerative diseases."

More on TREM2 and Immune Function in Alzheimer's Disease

You might recall research published early last year on TREM2 as a possible regulator of immune cell clearance of amyloid in Alzheimer's disease. Researchers here provide a further update on their investigations of the role of TREM2 in this process. To the degree that the immune system falters in this task of clearing metabolic waste with age, and to the degree that this issue can be reversed or overridden, this may prove to be a useful approach to age-related protein aggregates in the brain, and their contribution to neurodegenerative disease. As is so often the case, however, a treatment cannot be immediately and straightforwardly constructed based on manipulation of TREM2. Its relationship with immune cell activity and the Alzheimer's disease state is complex.

A hallmark of Alzheimer's disease is the formation of toxic deposits in the brain, so-called plaques. Specialized immune cells termed microglia protect the brain by clearing it from these toxic debris. TREM2 is a key factor in activating microglia and thus serves as an important target for novel therapeutic approaches. To further explore these therapeutic options, scientists undertook a detailed analysis of disease development in mice with and without a functional TREM2 gene.

In mice with healthy TREM2, microglia cluster around small emerging plaques early in the disease process and prevent them from enlarging or spreading. Researchers were able to show that microglia are specifically attracted to amyloid plaques. They surround individual plaques and engulf them piece by piece. In contrast, in mice lacking TREM2, microglia were unable to carry out this important task. Therapeutic activation of TREM2 in an early stage of the disease could thus help counteract the formation of toxic amyloid-beta protein aggregates.

However, the study results also call for caution when implementing such a therapy. While TREM2 prevents plaque formation early in disease progression, it may have the opposite effect later on. In more advanced stages of the disease, the plaques grew faster in mice with functional TREM2 than in mice lacking the corresponding gene. The researchers discovered that this could be explained by the fact that TREM2 induces microglia to produce a substance called ApoE, which enhances aggregate formation. "Our study shows that we have to be extremely careful and investigate a new therapeutic approach thoroughly in animal models before testing it on humans. According to our findings, it could have dramatic consequences if we over-activate microglia. In the future, it will be important to treat Alzheimer's disease in a stage-specific manner."

View the full article at FightAging

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