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- Changes in T Cell Populations that Characterize the Progression of Immunosenescence
- Journalists Have Very Fragmentary, Incomplete Views of the Longevity Industry
- Considering the Experience of Being One of the Last Mortals
- Cofilin May Link Amyloid-β Aggregation and Tau Aggregation in Alzheimer's Disease
- Reviewing the Reserve Supply of Immature Neurons in the Adult Brain
- VCAM1 Levels Correlate with Parkinson's Disease Severity
- Impaired Insulin Signaling and Chronic Inflammation in the Alzheimer's Brain
- Another Cholesterol-Lowering Variant that Reduces Heart Disease Risk, but This One Has Unfortunate Side Effects
- Cellular Senescence in the Development of Cataracts
- Repeated Cycles of Incomplete Healing as a Cause of Aging
- A Conservative View of the Present State of Senolytic Development for Rejuvenation
- The Pension Industry Will Change Radically, Willingly or Otherwise
- Walking Pace Correlates with Life Expectancy
- How Might Nutrient Rich Diets Turn Our Gut Bacteria Against Us?
- Mitochondrial DNA Damage in Age-Related Macular Degeneration
Changes in T Cell Populations that Characterize the Progression of Immunosenescence
Immunosenescence is the name give to the age-related decline in effectiveness of the immune system. Some authors consider this to be distinct from inflammaging, the growth in chronic inflammation due to overactivation of the immune system in response to molecular damage and the presence of senescent cells, while others consider that chronic inflammation to be an aspect of immunosenescence. In today's open access paper, researchers review immunosenescence from the perspective of the adaptive immune system, here meaning detrimental changes in T cell populations. The contributing causes of these changes are given as (a) the atrophy of the thymus, (b) a growing bias towards production of myeloid rather than lymphoid cells in the bone marrow, and (c) the burden of persistent infection, particularly cytomegalovirus.
The progressive age-related atrophy of the thymus, known as thymic involution, may be the most important of these issues. Thymocytes created in the bone marrow migrate to the thymus, where they mature into T cells. As active thymic tissue is replaced with fat, the supply of new T cells diminishes. While the overall number of T cells remains much the same throughout life, these cells become increasingly dysfunctional due to a lack of replacements. Growing numbers of T cells in the old are senescent or exhausted, or uselessly specialized in large numbers to fight persistent pathogens such as cytomegalovirus. Ever fewer naive T cells capable of tackling new threats remain, and immune capability declines.
The importance of the thymus to immune aging is why, over the years, many research projects have sought to regrow and restore the thymus. Unfortunately none of these have yet resulted in reliable approaches in humans. Delivery of recombinant KGF was perhaps the most promising, given that it works very well to regrow the thymus in aged mice and non-human primates. The only human trial failed miserably, however, and no-one seems much interested in looking further into why this was the case. At the present time the closest approach to clinical application may that of Lygenesis: grow thymic tissue organoids and implant them into lymph nodes. I'm of the belief that upregulating FOXN1, a master regulator of thymic growth and function, is probably the best option, however. There is a long history of successfully achieving thymic regrowth via this method in mice, and the regulatory biochemistry appears to be the same in other mammalian species.
Immunosenescence: participation of T lymphocytes and myeloid-derived suppressor cells in aging-related immune response changes
Immunosenescence was initially defined as a group of changes that occur in the immune response during the aging process. The reason for that is the immune system was believed to collapse with the aging process, considering the increased susceptibility of these individuals to infectious diseases and developing cancer, reduced production of antibodies against specific antigens, increase in autoantibodies, decrease in T-lymphocyte proliferation, in addition to thymic involution. However, immunosenescence is currently defined by some researchers as remodeling of the immune system, suggesting plasticity of the immune system in the aging process. According to these researchers, the aging process does not necessarily bring an inevitable decline of immune functions; what happens is a rearrangement or an adaptation of the immune system to adjust the body that has been exposed to different pathogens throughout life. Depending on how successful that rearrangement or adaptation is, senior individuals can reach longevity with quality of life or, conversely, develop chronic diseases (comorbidities) and/or be often hospitalized due to severe infections.
This adaptation of the immune system brought by aging seems to result in reduced number and repertoire of T cells due to thymic involution, accumulation of memory T cells from chronic infections, homeostatic proliferation compensating for the number of naïve T cells, decreased proliferation capacity of T cells against stimuli, T cell replicative senescence and inflammaging, besides accumulation of myeloid-derived suppressor cells (MDSC).
As we get older, during hematopoiesis in the bone marrow, the myeloid lineage tends to increase, which can favor the accumulation of MDSC. These cells are able to suppress T cells proliferation and function, and produce pro-inflammatory cytokines. Moreover, there is thymus involution and replacement of thymic tissue by adipose tissue. Hence, there is reduced T cell receptor (TCR) variability and release of naïve T cells. The decreased thymic release of naïve cells, together with the immune response against infections throughout life, lead to the accumulation of memory T cells. In elderly individuals, both naïve and memory T cells can be maintained thanks to homeostatic proliferation, which shortens the telomeres of these cells, resulting in replicative senescence of T cells that produce pro-inflammatory cytokines, and promote inflammaging. The shortening of telomeres also decreases the proliferation capacity of T cells, which will produce less interleukin-2, further decreasing the proliferation of these cells.
Considering T cells are essential for the adequate response against pathogens and neoplasms, and for protection after vaccination, it seems reasonable that changes in T cells quantity, phenotype, and function play an important role in immunosenescence. By understanding each of the mechanisms originated by remodeling of the immune system brought by aging, we could use the cells addressed in the present study (T cells and MDSC) as early and minimally invasive biomarkers for aging-related diseases. The aim is to minimize the limitations of immunosenescence and ensure better treatment for the vulnerable elderly population.
Journalists Have Very Fragmentary, Incomplete Views of the Longevity Industry
The lengthy and somewhat overwrought article I'll point out today is a good example of the way in which journalists fail when writing on the topic of the growing biotechnology industry that is making the first steps towards the medical control of aging. They talk to just a few people, and thus have a very narrow (generously) or absolutely incorrect (more accurately) view of what might be happening, the prospects for the future, and the shape of the field as a whole. In this case the few people are the folk at AgeLab at MIT, and George Church, with a focus on the veterinary deployment of gene therapies by Rejuvenate Bio, and a fairly traditional Alzheimer's researcher.
To speak directly, and without meaning to be cruel about it, AgeLab should not exist. It is an entity focused on coping with the realities of aging, making recommendations on small ways that older people might do a little better under the burden of aging. This is a waste of funding in a world in which there is even the slightest possibility of treating aging as a medical condition, and the present state of senolytics, among many other signs, shows that there is far more than a slight possibility of that outcome. Unfortunately AgeLab is far from the only organization set up on the premise that aging cannot be changed, and that the only thing to be done is cope. Holding it up in any discussion of where things might be going in the future is just silly. As rejuvenation works, the AgeLabs of the world will vanish, and rightfully so.
The genetic approach to aging, of using gene therapies of various sorts to adjust the operation of metabolism in late life is espoused by George Church and others. This seems to me just an incremental advance over small molecule calorie restriction mimetic or other stress response upregulation efforts. Gene therapy can be more precise, with fewer off-target effects, and a more flexible, direct development program. But at the end of the day this is still largely a case of altering metabolism to better resist aging rather than addressing the underlying causes of aging. This tweaking of metabolic processes simply cannot produce sizable benefits, as the underlying damage still exists, and the gene therapy can only tweak one set of mechanisms related to that damage, leaving all the others to fester. It will certainly look at lot better than the medicines of yesterday, which failed to even achieve this much, but why aim low? This type of approach to aging is the majority of the field still, but it is not the future of therapies for aging. The effect sizes won't be large enough and reliable enough in comparison to those of clearing senescent cells or other forms of damage repair.
The traditional Alzheimer's researchers, those associated with a few decades of failure to make progress towards therapies, can be pessimistic. If one talks to them, but not to the researchers running new ventures and new programs that offer real signs of progress in different approaches to treating the condition, then one comes away with the idea that everything is intractable and the field is making only slow progress, if it progresses at all. Similarly, in the bigger picture, one cannot look at the longevity industry, ignore the approach of rejuvenation through repair of damage, and come away with anything other than an incomplete view of what is taking place, an incorrect view of what is important for the future, and an incorrect view of what the plausible pace of progress might be in the years ahead.
Can We Live Longer but Stay Younger?
Where fifty years ago it was taken for granted that the problem of age was a problem of the inevitable running down of everything, entropy working its worst, now many researchers are inclined to think that the problem is "epigenetic": it's a problem in reading the information - the genetic code - in the cells. To use a metaphor of the Harvard geneticist David Sinclair, the information in each cell is digital and perfectly stored; it's the "readout," the active expression of the information, that's effectively analogue, and subject to occlusion by the equivalent of dirt and scratches on the plastic surface of a CD. Clear those off, he says, and the younger you, still intact in the information layer, jumps out - just as the younger Beatles jump out from a restored and remastered CD.
We don't have to micromanage the repair, the Harvard molecular biologist George Church observes: "If we think epigenetically, we can see that we can make the cells industriously do the repair themselves." He is among a group of engineer-entrepreneurs who are trying not to make better products for aging people but to make fewer aging people to sell products to. Perhaps aging is not a condition to be managed but a mistake to be fixed. Sinclair, for one, has successfully extended the life of yeast, and says that he is moving on to human trials. He is an evangelist for the advantages of what he calls "hormesis" - the practice of inducing metabolic stress by short intense exercise or intermittent fasting. "Every day, try to be hungry and out of breath" is his neatly epigenetic epigram.
Anti-aging research, in its "translational," or applied, form, seems to be proceeding along two main fronts: through "small molecules," meaning mostly dietary supplements that are intended to rev up the right proteins; and, perhaps more dramatically, through genetic engineering. Typically, genetic engineering involves adding or otherwise manipulating genes in a population of animals, often mice, perhaps by rejiggering a mouse's genome in embryo and then using it to breed a genetically altered strain. In mice studies, genetic modifications that cause the rodents to make greater amounts of a single protein, sirtuin 6, have resulted in longer life spans (although some scientists think that the intervention merely helped male mice to live as long as female mice).
Church and Noah Davidsohn, a former postdoc in his lab, have engaged in a secretive but much talked-about venture to make old dogs new. They have conducted gene therapy on beagles with the Tufts veterinary school, and are currently advertising for Cavalier King Charles spaniels, which are highly prone to an incurable age-related heart condition, mitral-valve disease; almost all of them develop it by the age of ten. Using a genetically modified virus, Church and Davidsohn's team will insert a piece of DNA into a dog's liver cells and get them to produce a protein meant to stop the heart disease from progressing. But the team has larger ambitions. It has been identifying other targets for gene-based interventions, studying a database of aging-related genes: genes that are overexpressed or underexpressed - that make too much or too little of a particular protein - as we grow old. In the CD replay of life, these are the notes that get muffled or amplified, and Davidsohn and Church want to restore them to their proper volume.
Many problems cling to this work, not least that there are surprisingly few "biomarkers" of increased longevity. One researcher makes a comparison with cancer research: we know a patient's cancer has been successfully treated when the cancer cells go away, but how do you know if you've made people live longer except by waiting decades and seeing when they die? Ideally, we'd find something that could be measured in a blood test, say, and was reliably correlated with someone's life span.
Church is optimistic about the genetic-engineering approach. "We know it can work because we've already had success reprogramming embryonic stem cells: you can take a really old cell and turn that back into a young cell. We're doing it now. Most of the work was done in mice, where we've extended the life of mice by a factor of two. It isn't seen as impressive, because it's mice, but now we're working on dogs. There are about nine different pathways that we've identified for cell rejuvenation, one of which eliminates senescent cells" - moldering cells that have stopped dividing and tend to spark inflammation, serving as a perpetual irritant to their neighbors.
Considering the Experience of Being One of the Last Mortals
With the development of rejuvenation therapies underway, and accelerating, somewhere ahead lies a dividing line. Some people will be the last to age to death, too comprehensively damaged for the technologies of the time to recover. Everyone else will live indefinitely in youth and health, protected from aging by periodic repair of the underlying cell and tissue damage that causes dysfunction and disease. Where is that dividing line? No one can say in certainty. I look at the children of today, with long lives ahead of them, and find it hard to believe that in a hundred years the problem won't be solved well in time for them to live for as long as they choose. Equally, people in middle age today will certainly benefit greatly from the advent of first generation rejuvenation technologies, such as senolytics, each narrowly focused on one mechanism of aging. Yet I'm skeptical that matters will progress rapidly enough to rescue them. So somewhere between those two points are the people on the very edge; the last mortals.
In a sense this isn't terribly profound at all. It is the same story for every as yet uncontrolled medical condition, where the medical research community is working towards effective treatments that will arrive at some uncertain future date. There will be those who are the last to die, just as the therapies that save everyone else are rolling out. It is only the magnitude that is greater in the case of aging - a hundred or a thousand times greater. Does the fact that it affects everyone mean that there will be public disorder, disputes between the first immortals and the last mortals, where only private, personal existential crises exist today? I think claims of societal unrest as a result of the realization that your children will live indefinitely, while you yourself will not, are likely overwrought.
The Last Mortals
Ever-growing lifespans are the result of regular advances in medical science. In 1900 the three leading causes of death in the United States were pneumonia/influenza, tuberculosis, and diarrhoea. Only a century and a bit on, many of the major acute illnesses are tractable. Every month brings striking new medical advances. Increasingly, medical research is shifting from acute conditions such as influenza towards chronic conditions including diabetes and Alzheimer's. Ageing is the ultimate chronic condition, and there seems to be no reason, in principle at least, that would prevent us from discovering a means of halting or reversing ageing itself.
What if that all happens sooner rather than later? But what if it's not soon enough? Imagine that, after a few more breakthroughs, a scientific consensus emerges that we will have conquered illness and ageing by the year 2119; anyone alive in 2119 is likely to live for centuries, even millennia. You and I are very unlikely to make it to 2119. But we are likely to make it relatively close to that date - in fact, relative to the span of human history, we've already made it very close right now. Think that through, carefully. What would it mean to realize that you very nearly got to live forever, but didn't? What would it mean if, in our looming senescence, we were increasingly forced to share social space with young people whose anticipated allotment of time massively dwarfs our own? We would then be the last mortals.
To be precise, the kind of immortality I have in mind can be called biological immortality. A biologically immortal organism does not die from illness or ageing - though they may still die in a plane crash. If humans acquired biological immortality, our expected lifespans would jump to enormous lengths. Almost everyone would still eventually die; statistics dictate that if you fly on planes every few weeks for eternity, eventually one will crash. This point allows us to sidestep one of the perennial questions about immortality: is endless life something we'd really want? What is distinctive for biological immortals is that death becomes only a possibility, an option, not an inevitability on a fixed timetable. This sort of immortality, I would think, is definitely not a curse. To have the option of living healthily a very long time, possibly for as long as one could want (but no longer), seems like an unmitigated blessing.
Until now, the wish for immortality was mere fantasy. No one has ever lived beyond 122 years, and no one has reasonably expected to do so. But what happens once the scientists tell us that we're drawing near, that biological immortality will be ready in a generation or two - then what? Seneca told us to meet death cheerfully, because death is "demanded of us by circumstances" and cannot be controlled. Death's inevitability is what makes it unreasonable to trouble oneself. Yet, as I've been arguing, soon death may cease to be inevitable. It may become an option rather than a giver of orders. And, as the fantasy of immortality becomes a reasonable desire, this will generate not only new sorts of failed desires, but also new ways to become profoundly envious.
Cofilin May Link Amyloid-β Aggregation and Tau Aggregation in Alzheimer's Disease
The early stage of Alzheimer's disease is characterized by the slowly increasing aggregation of amyloid-β into solid deposits, something that may occur due to failing clearance of metabolic waste from the brain via drainage paths for cerebrospinal fluid. The complex biochemistry surrounding amyloid-β is damaging to the operation of brain cells, but not damaging enough to cause more than mild cognitive impairment in and of itself. Unfortunately, the presence of amyloid-β also in some way creates the foundation for the second stage of the condition, in which a modified form of tau protein forms aggregates known as neurofibrillary tangles. These aggregates and their surrounding biochemistry are far more harmful, causing major neural dysfunction and cell death in the ultimately fatal end stages of Alzheimer's disease.
How does amyloid-β aggregation cause tau aggregation? The answer is unlikely to be simple, and unlikely to involve only one mechanism, as little in biochemistry is anything other than complicated. There is a good deal of evidence to suggest that chronic inflammation and associated dysfunction of immune cells such as microglia in the central nervous system are important bridging mechanisms between amyloid-β and tau. For example, clearing out senescent microglia and thus reducing neuroinflammation turns back tau aggregation in mouse models. Given present progress in senolytic therapies, it won't be too long now before the research community finds out how well this approach does in humans.
What about other mechanisms, however? Today's research suggests that amyloid-β disrupts the normal activity of tau in a previously unsuspected way. Tau is a normally a part of the cellular cytoskeleton, the microtubules that support cell structure. The presence of amyloid-β encourages another protein, cofilin, to disrupt the microtubules and thus free up tau from its usual location and behavior. The evidence from mice in this study supports the view that this process is important in the generation of the altered forms of tau that eventually form neurofibrillary tangles. How does this process interact with neuroinflammation and bad behavior on the part of microglia? That remains to be determined.
Cofilin may be early culprit in tauopathy process leading to brain cell death
The two primary hallmarks of Alzheimer's disease are clumps of sticky amyloid-beta (Aβ) protein fragments known as amyloid plaques and neurofibrillary tangles of a protein called tau. Abnormal accumulations of both proteins are needed to drive the death of brain cells, or neurons. But scientists still have a lot to learn about how amyloid impacts tau to promote widespread neurotoxicity, which destroys cognitive abilities like thinking, remembering and reasoning in patients with Alzheimer's. While investigating the molecular relationship between amyloid and tau, neuroscientists have now discovered that the Aβ-activated enzyme cofilin plays an essential intermediary role in worsening tau pathology.
The research introduces a new twist on the traditional view that phosphorylation of tau is the most important early event in tau's detachment from brain cell-supporting microtubules and its subsequent build-up into neurofibrillary tangles. These toxic tau tangles disrupt brain cells' ability to communicate, eventually killing them. Without microtubules, axons and dendrites could not assemble and maintain the elaborate, rapidly changing shapes needed for neural network communication, or signaling. Tau molecules are like the railroad track ties that stabilize and hold train rails (microtubules) in place.
Using a mouse model for early-stage tauopathy, researchers showed that Aβ-activated cofilin promotes tauopathy by displacing the tau molecules directly binding to microtubules, destabilizes microtubule dynamics, and disrupts synaptic function - all key factors in Alzheimer's disease progression. Unactivated cofilin did not. The researchers also demonstrated that genetically reducing cofilin helped prevent the tau aggregation leading to Alzheimer's-like brain damage in mice. "Our data suggests that cofilin kicks tau off the microtubules, a process that possibly begins even before tau phosphorylation. That's a bit of a reconfiguration of the canonical model of how the pathway leading to tauopathy works."
Activated cofilin exacerbates tau pathology by impairing tau-mediated microtubule dynamics
Alzheimer's disease (AD) is a progressive neurodegenerative disorder and the most common form of dementia. While the accumulation of Aβ is pivotal to the etiology of AD, both the microtubule-associated protein tau (MAPT) and the F-actin severing protein cofilin are necessary for the deleterious effects of Aβ. However, the molecular link between tau and cofilin remains unclear. In this study, we found that cofilin competes with tau for direct microtubule binding in vitro, in cells, and in vivo, which inhibits tau-induced microtubule assembly. Genetic reduction of cofilin mitigates tauopathy and synaptic defects in Tau-P301S mice and movement deficits in tau transgenic C. elegans. The pathogenic effects of cofilin are selectively mediated by activated cofilin, as active but not inactive cofilin selectively interacts with tubulin, destabilizes microtubules, and promotes tauopathy. These results therefore indicate that activated cofilin plays an essential intermediary role in neurotoxic signaling that promotes tauopathy.
Reviewing the Reserve Supply of Immature Neurons in the Adult Brain
To what degree can the adult brain restructure and regenerate itself? In one sense the components of the central nervous system, brain included, are clearly among the least regenerative of tissues in mammalian species. In another sense the brain is capable of significant compensatory change following damage. Further, the normal operation of the brain over time depends upon the plasticity of neural circuits in response to changing circumstances: learning, memory, and so forth.
The authors of today's open access research propose that these capacities for regeneration and change may arise not just from a supply of daughter cells created by neural stem cell populations, but also from a reserve population of immature neurons that are generated during early development and then retained throughout life. This hypothesis lacks solid evidence, but it is this sort of speculation - what is this apparently inactive cell population actually doing? - that drives further investigations.
Looking at the broader picture, it is a question of great interest to researchers in the field as to whether or not it is possible to upregulate the existing mechanisms of repair and plasticity in the central nervous system. Are there comparatively simple signal or regulatory proteins that can be targeted to change cell behavior in ways that provoke greater regeneration and maintenance in the aging brain? This is an open question for human medicine, though it is certainly the case that many studies in mice have provided promising data over the years. It remains to be seen as to where that work will lead.
Newly Generated and Non-Newly Generated "Immature" Neurons in the Mammalian Brain: A Possible Reservoir of Young Cells to Prevent Brain Aging and Disease?
The aging of the brain, especially in the light of a progressive increase of life expectancy, will impact the majority of people during their lifetime, putting at stake their later life and that of their relatives. This cannot be seen only as a health problem for patients but as a more general, worrisome, social, and economic burden. In spite of fast and substantial advancements in neuroscience/neurology research, resolutive therapeutic solutions are lacking.
For a long time, some hopes have been recognized in structural plasticity: The possibility for a "generally static" brain to undergo structural changes throughout life that may go beyond the modifications of synaptic contacts between pre-existing neuronal elements. During the last five decades, the discovery that the genesis of new neurons (adult neurogenesis) can still occur in some regions of the central nervous system (CNS) supported such hopes, suggesting that young, fresh neurons might replace the lost/damaged ones.
The real roles and functions of adult neurogenesis are far from being elucidated, and it appears clear that the new neurons can mainly serve physiological functions within the neural circuits, rather than being useful for repair. Interestingly, and adding further complexity, non-newly generated, immature neurons sharing the same molecular markers of the newly born cells are also present in the mature brain.
Independently from any specific physiological function (at present unknown), the novel population of "immature" neurons (nng-INs) raise interest in the general context of mammalian structural plasticity, potentially representing an endogenous reserve of "young", plastic cells present in cortical and subcortical brain regions. Finding more about such cells, especially regarding their topographical and phylogenetic distribution, their fate with increasing age, and the external/internal stimuli that might modulate them, would open new roads for preventive and/or therapeutic approaches against age-related brain damage and cognitive decline.
A current hypothesis is that in the large-brained, long-living humans the neurons generated at young ages might mature slowly, maintaining plasticity and immaturity for very long periods. Hence, immature neurons, intended as both newly generated (in neurogenic sites) and non-newly generated (nng-INs in cortex and subcortical regions), might represent a form of "reserve" of young neurons in the absence of continuous cell division. In this context, solid evidence suggests that "adult" neurogenesis in mammals should not be considered as a constitutive, continuous process taking place at the same rate throughout life, but rather as an extension of embryonic neurogenesis, which can persist for different postnatal periods by decreasing (even ceasing) at different ages and in different brain regions.
There is no sharp boundary between developmental processes and subsequent tissue maintenance and aging processes and some events, such as adult neurogenesis, have all the hallmarks of late developmental processes. In that sense, adult neurogenesis is not at all similar to the cell renewal/regenerative processes known to occur in other stem cell systems, such as the skin, blood, or bone; rather, it is characterized by progressive neural stem cell/progenitor depletion, the cell addition being directed at the completion of organ or tissue formation, not at the replacement of lost cells. This aspect is more prominent and precocious in large-brained mammals, especially humans.
VCAM1 Levels Correlate with Parkinson's Disease Severity
Levels of VCAM1 in the bloodstream increase with age, and it appears to be an important signal molecule in at least the brain. Its expression is upregulated by inflammatory cytokines, and so is a marker of inflammatory disease. Chronic inflammation of course increases with age. Researchers have shown that blocking VCAM1 can prevent suppression of neurogenesis due to delivery of old blood plasma into young mice, which is an interesting result, as one might not expect detrimental reactions to inflammatory signaling to have such a narrow bottleneck of regulation. Would a method of interfering with VCAM1 assist in tissue maintenance and cognitive function in older individuals? That remains to be determined with any certainty. The work here showing a correlation between VCAM1 and severity of Parkinson's disease, a neurodegenerative condition, reinforces the point that high levels of VCAM1 are undesirable.
There is increasing evidence that Parkinson's disease (PD) pathology is accompanied by ongoing inflammatory processess. This neuroinflammatory component is particularly relevant for better understanding disease progression accordingly developing disease-modifying therapies. Therefore, the present study explored dysregulated inflammatory profiles in the peripheral blood cells and plasma of PD patients within the context of established clinical indicators. We performed a screening of selected cell-surface chemokine receptors and adhesion molecules in peripheral blood mononuclear cells (PBMCs) from PD patients and age-matched healthy controls in a flow cytometry-based assay. ELISA was used to quantify VCAM1 levels in the plasma of PD patients.
The present data illustrate the role soluble VCAM1 (sVCAM1) levels may play in PD pathology. The levels of sVCAM1 observed here were even higher than those reported for patients with rheumatoid arthritis, multiple sclerosis, and neuromyelitis optica. Although substantial evidence exists for the association between increased sVCAM1 and age and cognitive impairment, the use of age-matched healthy donors in this study has illustrated that the increase observed in PD is independent of physiological aging. Furthermore, sVCAM1 correlated with both disease stage and the motor aspects of daily living.
Whether elevated sVCAM1 levels actively drive disease progression in PD or are a consequence of it remains to be fully understood. Of note, VCAM1 has already been implicated to be a potential mediator of PD pathogenesis. Thus, whether targeting the VCAM1-VLA4-axis is a viable therapeutic avenue remains to be established. Indeed, promising evidence for the therapeutic potential of the VCAM1-VLA4 axis in age-related pathologies of the central nervous system already exists; it has been shown that blocking VCAM1 slows down normal brain aging, induces neurogenesis, and ameliorates neuroinflammation. Our chemotaxis assay revealed diminished lymphocytic migration in PD patients which may be indicative of compromised cellular adherence and infiltration of endothelial barriers. Therefore, additional investigations and in vivo studies addressing both the expression and functional state of VCAM1 on brain endothelial cells are necessary.
Impaired Insulin Signaling and Chronic Inflammation in the Alzheimer's Brain
In past years, there has been considerable discussion of Alzheimer's disease as a type 3 diabetes. This is by no means a formal designation, but enough papers have put forward the concept that when a new version of diabetes was in fact discovered not so long ago, it had to be designated type 4. Why call Alzheimer's a form of diabetes? Because dysregulation of insulin metabolism appears to be a feature of the condition. In the paper here, these issues with insulin signaling are linked to the generation of chronic inflammation. This makes a great deal of sense in the broader context of what is known of Alzheimer's disease, as dysregulation of immune cells in the brain, and rising levels of inflammatory signaling, are thought to arise from the presence of amyloid-β and in turn generate tau aggregates and severe pathology in the brain. In effect, inflammation bridges the early, mild stages of the condition and the later severe stages and their very different biochemistries.
Recently, type 2 diabetes mellitus (T2DM) has been identified as a risk factor for Alzheimer's disease (AD). Epidemiological studies of patient data sets have found a clear correlation between T2DM and the risk of developing AD or other neurodegenerative disorders. In one study, 85% of AD patients had diabetes or showed increased fasting glucose levels, compared to 42% in age-matched controls. In longitudinal studies of cohorts of people, it was found that glucose intolerance was a good predictor for the development of dementia later in life.
When analyzing the brain tissue of AD patients, it was observed that insulin signaling was much desensitized, even in AD patients that did not have T2DM. One study found that the levels of insulin, IGF-1, and IGF-II were much reduced in brain tissue. In addition, levels of the insulin receptor, the insulin-receptor associated PI3-kinase, and activated Akt/PKB kinase were much reduced. A second study found increased levels of IGF-1 receptors and the localization of insulin receptors within cells rather than on the cell surface where they could function.
Insulin is an important growth factor that regulates cell growth, energy utilization, mitochondrial function and replacement, autophagy, oxidative stress management, synaptic plasticity, and cognitive function. Insulin desensitization, therefore, can enhance the risk of developing neurological disorders in later life. Other risk factors, such as high blood pressure or brain injury, also enhance the likelihood of developing AD. All these risk factors have one thing in common - they induce a chronic inflammation response in the brain. Insulin reduces the chronic inflammation response by inhibiting secondary cell signaling induced by pro-inflammatory cytokines. A desensitization of insulin signaling enhances the inflammation response and the desensitization observed in T2DM, therefore, not only compromises growth factor signaling, and energy utilization in the brain, but also facilitates the chronic inflammation response.
Another Cholesterol-Lowering Variant that Reduces Heart Disease Risk, but This One Has Unfortunate Side Effects
In recent years, researchers have discovered a number of human gene variants or mutations that significantly lower blood cholesterol, and this also the risk of heart disease, such as DSCAML1, ANGPTL4, and ASGR1. Why does this work? Oxidized cholesterol contributes to the development of atherosclerosis with advancing age, by causing macrophages to falter in their work of removing cholesterol from blood vessel walls, become inflammatory, transform into foam cells, and die, leaving debris that grows the lesions the cells are trying to repair. Reducing overall cholesterol works because it reduces oxidized cholesterol as well.
Yet this business of reducing blood cholesterol is unfortunately far from the most efficient way to tackle atherosclerosis. It can only slow it down, and not produce significant reversal of existing fatty lesions in blood vessel walls. Nonetheless, when lowered cholesterol levels are in place for the entire lifespan rather than just as a result of statin drugs in later life, and there is a considerable prevention effect, then effect sizes can be quite large. Sadly, the mutation in APOB noted here has unpleasant side-effects that make this gene and its protein a less desirable target for therapy than the others mentioned above.
A new study finds that protein-truncating variants in the apolipoprotein B (APOB) gene are linked to lower triglyceride and LDL cholesterol levels, and lower the risk of coronary heart disease by 72 percent. Protein-truncating variants in the APOB gene are among the causes of a disorder called familial hypobetalipoproteinemia (FHBL), which causes a person's body to produce less low-density lipoproteins (LDL) and triglyceride-rich lipoproteins. People with FHBL generally have very low LDL cholesterol, but are at high risk of fatty liver disease.
"An approved drug, Mipomersen, mimics the effects of having one of these variants in APOB, but due to the risk of fatty liver disease, clinical trials for cardiovascular outcomes won't be done. Using genetics, we provided evidence that targeting this gene could reduce the risk of coronary heart disease."
The researchers sequenced the APOB gene in members of 29 Japanese families with FHBL. Eight of the Japanese families had protein-truncating variants in APOB, and individuals with one of those variants had LDL cholesterol levels 55 mg/DL lower and triglyceride levels 53 percent lower than individuals who did not have an APOB variant. The researchers also sequenced the APOB gene in 57,973 participants of a dozen coronary heart disease case-control studies of people with African, European, and South Asian ancestries, 18,442 of whom had early-onset coronary heart disease. Again, they found that people with these APOB gene variants had lower LDL cholesterol and triglyceride levels. Only 0.038 percent of the people with coronary heart disease carried an APOB variant, while 0.092 percent of those without coronary heart disease did, indicating that carrying gene variants in APOB reduces the risk of coronary heart disease.
Cellular Senescence in the Development of Cataracts
The ability to selectively destroy senescent cells through the use of senolytic therapies doesn't make greater understanding of the biochemistry of senescent cells irrelevant, but it does mean that we don't have to wait around for that greater understanding to arrive in order for the development of therapies to get started. Destroy the bad cells now, benefit the patients now, and let the ongoing research proceed at its own pace. The open access paper here is an example of that ongoing research, an exploration of the proteins that might be important in cellular senescence in cataracts, a prominent cause of age-related blindness. Regardless of the outcome here, senolytic therapies should be under development to treat cataracts now, not later.
Senescence is a leading cause of age-related cataract (ARC). The current study indicated that the senescence-associated protein, p53, total laminin (LM), LMα4, and transforming growth factor-beta1 (TGF-β1) in the cataractous anterior lens capsules (ALCs) increase with the grades of ARC. In cataractous ALCs, patient age, total LM, LMα4, TGF-β1, were all positively correlated with p53.
In lens epithelial cell senescence models, matrix metalloproteinase-9 (MMP-9) alleviated senescence by decreasing the expression of total LM and LMα4; TGF-β1 induced senescence by increasing the expression of total LM and LMα4. Furthermore, MMP-9 silencing increased p-p38 and LMα4 expression; anti-LMα4 globular domain antibody alleviated senescence by decreasing the expression of p-p38 and LMα4; pharmacological inhibition of p38 MAPK signaling alleviated senescence by decreasing the expression of LMα4. Finally, in cataractous ALCs, positive correlations were found between LMα4 and total LM, as well as between LMα4 and TGF-β1.
Taken together, our results implied that the elevated LMα4, which was possibly caused by the decreased MMP-9, increased TGF-β1 and activated p38 MAPK signaling during senescence, leading to the development of ARC. LMα4 and its regulatory factors show potential as targets for drug development for prevention and treatment of ARC.
Repeated Cycles of Incomplete Healing as a Cause of Aging
The authors of the open access paper here have an intriguing view of the way in which regenerative processes run awry with age, and thus contribute to the aging process. As is the case for many single mechanism proposals regarding aging, I think that the viewpoint is useful, but the mechanism in question is probably not as important to aging as proposed here - it is one of many issues. Nonetheless, this is an interesting example of the way in which it is hard to pin down the ordering of specific mechanisms in aging; it is quite possible to argue for A to cause B or B to cause A and present a good case for either. Here, for example, dysregulated regeneration is thought to be a cause of senescent cell accumulation, whereas it is equally possible to argue that the chronic inflammatory signaling produced by senescent cells disrupts the usual short-lived cycle of inflammation that is necessary to coordinate various cell populations necessary to the regenerative process.
The rate of biological aging varies cyclically and episodically in response to changing environmental conditions and the developmentally-controlled biological systems that sense and respond to those changes. Mitochondria and metabolism are fundamental regulators, and the cell is the fundamental unit of aging. However, aging occurs at all anatomical levels. At levels above the cell, aging in different tissues is qualitatively, quantitatively, and chronologically distinct. For example, the heart can age faster and differently than the kidney and vice versa. Two multicellular features of aging that are universal are: (1) a decrease in physiologic reserve capacity, and (2) a decline in the functional communication between cells and organ systems, leading to death.
Decreases in reserve capacity and communication impose kinetic limits on the rate of healing after new injuries, resulting in dyssynchronous and incomplete healing. Exercise mitigates against these losses, but recovery times continue to increase with age. Reinjury before complete healing results in the stacking of incomplete cycles of healing. Developmentally delayed and arrested cells accumulate in the three stages of the cell danger response (CDR1, 2, and 3) that make up the healing cycle. Cells stuck in the CDR create physical and metabolic separation - buffer zones of reduced communication - between previously adjoining, synergistic, and metabolically interdependent cells. Mis-repairs and senescent cells accumulate, and repeated iterations of incomplete cycles of healing lead to progressively dysfunctional cellular mosaics in aging tissues.
Metabolic cross-talk between mitochondria and the nucleus, and between neighboring and distant cells via signaling molecules called metabokines regulates the completeness of healing. Purinergic signaling and sphingolipids play key roles in this process. When viewed against the backdrop of the molecular features of the healing cycle, the incomplete healing model provides a new framework for understanding the hallmarks of aging and generates a number of testable hypotheses for new treatments.
A Conservative View of the Present State of Senolytic Development for Rejuvenation
Here, one of the leading researchers working on the biochemistry of senescent cells - and their relevance to aging - considers the state of development of senolytic therapies. These are treatments, largely small molecule drugs at this stage, but also including suicide gene therapies, immunotherapies, and more, that are capable of selectively destroying some fraction of the senescent cells present in old tissues. There is tremendous enthusiasm in the scientific and development communities for the potential to create significant degrees of rejuvenation via this approach. The results in mice are far and away more impressive and reliable than anything else that has yet been tried in the matter of aging and age-related disease. Simple one time treatments with senolytics lead to significant extension of life span and reversal of aspects of age-related disease. Leading researchers, of course, have to be far more muted when writing for scientific journals, so the tone here is more cautious than enthused.
Healthy aging is limited by a lack of natural selection, which favors genetic programs that confer fitness early in life to maximize reproductive output. There is no selection for whether these alterations have detrimental effects later in life. One such program is cellular senescence, whereby cells become unable to divide. Cellular senescence enhances reproductive success by blocking cancer cell proliferation, but it decreases the health of the old by littering tissues with dysfunctional senescent cells (SNCs). In mice, the selective elimination of SNCs (senolysis) extends median life span and prevents or attenuates age-associated diseases. This has inspired the development of targeted senolytic drugs to eliminate the SNCs that drive age-associated disease in humans.
SNCs produce a bioactive "secretome," referred to as the senescence-associated secretory phenotype (SASP). This can disrupt normal tissue architecture and function through diverse mechanisms, including recruitment of inflammatory immune cells, remodeling of the extracellular matrix, induction of fibrosis, and inhibition of stem cell function. Paradoxically, although cellular senescence has evolved as a tumor protective program, the SASP can include factors that stimulate neoplastic cell growth, tumor angiogenesis, and metastasis, thereby promoting the development of late-life cancers. Indeed, elimination of SNCs with aging attenuates tumor formation in mice, raising the possibility that senolysis might be an effective strategy to treat cancer.
Given that our knowledge of SNCs in vivo is limited, how should researchers identify senolytic drug targets? One strategy is to identify vulnerabilities shared by cancer cells and SNCs and then use tailored variants of anticancer agents to target such vulnerabilities to selectively eliminate SNCs. Although cancer therapeutics that interfere with cell division are unsuitable as senolytic drugs, agents that block the pathways that cancer cells rely on for survival might be worth pursuing as senolytics. For example, resistance to apoptosis (a form of programmed cell death) is a feature shared by cancer cells and SNCs. Proof-of-principle evidence for the effectiveness of this strategy comes from targeting the BCL-2 protein family members: BCL-2, BCL-XL, and BCL-W. These antiapoptotic proteins are frequently overexpressed in both cancer cells and SNCs. Two targeted cancer therapeutic agents, ABT-263 and ABT-737, have been shown to selectively eliminate SNCs in mice by blocking the interactions of BCL-2, BCL-XL, and BCL-W.
Senolytic drugs that inhibit targets originally discovered in oncology could yield promising first-generation drugs to treat humans. However, this strategy may not accomplish the long-term goal of developing ideal senolytics that selectively, safely, and effectively eliminate SNCs upon systemic administration. Efforts to identify such "next-generation" senolytics could nonetheless benefit from general principles that have been used in anticancer drug discovery. For instance, it will be important to focus drug development on age-associated degenerative diseases in which SNCs are clear drivers of pathophysiology and in which senolysis could be disease modifying (e.g., osteoarthritis and atherosclerosis).
As knowledge of the fundamental biology and vulnerabilities of SNCs expands, the rational design of targeted senolytics is expected to yield therapies to eliminate SNCs that drive degeneration and disease. This positive outlook is based on successes in oncology and because the main limitation of cancer therapies - the clonal expansion of drug-resistant cells - does not apply to SNCs. Additional confidence comes from the recent progress in bringing senolytic agents into clinical trials. The first clinical trial is testing UBX0101 for the treatment of osteoarthritis of the knee. Success in these first clinical studies is the next critical milestone on the road to the development of treatments that can extend healthy longevity in people.
The Pension Industry Will Change Radically, Willingly or Otherwise
Promises to pay at a future date are a dangerous tool in the hands of politicians and state employees, those who suffer little to no personal consequences when past promises are revealed to be based on faulty assumptions and thin air. Either someone ends up paying, usually the taxpayers, or the promises are broken. Pensions are, of course, just such a promise. The pensions industry in the US is a good example of the way in which entitlement schemes run awry even without any sort of external shock to the system, such as large numbers of pension recipients suddenly living 5-10 years longer than the models predict. This seems likely to happen in the relatively near future, given progress towards the effective targeting of mechanisms of aging by the research and medical development communities. There must and will be radical change in pensions, either willingly or otherwise.
If you work in social security, it's possible that your nightmares are full of undying elderly people who keep knocking on your door for pensions that you have no way of paying out. Tossing and turning in your bed, you beg for mercy, explaining that there's just too many old people who need pensions and not enough young people who could cover for it with their contributions; the money's just not there to sustain a social security system that, when it was conceived in the mid-1930s, didn't expect that many people would ever make it into their 80s and 90s.
When you wake up, you're relieved to realize that there can't be any such thing as people who have ever-worsening degenerative diseases yet never die from them, but that doesn't make your problem all that better; you still have quite a few old people, living longer than the pension system had anticipated, to pay pensions to, and the bad news is that in as little as about 30 years, the number of 65+ people worldwide will skyrocket to around 2.1 billion, growing faster than all younger groups put together. Where in the world is your institution going to find the budget?
Suppose for a moment that human aging never existed and that, barring accidents and communicable diseases, people went on living for centuries - their health, independence, and most importantly, ability to work, remaining pretty much constant over time. In a scenario like this, it's difficult to imagine why any government would go through the trouble of setting up a pension system that works the way the current one does. Paying out money to perfectly able-bodied people to do nothing for the rest of their lives just because they're over 65 would make no sense at all.
Thus retirement exists out of necessity more than desire. The health of average retirees doesn't interfere just with their ability to work but also to enjoy life in general. Most people over the age of 65 suffer two or more chronic illnesses; the risk of developing diabetes, cancer, cardiovascular diseases, dementia, and so on skyrockets with age. Many people imagine a longer, drawn-out old age in which ill health and the consequent medical expenses and pensions are extended accordingly, just as in the nightmares of social security planners. This is most definitely not what life extension is about, and it's obvious that extending old age as it is right now would not be a solution to the problem of pensions.
However, lifespan and healthspan - that is, the length of your life and the portion of life you spend in good health - are causally connected; you don't just drop dead because you're 80 or 90 irrespective of how healthy you are. The reason we tend to die at around those ages is that our bodies accumulate different kinds of damage in a stochastic fashion; as time goes by, the odds of developing diseases or conditions that eventually become fatal go higher and higher, even though which specific condition will kill you depends a lot on your genetics, lifestyle, and personal history. The idea behind life extension isn't to just "stretch" lifespan; rather, the idea is to extend healthspan, that is preserving young-adult-like good health well into your 80s or 90s, and the logical consequence of being perfectly healthy for longer is that you will also live for longer.
Again, the fundamental reason that pensions exist is to economically support people who are no longer able to do it themselves. We need to have such a system in place if we don't want to abandon older people to their fate. If life extension treatments take ill health and age-related disabilities out of the equation entirely, pensions as we know them today will no longer be needed, because you will be able to support yourself through your own work regardless of your age.
Walking Pace Correlates with Life Expectancy
Walking pace, like grip strength, is one of the simple measures used by physicians to assess the progression of frailty in old age. Researchers here report on epidemiological data that shows an association between life expectancy and walking pace, in that older individuals who walk more slowly tend to have a shorter life expectancy. This is only to be expected: a slower pace tends to arise due to the presence of chronic age-related disease, lack of fitness, and in general a higher burden of cell and tissue damage, all of which are known to lead to a greater mortality risk.
People who report that they have a slower walking pace have a lower life expectancy than fast walkers. The research, using data from the UK Biobank of 474,919 people recruited within the UK, found those with a habitually fast walking pace have a long life expectancy across all levels of weight status - from underweight to morbidly obese. Underweight individuals with a slow walking pace had the lowest life expectancy (an average of 64.8 years for men, 72.4 years for women). The same pattern of results was found for waist circumference measurements. This is the first time research has associated fast walking pace with a longer life expectancy regardless of a person's body weight or obesity status.
"Our findings could help clarify the relative importance of physical fitness compared to body weight on life expectancy of individuals. In other words, the findings suggest that perhaps physical fitness is a better indicator of life expectancy than body mass index (BMI), and that encouraging the population to engage in brisk walking may add years to their lives. Studies published so far have mainly shown the impact of body weight and physical fitness on mortality in terms of relative risk, for example a 20 per cent relative increase of risk of death for every 5 unit BMI increase, compared to a reference value of a BMI of 25 (the threshold between normal weight and overweight). However, it is not always easy to interpret a "relative risk". Reporting in terms of life expectancy, conversely, is easier to interpret and gives a better idea of the separate and joint importance of body mass index and physical fitness."
How Might Nutrient Rich Diets Turn Our Gut Bacteria Against Us?
Nutrient rich diets are harmful, even if only considering the accumulation of visceral fat tissue that results from eating more calories than are strictly necessary for sustained periods of time. Visceral fat tissue produces chronic inflammation, and that in turn accelerates progression of all of the common age-related conditions. High nutrient diets also have an effect on gut bacteria, however, and it is becoming apparent that the state of these bacterial populations has a noteworthy influence on the course of long-term health. This may be as large an effect as that of exercise, but this remains to be determined in certainty.
Together with our microbes, we form a synergist relation, which is termed holobiont or metaorganism. Disturbance of this host-microbe homeostasis can lead to dysbiosis (microbial imbalance on or inside the host) and/or disease development. It is well documented that inflammatory diseases are accompanied by changes in microbial density or microbial community composition. However, comprehensive sequencing approaches have not yet led to the identification of a key pathogen, nor to the discovery of a specific pathobiome that is responsible for the disease. On the contrary, it is becoming more and more apparent that our associated microbiota is not as specific as we thought and that, even within the same individual, microbial community composition underlies strong temporal variability.
Inflammatory diseases, such as inflammatory bowel diseases, are dramatically increasing worldwide, but an understanding of the underlying factors is lacking. We here present an ecoevolutionary perspective on the emergence of inflammatory diseases. We propose that adaptation has led to fine-tuned host-microbe interactions, which are maintained by secreted host metabolites nourishing the associated microbes.
A constant elevation of nutrients in the gut environment leads to an increased activity and changed functionality of the microbiota, thus severely disturbing host-microbe interactions and leading to dysbiosis and disease development. In the past, starvation and pathogen infections, causing diarrhea, were common incidences that reset the gut bacterial community to its "human-specific-baseline." However, these natural clearing mechanisms have been virtually eradicated in developed countries, allowing a constant uncontrolled growth of bacteria. This leads to an increase of bacterial products that stimulate the immune system and ultimately might initiate inflammatory reactions.
Mitochondrial DNA Damage in Age-Related Macular Degeneration
One of the early features of age-related macular degeneration, in which the retina degenerates, causing progressive blindness, is a rising level of oxidative stress in the retinal pigment epithelium. Researchers here consider a role for mitochondrial DNA damage in the generation of this oxidative damage. Mitochondria are the power plants of the cell, descendants of ancient symbiotic bacteria that still retain a little of their original DNA. They carry out energetic chemical operations that result in a flow of oxidative molecules as a by-product. Damage to mitochondrial DNA that causes loss of proteins essential to the molecular machinery inside a mitochondrion can lead to a sizable leap in production of oxidative molecules, not just by mitochondria, but exported by the cell into the surrounding tissue.
Age-related macular degeneration (AMD) is a complex eye disease that affects millions of people worldwide and is the main reason for legal blindness and vision loss in the elderly in developed countries. Although the cause of AMD pathogenesis is not known, oxidative stress-related damage to retinal pigment epithelium (RPE) is considered an early event in AMD induction. However, the precise cause of such damage and of the induction of oxidative stress, including related oxidative effects occurring in RPE and the onset and progression of AMD, are not well understood.
Many results point to mitochondria as a source of elevated levels of reactive oxygen species (ROS) in AMD. This ROS increase can be associated with aging and effects induced by other AMD risk factors and is correlated with damage to mitochondrial DNA. Therefore, mitochondrial DNA (mtDNA) damage can be an essential element of AMD pathogenesis. This is supported by many studies that show a greater susceptibility of mtDNA than nuclear DNA to DNA-damaging agents in AMD. Therefore, the mitochondrial DNA damage reaction (mtDDR) is important in AMD prevention and in slowing down its progression as is ROS-targeting AMD therapy. However, we know far less about mtDNA than its nuclear counterparts. Further research should measure DNA damage in order to compare it in mitochondria and the nucleus, as current methods have serious disadvantages.