Fight Aging! Newsletter, June 3rd 2019

Nobuaki Nagashima was in his mid-20s when he began to feel like his body was breaking down. He was based in Hokkaido, the northernmost prefecture of Japan, where for 12 years he had been a member of the military, vigorously practising training drills out in the snow. It happened bit by bit - cataracts at the age of 25, pains in his hips at 28, skin problems on his leg at 30. At 33, he was diagnosed with Werner syndrome, a disease that causes the body to age too fast. Among other things, it shows as wrinkles, weight loss, greying hair, and balding. It's also known to cause hardening of the arteries, heart failure, diabetes, and cancer.

DNA, and the histones that package it up, can acquire chemical marks. These don't change the underlying genes, but they do have the power to silence or to amplify a gene's activity. Steve Horvath, professor of human genetics and biostatistics at the University of California, Los Angeles, has used one type of these, called methylation marks, to create an "epigenetic clock" that, he says, looks beyond the external signs of ageing like wrinkles or grey hair, to more accurately measure how biologically old you are. The marks can be read from blood, urine, organ or skin tissue samples. Horvath's team analysed blood cells from 18 people with Werner syndrome. It was as if the methylation marking was happening on fast-forward: the cells had an epigenetic age notably higher than those from a control group without Werner.

Scientists now understand that WRN is key to how the whole cell, how all our DNA works - in reading, copying, unfolding and repairing. Disruption to WRN leads to widespread instability throughout the genome. "The integrity of the DNA is altered, and you get more mutations... more deletions and aberrations. This is all over the cells. Big pieces are cut out and rearranged." The abnormalities are not just in the DNA but in the epigenetic marks around it too. The big question is whether these marks are imprints of diseases and ageing or whether the marks cause diseases and ageing - and ultimately death. And if the latter, could editing or removing epigenetic marks prevent or reverse any part of ageing or age-related disease?

Before we can even answer that, the fact is, we know relatively little about the processes through which epigenetic marks are actually added and why. Horvath sees methylation marks as like the face of a clock, not necessarily the underlying mechanism that makes it tick. The nuts and bolts may be indicated by clues like the WRN gene, and other researchers have been getting further glimpses beneath the surface. There's a feverishness around the idea of resetting or reprogramming the epigenetic clock, Horvath tells me. He sees huge potential in all of it, but says it has the feel of a gold rush. "Everybody has a shovel in their hand."

The cerebrospinal fluid (CSF) is an important part of the central nervous system, as it allows exchange of water, small molecules, and proteins between the brain parenchyma and arterial and venous blood, by either passive diffusion or active transport. The CSF therefore plays an important role in regulating brain homeostasis, waste clearance, as well as intracranial pressure and blood supply. During aging, CSF turnover can be disrupted which could contribute to the etiology of age-related neurocognitive disorders. Several studies revealed that patients with Alzheimer's disease (AD) have disrupted CSF pressure, turnover, and oscillations. Moreover, biomarkers for AD are found in the CSF, and their abundance was shown to have predictive value for clinical progression.

The increase of intracranial pressure during the cardiac cycle causes a flow from the blood and brain interstitial fluid to the CSF, and a net CSF flow toward its extracerebral compartment and venous blood. Since this CSF flow is important for protein clearance from the brain, it is possible that impaired CSF flow could be associated with cognitive decline. Moreover, CSF flow is linked with brain perfusion, defects of which are known causes of neurocognitive disorders in the elderly. A number of studies suggested that the choroid plexus and the ventricular walls degenerate with the progression of AD, but none could determine whether disrupted CSF flow causes cognitive decline, or whether it is a by-product of AD or normal aging.

To the authors' knowledge, there are no published studies that investigated the relationship between CSF flow alterations and cognitive deficit in the elderly, adjusting for cardiovascular risk factors for the development of neurocognitive disorders. The purpose of this study was therefore to evaluate the association of CSF flow in the brain ventricles and cervical spine with cognitive deficit in a cohort of elderly patients admitted to our geriatric unit for non-acute reasons. The hypothesis was that reduced CSF flow would be associated with cognitive deficit.

The cohort comprised 71 women and 21 men, aged 73 to 96 years. Patients with lower CSF flow had significantly worse memory, visuo-constructive capacities, and verbal fluency. It is therefore possible that CSF flow alterations are responsible for at least a part of the cognitive deficit observed in our patients. Better diagnosis and treatment of CSF flow alterations in geriatric patients suffering from neurocognitive disorders is therefore recommended.

It is often argued that improvements in population health, and life expectancy in particular, are best pursued via investments in medical services. Over the last few decades evidence has accumulated, showing that more powerful determinants of health and life expectancy lie elsewhere. Making high-yield investments to extend life expectancy requires an understanding of the relative contributions of health care and other determinants of health to health outcomes. It is estimated that a lack of access to medical care accounts for only about 10% of premature deaths. The methodology underlying these estimates, however, remains obscure. In this article we review four different estimates of the contributions of health care to premature mortality and other health outcomes.

The estimates converge around Schroeder's conclusion that health care accounts for between 5% and 15% of the variation in premature death. The various methods were consistent in showing that social and behavioral factors account for a much higher percentage of the variation in premature mortality than health care does. For example, the McGinnis/Schroeder method estimates that social circumstances account for about 15% of the variance in early mortality. The Wennberg method estimates that social circumstances account for 29% of variability, and the Park model estimates that social effects account for 46%. Similarly, the McGinnis/Schroeder method estimates that behavior patterns account for 40% of the variability in early mortality, the Wennberg method estimates 65%, and the Park method estimates 29%. In sum, these methods indicate that social and behavioral factors account for substantially more of the variability in premature mortality than health care does.

The suggestion that health care services account for only a small percentage of the variation in national life expectancy has important implications. Both personal and institutional health care expenditures are justified by confidence that health care spending enhances longevity and other indices of population health. Efforts to model the value of health care spending often assume that 100% of the variation in health outcomes is attributable to health care services. Even the most sophisticated models assume that 50% of the variation in population health is attributable to health care. Our analyses reaffirm the belief that health care is one component of a larger set of influences on health outcomes.

Aging is an inevitable biological process. Senescent cells accumulating in various tissues during aging contribute to organismal aging and disrupt wound healing after injury. Pressure ulcer wounds, particularly for elderly populations, have been reported to heal poorly, because of aging-related changes in skin tissue. Stem cells, holding great therapeutic promise for various aging-related disorders, have been demonstrated to accelerate wound healing in aged mice, though the underlying mechanisms remain unclear. And, whether stem cell-derived exosomes could promote wound healing in aged individuals is barely reported. In this study, exosomes from human embryonic stem cells (ESC-Exos) were locally applied to treat pressure ulcer wounds in an aged mice model induced by D-gal treatment. We found that chronic ESC-Exos treatment effectively rejuvenate endothelial cell senescence and promote angiogenesis, enhancing wound healing.

Angiogenesis, the process by which new blood vessels are formed, plays vital roles in wound healing. We have previously reported that the underlying mechanisms of tissue recovery after exosome treatment partly involve exosome-mediated pro-angiogenesis effects, including cutaneous wound healing, ischemic hindlimb injury repair, and bone regeneration. Vascular endothelial cells are major effector cells in the angiogenic process of pressure ulcer healing; aging-related endothelial dysfunction and impaired angiogenesis likely contribute to delayed wound healing in the elderly. And applying anti-aging agents to wound beds could rejuvenate cutaneous cell viability, promote neo-vascularization, and enhance wound healing in aged skin. Thus, rejuvenating endothelial senescent cells and reversing aging-associated angiogenic dysfunction seem to comprise a promising therapeutic approach for wound healing in aged individuals.

In our study, we found that the number of senescent endothelial cells at wound beds was significantly reduced after chronic application of ESC-Exos. Also, D-gal-induced senescence in HUVECs was used to evaluate the rejuvenative effects of ESC-Exos in vitro; we found that endothelial senescence is correlated with a decrease in endothelial function (e.g., proliferative, migrative, and tube formation capacities), which is in accordance with the results of previous research. Moreover, chronic ESC-Exos treatment could reduce the aging hallmarks and recover the compromised function. Thus, the therapeutic effects of ESC-Exos on pressure ulcer healing in aged skin may be mainly attributed to their function in rejuvenating endothelial senescent cells and recovering angiogenic function.

It has been suggested that obesity not only increases the onset of metabolic imbalances, but also decreases life span and impacts cellular processes in a manner similar to aging. A defining characteristic of aging is the gradual loss of physiological integrity, which results in increased vulnerability to disease and death. This loss of physiological integrity underlies multiple pathologies, including cancer, diabetes, cardiovascular disorders, and neurodegenerative disease. Recently, nine hallmarks which define the aging process have been described. We will briefly discuss each of the hallmarks of aging and the potential interactions between each hallmark and obesity.

Based on the evidence, two distinct hypotheses can be proposed. One is that the cellular responses provoked by an excess of nutrients cause obesity, and that obesity is responsible for accelerating the pace of aging. Supporting this hypothesis are the observations that knocking out the fat-specific insulin receptor, to produce extremely lean mice, and removal of visceral fat in rats increased life span; additionally, calorie restriction on lean strains of rats, had only a minor effects on lifespan. The alternative possibility is that the cellular responses provoked by an excess of nutrients are responsible for increasing the pace of aging. This common soil shared by both aging and obesity has been named "adipaging", and there is some evidence of commonalities: hyperglycaemia, for example, induces senescence and the SASP in endothelial cells and macrophages while glucose reduction prevents replicative senescence in human mesenchymal stem cells.

Telomere Attribution

Obesity causes oxidative stress and inflammation, which may increase the rate of telomere shortening. Although the association is weak or moderate, results show a trend toward a negative association between obesity, in particular central obesity, and telomere length. Human studies indicate that telomere shortening is directly correlated to adiposity, and telomere length is inversely associated with BMI. However, this association is not linear across the age and it is stronger in younger compared to older individuals. We feel that although the results cumulatively show a tendency toward an inverse correlation between obesity and telomere length; it is more prudent to conclude that the available studies are heterogeneous and show a weak statistical significance.

Epigenetic Alteration

Several studies demonstrated that obesity is associated with extensive changes in gene expression in multiple tissues and that increased BMI is associated with an altered methylation of specific genes. For instance, it was shown that obesity is associated with methylation changes in blood leukocyte DNA that could lead to immune dysfunction. Investigation of the association between BMI and epigenetic age in blood cells demonstrated that BMI is positively associated with epigenetic aging in middle-aged individuals. The impact of obesity on epigenetic aging is also described: obesity accelerates epigenetic changes associated with aging in the human liver resulting in an apparent age acceleration of 2.7 years for a 10-point increase in BMI, supporting the idea that obesity may accelerate the aging process.

Mitochondrial Dysfunction

Obesity has also been associated with mitochondrial dysfunction. Calorie restriction, conversely, which increases longevity, maintains mitochondrial function. Several studies showed that obesity induces a reduction in mitochondrial biogenesis and a decreased mitochondrial oxidative capacity in adipocytes of both rodents and humans. In obese individuals, reduced mitochondrial biogenesis is associated with metabolic alterations, low-grade inflammation, and insulin resistance. Several lines of evidence suggest that obesity induces a shift toward a fission process linked to mitochondrial dysfunction in liver and skeletal muscle. In skeletal muscle of obese mice, an increased mitochondrial fission was observed and the activity of protein involved in mitochondrial dynamic was altered. Aging and obesity appear superimposable in their impact on mitochondria and it is reasonable to hypothesize that they could exert additive effects.

Cellular Senescence

It has been demonstrated that SA β-gal+ cells are more abundant in pre-adipocyte and endothelial cells isolated from obese compared to lean rats and human, moreover there is a positive correlation between BMI and adipose tissue SA β-gal activity and p53. There is an accumulation of senescent T cells and an increased number of macrophages in the inflammatory foci of the visceral adipose tissue of obese mice, and obese mice accumulate senescent glial cells in the brain. There appears to be a strong relationship between obesity and senescence. Obesity may promote the aging process by inducing senescence. Conversely, senescence and the resulting pro-inflammatory secretory phenotype could contribute to the morbidity associated with obesity and plays a role in the development of insulin resistance and diabetes. There is a vast literature in support of this view.

Deregulated Nutrient Sensing

In biogerontology, the IIS and mTOR pathway are considered "accelerators" of the aging process. There is accumulating literature suggesting that in obesity, these pathways are over-activated. In contrast, there is also accumulating literature showing that pro longevity pathways, such as the AMPK and sirtuins pathways are dampened by obesity. In conclusion, there is solid evidence that obesity deregulates cellular mechanisms related to nutrient sensing.

Altered Intercellular Communication

It is accepted that aging impacts the organism at the cellular level, but also decreases the capacity of cells of an organism to interact. During aging, there is a decreased communication at the neuronal, neuroendocrine, and endocrine levels. Two of the most compelling examples of impaired communication are inflammaging and immunosenescence. The inflammaging phenotype results in elevated cytokines. These cytokines can accelerate and propagate the aging process. The literature persuasively suggests that the accumulation of pro-inflammatory cells, in the adipose tissue of obese patients, through cytokines and extracellular vesicles, accelerates the rate of aging both in the adipose tissue itself and the entire organism.

Genomic Instability

The impact of obesity on genomic instability has been analyzed. Results from animal studies and studies in humans, monitoring DNA damage in lymphocytes and sperm, were analyzed. However, heterogeneity in the study design, methodology, and confounding factors, preclude the conclusion that an association exists between obesity and DNA damage. Nevertheless, the causal relation between excess of body weight and genomic instability is supported by mechanistic studies. Oxidative damage seems as the one mechanism regarded as the most relevant.

Loss Of Proteostasis

With age, the ability of many cells and organs to preserve proteostasis under resting and stressful conditions is gradually compromised. Key pathways affected by the aging process alter components of the proteostasis machinery, e.g., by inducing reduction of chaperones or proteasomal degradation. Obesity can induce prolonged or chronic unfolded protein response possibly mediated by proteasome dysfunctions. In the livers of mouse models of obesity, proteasome activity is reduced and polyubiquinated proteins accumulate. In these mice, impaired proteasome function leads to hepatic steatosis, hepatic insulin resistance, and unfolded protein response activation. Treatment with chemical chaperones partially reverted this phenotype.

For those unfamiliar, the XPRIZE Foundation is famous for designing large global competitions to incentivize the development of technological breakthroughs. On April 29th and 30th, the XPRIZE Foundation hosted an event at its headquarters in Culver City, California that could have a profound effect on the evolving landscape of biorejuvenation research: the Future of Longevity Impact Roadmap Lab. With this event, the purpose of which was to gather subject matter experts to brainstorm a potential longevity-research prize, XPRIZE has turned its focus towards solving the critical problem of age-related diseases on society and extending healthy human lifespan for all.

The attendees were a diverse crowd, a veritable who's who of the broader pro-longevity movement: researchers such as Steve Horvath and Greg Fahy, investors such as Sergey Young (board member of XPRIZE and creator of the 100 million Longevity Vision Fund), long-time advocates such as myself, Aubrey de Grey, and Jim Strole, global policy makers, journalists, cryonicists such as Max More, transhumanists such as Zoltan Istvan and Natasha Vita-More, and of course XPRIZE founder Peter Diamandis.

To facilitate this, the attendees, numbering approximately 70, were divided into tables of four or five - each person tasked with generating a preliminary idea for a longevity-focused XPRIZE and further charged with convincing the rest of their table that their proposed idea should be the one put forth by their table to the rest of the group for consideration. My table happened to include Aubrey de Grey, and thus I knew that a lively discussion was all but assured.

The idea I personally put forth was a conceptually simple one: meaningful physiological remediation of dementia (not just proxy diagnostics or biomarkers) by 2030. I thought this was well suited to the the XPRIZE qualities of "bold, but feasible" and "define the problem, not the solution", and it has several other factors in its favor, namely that dementia is by far the most damaging aspect of aging in terms of protracted emotional suffering and large-scale socioeconomic effects, it is the one aspect of aging that everyone already unequivocally believes is horrific and needs solving, the existing system has failed to solve it for decades, many promising therapy angles have no traditional profit motive and thus will not come to market without additional incentive, success would be clear to validate, and curing it would create an amazing and hopeful narrative with which to enlist the entire world in overcoming all of the diseases of aging.

Aubrey apparently agreed, and with his vote of confidence, this idea became one of the prize concepts pitched to the entire group for consideration. Ideas arising from the other tables' groups covered a wide range of topics as well, included growing fully functional organs from stem cells, demonstrating the arrest of epigenetic markers of aging, successful brain transplantation, creation of an ageless mouse, and restoration of homeostatic and damage repair mechanisms in the elderly.

In terms of an ideal XPRIZE contest, the sought-after configuration was maximal impact and audacity, a proof-of-concept expected date achievable within 10 or 15 years, and with the shortest possible time period between proof-of-concept and widespread adoption. When all was said and done, two concepts stood out. These were the aforementioned proposals put forth by Aubrey and myself: limited but specifically measured human rejuvenation by 2032 and meaningful physiological remediation of dementia by 2030. Of course, with the current exercise completed and the attendees now back to their respective homes and workplaces, it remains to be seen just how the outcome will inform the immediate plans of the XPRIZE Foundation.

The idea that new neurons continue to form into middle age, let alone past adolescence, is controversial, as previous studies have shown conflicting results. A new study is the first to find evidence of significant numbers of neural stem cells and newly developing neurons present in the hippocampal tissue of older adults, including those with disorders that affect the hippocampus, which is involved in the formation of memories and in learning. Researchers also found that people who scored better on measures of cognitive function had more newly developing neurons in the hippocampus compared to those who scored lower on these tests, regardless of levels of brain pathology.

The researchers think that lower levels of neurogenesis in the hippocampus are associated with symptoms of cognitive decline and reduced synaptic plasticity rather than with the degree of pathology in the brain. For patients with Alzheimer's disease, pathological hallmarks include deposits of neurotoxic proteins in the brain. "In brains from people with no cognitive decline who scored well on tests of cognitive function, these people tended to have higher levels of new neural development at the time of their death, regardless of their level of pathology. The mix of the effects of pathology and neurogenesis is complex and we don't understand exactly how the two interconnect, but there is clearly a lot of variation from individual to individual. The fact that we found that neural stem cells and new neurons are present in the hippocampus of older adults means that if we can find a way to enhance neurogenesis, through a small molecule, for example, we may be able to slow or prevent cognitive decline in older adults, especially when it starts, which is when interventions can be most effective."

The researchers looked at post-mortem hippocampal tissue from 18 people with an average age of 90.6 years. They stained the tissue for neural stem cells and also for newly developing neurons. They found, on average, approximately 2,000 neural progenitor cells per brain. They also found an average of 150,000 developing neurons. Analysis of a subset of these developing neurons revealed that the number of proliferating developing neurons is significantly lower in people with cognitive impairment and Alzheimer's disease. The scientists are now interested in finding out whether the new neurons discovered in the brains of older adults are behaving the way new neurons do in younger brains.

Decline in immune function has been well described in the setting of physiologic aging manifesting as impaired vaccine responses and diminution of antibody (Ab)-secreting cells with reduced numbers of lymph node germinal centers (GCs). CD4 T cells provide help to antigen-primed B cells to undergo proliferation, isotype switching, and somatic hypermutation resulting in the generation of long-lived plasma cells and memory B cells (MBCs).

This help is mediated by a specialized CD4 T-cell subset known as T follicular helper (Tfh) cells, characterized by the expression of CXCR5, which is required for the cells to migrate to the GC. We and others have described a circulating counterpart of CXCR5+ Tfh cells known as peripheral Tfh (pTfh) cells that are easily accessible from patient blood samples and are able to induce B cell differentiation. Studies in healthy adults have documented the importance of pTfh expansion at day 7 or day 28 post vaccination for their association with influenza vaccine response.

In order to understand the Ab response to influenza vaccine and the effect of aging with or without HIV infection, we conducted the present study in young and old HIV+ and HIV-uninfected healthy control [HC] participants who had already been classified as vaccine responders (VRs) and vaccine nonresponders (VNRs) based on their serologic responses to seasonal influenza vaccine. We focused on antigen-specific pTfh (Ag.pTfh). In this study, ex vivo quantitative and qualitative assessment of Ag.pTfh revealed key features of Ag.pTfh that favored vaccine responsiveness. In VRs, magnitude of response was impacted by both quality and quantity of Ag.pTfh cells, and these were compromised in old age in HCs and in young and old HIV+ individuals. In VNRs, in contrast, Ag.pTfh were heavily weighted towards an inflammatory phenotype irrespective of age or HIV status.

Our findings demonstrate that dysfunctional Ag.pTfh cells with an altered IL-21/IL-2 axis contribute to inadequate vaccine responses. Approaches for targeting inflammation or expanding functional Tfh may improve vaccine responses in aging and those aging with HIV infection.

In the late 1980s, researchers ushered one of the pioneering laboratory investigations in cell therapy for stroke, demonstrating the survival of rat fetal neocortical grafts in ischemic adult rat cortex. Subsequent studies showed that these grafted fetal cells integrated with the ischemic brain received afferent fibers and vascularization from the host intact tissue and responded to contralateral sensory stimulation with increased metabolic activity. Equally promising are the observations that stroke animals transplanted with fetal striatal cells into the ischemic striatum displayed some improvements in a simple cognitive task of passive avoidance, as well as in a more complex water maze learning test.

Over the next four decades of preclinical research, additional evidence of graft survival, migration, differentiation, and functional integration in the ischemic brain, modest anatomical reconstruction, and remodeling of brain circuitry, neurochemical, physiological, and behavioral recovery have been documented. Several mechanisms have also been postulated to mediate the therapeutic effects of cell transplants in stroke; although initially designed as a cell replacement for dead or ischemic cells, the current view puts robust bystander effects of the grafted cells to secrete therapeutic substances.

The recognition that stroke not only affects neurons but also other neural cell types, especially vascular cells, prompted the search for alternative regenerative processes that rescue in tandem neural and vascular cells, under the theme of attenuating the impaired neurovascular unit. Toward stimulating these non-neuronal repair processes, the stem cells' by-stander effects have been proposed, including the grafted cells' ability to secrete substances that promote neurogenesis, angiogenesis, vasculogenesis, anti-inflammation, among other therapeutic substances. Over the last five years, additional novel stem cell component-based mechanisms have been demonstrated to accompany stem cell therapy, such as the transfer of stem cell-derived mitochondria, exosomes, microvesicles, and microRNAs into the ischemic area.

Although safety of the grafted cells has been overwhelmingly documented, efficacy has not been forthcoming. This cell-based regenerative medicine remains designated as "experimental" in the clinic. Equally disappointing, two recently concluded clinical trials indicated stem cells are safe but not effective in stroke patients. These failed clinical trials may be due to a loss in translation of optimal laboratory stem cell transplantation protocols to clinical trial designs. The Good Manufacturing Practice (GMP)-manufactured stem cells are likely different from the laboratory-grade stem cells, in that the phenotype and biological properties originally designed to treat a specific disease in the laboratory may now have a different disease indication in the clinic. This highlights the importance of strict adherence to the basic science findings of optimal transplant regimen of cell dose, timing, and route of delivery in enhancing the functional outcomes of cell therapy.

Transcription factor FoxN1 is the mastermind of thymus organogenesis and identity, and is also an acknowledged direct molecular target of the glycolipoprotein Wnt4. As a consequence, Wnt4 plays a key role during embryonic thymus development and the maintenance of its identity in adulthood. Thymic epithelial cells secrete less Wnt4, while their Frizzled receptors (Fz4 and Fz6) become up-regulated indicating a potential compensatory mechanism and possibly enhanced Wnt4-binding. This loss of Wnt4 expression weakens thymic epithelial identity and allows for thymic adipose involution to occur. This latter process leads to the expansion of thymic adipose tissue orchestrated by transcription factor PPARgamma. The Wnt/b-catenin pathway and PPARgamma have been reported to act as mutual inhibitors of one another in several tissue contexts, including the thymus. We have previously shown that the addition of exogenous Wnt4 reinforces thymic epithelial identity and confers resistance in a steroid-induced model of senescence through suppressing PPARgamma.

Recent publications of various tissue contexts have suggested that Wnt molecules (including Wnt4) travel in conjunction with extracellular vesicles (EVs), more specifically exosomes. It has also been reported that a significant portion of the Wnts - including Wnt4 - may actually be displayed on exosomal surfaces. EVs are released by most cell types of all phyla and mediate various biological effects. Biological functions attributed with exosomes encompass several physiological and pathological conditions, including cell and tissue regeneration. The thymus epithelium has also been reported to be a rich source of exosomes with key immunological relevance e.g., in thymocyte selection. Yet to date, TEC (thymic epithelial cell) exosomes have not been linked with thymus tissue regeneration.

Our goal was to evaluate the Wnt4 and miR27b levels of Wnt4-transgenic thymic epithelial cell (TEC)-derived exosomes, show their regenerative potential against age-related thymic degeneration, and visualize their binding and distribution both in vitro and in vivo. First, transgenic exosomes were harvested from Wnt4 over-expressing TECs and analyzed by transmission electron microscopy. For functional studies, steroid-induced TECs were used as cellular aging models in which steroid-triggered cellular aging was efficiently prevented by transgenic exosomes. Finally, DiI lipid-stained exosomes were applied on the mouse thymus sections and also iv-injected into mice, for in vitro binding and in vivo tracking, respectively. In vivo injected DiI lipid-stained transgenic exosomes showed detectable homing to the thymus.

In summary, our findings indicate that exosomal Wnt4 and miR27b can efficiently counteract thymic adipose involution. Although extrapolation of mouse results to the human setting needs caution, our results appoint transgenic TEC exosomes as promising tools of immune rejuvenation.

The primary neuropathological signs of Alzheimer's disease (AD) are intraneuronal neurofibrillary tangles and extracellular β-amyloid (Aβ) plaques, along with accompanying synaptic and neuronal loss. In general, the distribution of neurofibrillary tangles in the AD brain follows a stereotypic pattern; beginning in the entorhinal/perirhinal cortex, progressing to limbic structures including the hippocampus, and then finally spreading neocortically across the frontal, temporal, and parietal cortex. Loss of neurons and severity of cognitive impairments in AD correspond closely with the burden of tangle pathology.

The neurodegenerative process is also mediated by excessive production and accumulation of Aβ peptides forming plaques. Generation of pathogenic Aβ peptides requires β-secretase (BACE1), which cleaves amyloid precursor protein (APP); the rate-limiting step in Aβ production. Synaptic dysfunction in AD, which is evident long before substantial neuronal loss, has been attributed to elevated BACE1 levels prompting the overproduction of toxic Aβ at synaptic terminals. Recently, it has been demonstrated that Aβ plaques create an environment that enhances the aggregation of tau, which in turn forms intracellular neurofibrillary tangles. Consequently, Aβ and neurofibrillary tangles jointly cooperate in the progression of AD. However, AD is not a normal part of aging and the biological mechanisms causing some individuals, but not others, to develop disease pathology remain unclear.

Epigenetic mechanisms could contribute to AD, as many manifestations of aging, including age-dependent diseases, have an epigenetic basis. Epigenetic marks like DNA methylation regulate gene transcription, are responsive to environmental changes, and show widespread remodeling during aging. Enhancers are genomic elements that modulate the complex spatial and temporal expression of genes, and are subject to epigenetic regulation. Prior genome-wide studies examining DNA methylation changes in the AD brain report a significant overlap between differential methylation and enhancer elements, suggesting that epigenetic disruption of enhancer function contributes to AD. Hence, in this study we perform a genome-wide analysis of DNA methylation at enhancers in neurons from AD brain.

We identify 1224 differentially methylated enhancer regions; most of which are hypomethylated in AD neurons. Methylation losses occur in normal aging neurons, but are accelerated in AD. Integration of epigenetic and transcriptomic data demonstrates a pro-apoptotic reactivation of the cell cycle in post-mitotic AD neurons. Furthermore, AD neurons have a large cluster of significantly hypomethylated enhancers in the DSCAML1 gene that targets BACE1. Hypomethylation of these enhancers in AD is associated with an upregulation of BACE1 transcripts and an increase in amyloid plaques, neurofibrillary tangles, and cognitive decline.

New research shows that viruses interact with proteins in the biological fluids of their host which results in a layer of proteins on the viral surface. This coat of proteins makes the virus more infectious and facilitates the formation of plaques characteristic of neurodegenerative diseases such as Alzheimer's disease. Before entering a host cell, viruses are just nanometer-sized particles, very similar to artificial nanoparticles used in medical applications for diagnosis and therapy. Scientists have found that viruses and nanoparticles share another important property; they both become covered by a layer of proteins when they encounter the biological fluids of their host before they find their target cell. This layer of proteins on the surface influence their biological activity significantly.

Researchers studied the protein corona of respiratory syncytial virus (RSV) in different biological fluids. The virus remains unchanged on the genetic level, but acquires different identities by accumulating different protein coronae on its surface depending on its environment. This makes it possible for the virus to use extracellular host factors for its benefit, and many of these different coronae make RSV more infectious.

Researchers also found that viruses such as RSV and herpes simplex virus type 1 (HSV-1) can bind a special class of proteins called amyloid proteins. Amyloid proteins aggregate into plaques that play a part in Alzheimer's disease where they lead to neuronal cell death. The mechanism behind the connection between viruses and amyloid plaques has been hard to find till now, but researchers found that HSV-1 is able to accelerate the transformation of soluble amyloid proteins into thread-like structures that constitute the amyloid plaques. In animal models of Alzheimer's disease, they saw that mice developed the disease within 48 hours of infection in the brain. In absence of an HSV-1 infection the process normally takes several months.

Aging is a risk factor for cardiovascular disease, and oxidative stress has been considered as a possible mechanism underlying aging-related pathologies. It was hypothesized that oxidative stress is associated with inflammation, which is an important contributor of aging. However, the signaling pathway connecting oxidative stress, inflammation, and aging remains undefined, and there is no effective therapeutic approach to alleviate aging-associated cardiovascular disease. Tumor necrosis factor-α (TNF-α), one of major inflammatory cytokines, is regulated by nuclear factor kappa B (NF-κB). It was reported that ischemic injury triggers the activation of NF-κB, which activates the transcription of inflammatory cytokines such as TNF-α. However, whether NF-κB regulates TNF-α in the aging process is not known.

It is known that mesenchymal stem cells (MSC) can improve heart function after infarction, and the beneficial effect of MSCs is mediated by paracrine factors which are transported by exosomes. Exosomes contain functional miRNAs and long noncoding RNAs (lncRNA) and serve as intercellular shuttles to deliver important messages to alter the gene expression and cellular functions of distant organs. We and others have reported that bone marrow MSC-derived exosomes improve heart function after infarction, and several miRNA-mediated exosomes' repair functions. However, it is unknown whether exosomes could prevent aging-induced cardiac dysfunction.

Because lncRNAs are more tissue-specific and developmental stage-specific compared to miRNA, we chose to investigate the role of lncRNA in exosomes. More recently, one report showed that lncRNA metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) is associated with the aging process. However, it is unknown whether MSC exosomes contain lncRNA MALAT1 and whether lncRNA MALAT1 in exosomes could have a functional role in preventing aging-induced cardiac dysfunction. In this study, we explored whether umbilical mesenchymal stem cell (UMSC) derived exosomes could prevent aging-induced cardiac dysfunction and determined whether the potential mechanism was mediated by the exosome/lncRNA MALAT1/NF-κB/TNF-α pathway.

We discovered that human umbilical cord mesenchymal stem cell- (UMSC-) derived exosomes prevent aging-induced cardiac dysfunction. Silencer RNA against lncRNA MALAT1 blocked the beneficial effects of exosomes. In summary, we discovered that UMSC-derived exosomes prevent aging-induced cardiac dysfunction by releasing novel lncRNA MALAT1, which in turn inhibits the NF-κB/TNF-α signaling pathway. These findings will lead to the development of therapies that delay aging and progression of age-related diseases.

Cellular aging, a progressive functional decline driven by damage accumulation, often culminates in the mortality of a cell lineage. Certain lineages, however, are able to sustain long-lasting immortality, as prominently exemplified by stem cells. Here, we show that Escherichia coli cell lineages exhibit comparable patterns of mortality and immortality. Through single-cell microscopy and microfluidic techniques, we find that these patterns are explained by the dynamics of damage accumulation and asymmetric partitioning between daughter cells.

Experimental data from long-term microscopy of bacterial lineages revealed that, in the presence of intracellular damage, each cellular division produces two physiologically asymmetric daughters. This asymmetry is generated because the damage harbored by the mother is biased toward the old cell pole, causing the daughter that inherits this pole - termed the old daughter - to age. Its sibling, on the other hand, rejuvenates through the inheritance of a lower damage load, being called the new daughter. Therefore, by partitioning damage with asymmetry, bacterial populations engage in a trade-off in which the fast growth of new daughters is sustained at the expense of the declining cellular function of old daughters.

At low damage accumulation rates, both aging and rejuvenating lineages retain immortality by reaching their respective states of physiological equilibrium. We show that both asymmetry and equilibrium are present in repair mutants lacking certain repair chaperones, suggesting that intact repair capacity is not essential for immortal proliferation. We show that this growth equilibrium, however, is displaced by extrinsic damage in a dosage-dependent response. Moreover, we demonstrate that aging lineages become mortal when damage accumulation rates surpass a threshold, whereas rejuvenating lineages within the same population remain immortal. Thus, the processes of damage accumulation and partitioning through asymmetric cell division are essential in the determination of proliferative mortality and immortality in bacterial populations. This study provides further evidence for the characterization of cellular aging as a general process, affecting prokaryotes and eukaryotes alike and according to similar evolutionary constraints.

Age-related hearing loss (ARHL) has been considered as a promising modifiable risk factor for cognitive impairment and dementia. Nonetheless, the relationship between ARHL and Alzheimer's disease (AD) is still controversial. Besides the insufficient statistical power due to small sample size, their relationship might be further complicated by misclassification bias due to misdiagnosis, given that (1) AD was defined in previous observational studies mostly without pathological evidence, such as amyloid PET imaging or cerebrospinal fluid (CSF) biomarkers; (2) aged subjects with hearing loss (HL) might be more intellectually capable than the cognitive tests suggest. Therefore, investigating the association between ARHL and AD biomarkers might be less biased and more informative about the causal relationship.

Degeneration of the auditory system was reported in AD decades ago. In addition to confirming the prior findings that ARHL is associated with temporal lobe atrophy, we demonstrated for the first time, a strong link between ARHL and the amount of tau and phosphorylated tau (ptau) in CSF as well as reserve capability of entorhinal cortex. These influences seemed to be more obvious in the non-demented stage of the AD continuum. We did not find a significant relationship between ARHL and Aβ levels.

While AHRL can contribute to depression that may exacerbate the cognitive impairment and neurodegeneration biomarker profile, our results suggested that the neurodegenerative effects of ARHL might be driven by accelerating cerebrospinal fluid tau levels and atrophy of entorhinal cortex. Furthermore, our findings suggest that prevention or management of ARHL in preclinical and prodromal stage of AD might be effective in combating neurodegeneration.