Fight Aging!

Epigenetic clocks are a topic of considerable interest in the research community. They are perhaps the most promising of the present techniques for assessing biological age, the closest to becoming a useful biomarker of aging. Epigenetic clocks are weighted algorithmic combinations of the DNA methylation status of various sites on the genome, reflecting changes that are very similar for everyone, and which map to age with a margin of error of a few years. These changes are likely reactions to the growing damage and dysfunction of aging - and since everyone ages for the same underlying reasons, it makes sense for some of the changes that take place in cellular processes to be much the same for everyone. The initial epigenetic clocks are now being joined by many others, as there are any number of ways in which to create a viable combination of epigenetic marks that reflects aging.

The interesting aspect of an epigenetic age measure is the degree to which it is higher or lower than chronological age for a given individual. Acceleration of epigenetic age, a higher epigenetic age than chronological age, is quite robustly correlated with incidence of many age-related conditions, as well as with mortality risk. If aging is damage, then more damage has the expected outcome. Today's research materials, looking into lung function and epigenetic age, are illustrative of the numerous other correlational studies published in recent years.

The development of biomarkers of aging is an important topic. A low-cost way to quickly and rigorously measure the damage and dysfunction of age would greatly speed up research and development of rpotential rejuvenation therapies. At present, the only rigorous test of an approach to slow or reverse aging (versus treating a specific age-related condition) is a life span study. That is out of the question for human trials, and even in mice running a life span study is an expensive, slow proposition. As a result, researchers are beginning to use epigenetic age assessments in their studies of aging. Unfortunately, these tools are not yet finalized. Because it is unclear as to what exactly causes the characteristic epigenetic changes of age, it is unknown as to how an epigenetic clock will react to any given new class of ejuvenation therapy. The outcome of an assessment isn't yet actionable, whatever the result. The clocks will have to be calibrated and verified alongside rejuvenation therapies as they are developed - the results cannot yet be taken at face value.

Association of adult lung function with accelerated biological aging

Using longitudinal data from two population-based cohorts we have examined the association of lung function with epigenetic aging and shown that lung function is associated with measures of epigenetic age acceleration, particularly in women and with increasing age. Lung function decline is found to be strongly associated with increase in DNA methylation-based lifespan predictors, plasma protein levels, and their related age adjusted measures.

Our findings suggest that lung function is associated with age acceleration in women and particularly in women above age of 50 years. Forced expiratory volume in one second (FEV1) was found to be declining at a rate of 9.5 mL per year of age acceleration using regression between epigenetic and chronological ages (AAres) and 11.3 mL per year of age acceleration using intrinsic epigenetic age acceleration (IEAA). This same trend was observed for forced vital capacity (FVC). This observation was further supported by measures in an older group of women showing a greater effect of age acceleration on lung function decline.

When the association from the repeated measures from two time points was assessed, a marginal association was found in female subjects, showing a 3.94 ml decline in FVC per year of epigenetic age acceleration (AAres). In contrast, while measuring the effect of age acceleration on lung function decline between baseline and follow-up, there were no significant associations, suggesting that decline in lung function is proportional to the overall degree of biological aging.

In conclusion, this study suggests that epigenetic age acceleration is significantly associated with lung function in women older than 50 years. We hypothesised that this could be due to menopause. However, we have observed that menopause has minimal effect and therefore there is possibility of other unknown physiological factors at older age in females mediating the epigenetic age acceleration effect on lung function. While, it is still unknown what exactly epigenetic aging from DNA methylation measures, this study suggests it can be utilised as one of the important factors to assess women's lung health in old age. DNA methylation-based lifespan predictors, such as DNAm GrimAge and plasma protein levels are strongly associated with lung function. Therefore this study suggests that these can be utilised as important factors to assess lung health in adults.

The brain is known to shrink with age, by about 5% per decade in later adult life, though the underlying processes leading to this loss of volume are not well understood in detail. The research here adds to existing evidence for loss of volume to correlate with loss of cognitive function. It is unclear as to what can be done specifically to address this issue beyond developing the means to repair the list of damage and dysfunction that causes aging, and observing the results as repair therapies are deployed, first in animals, and then in humans.

The human cerebellum plays an essential role in motor control, is involved in cognitive function and helps to regulate emotional responses. However, little is known about the relationship between cerebellar lobules and age-related memory decline. We aimed to investigate volume alterations in cerebellar lobules at different ages and assess their correlations with reduced memory recall abilities.

A sample of 275 individuals were divided into the following four groups: 20-35 years (young), 36-50 years (early-middle age), 51-65 years (late-middle age), and 66-89 years (old). Volumes of the cerebellar lobules were obtained using volBrain software. Group differences in cerebellar lobular volumes were assessed, and multiple comparisons were used to investigate the relationship between lobular volumes and memory recall scores.

We found that older adults had smaller cerebellar volumes than the other subjects. Volumetric decreases in size were noted in bilateral lobule VI and lobule crus I. Moreover, the volumes of bilateral lobule crus I, lobule VI, and right lobule IV were significantly associated with memory recall scores. Thus some lobules of the cerebellum appear more predisposed to age-related changes than other lobules. These findings provide further evidence that specific regions of the cerebellum could be used to assess the risk of memory decline across the adult lifespan.

Link: https://doi.org/10.21037/qims.2019.10.19

Severed nerves left with a significant gap between the ends do not regrow in adult mammals. Scarring rather than regeneration takes place, and loss of function is permanent. All is not bleak, however. Researchers here report on progress in guided nerve regrowth, using a implant that encourages regeneration of nerve tissue across a comparatively large distance. The prospects for recovery from damage to the peripheral nervous system are becoming brighter. Assuming it is accompanied by removal of scar tissue at the nerve ends, the regenerative approach illustrated here could, in principle, be applied well after an injury has taken place, and is thus particularly interesting.

Peripheral nerves can regrow up to a third of an inch on their own, but if the damaged section is longer than that, the nerve can't find its target. Often, the disoriented nerve gets knotted into a painful ball called a neuroma. The most common treatment for longer segments of nerve damage is to remove a skinny sensory nerve at the back of the leg - which causes numbness in the leg and other complications, but has the least chance of being missed - chop it into thirds, bundle the pieces together and then sew them to the end of the damaged motor nerve, usually in the arm. But only about 40 to 60% of the motor function typically returns.

Researchers have now created a biodegradable nerve guide - a polymer tube - filled with growth-promoting protein that can regenerate long sections of damaged nerves, without the need for transplanting stem cells or a donor nerve. The nerve guide returned about 80% of fine motor control in the thumbs of four monkeys, each with a 2-inch nerve gap in the forearm. The experiment had two controls: an empty polymer tube and a nerve graft. Since monkeys' legs are relatively short, the usual clinical procedure of removing and dicing a leg nerve wouldn't work. So, the scientists removed a 2-inch segment of nerve from the forearm, flipped it around and sewed it into place, setting a high bar for the nerve guide to match.

Functional recovery was just as good with the guide as it was with this best-case-scenario graft, and the guide outperformed the graft when it came to restoring nerve conduction and replenishing Schwann cells - the insulating layer around nerves that boosts electrical signals and supports regeneration. In both scenarios, it took a year for the nerve to regrow. The empty guide performed significantly worse all around.

Link: https://www.eurekalert.org/pub_releases/2020-01/uop-rrd011720.php

Cellular senescence contributes meaningfully to near all age-related conditions, judging by the research of the past few years. In only a very few cases has clearance of senescent cells failed to perform well as a basis for therapy. In just the past year, papers have been published on the role of senescent cells in twenty or more very different age-related conditions. In many cases, the researchers demonstrated that clearance of a sizable fraction of the senescent cells present in tissues, using one of the available senolytic mouse models or small molecule therapies, reversed the progression of the age-related condition under study. When it comes to the diseases of aging, senolytic therapies are about as close to a panacea as it is possible to be, at least in animal studies.

Cells become senescent constantly, largely somatic cells reaching the Hayflick limit on replication. Cells also become senescent in reaction to DNA damage, environmental toxicity, tissue injury, and the signaling of senescent neighbors, however. Senescence is useful in the short term, assisting regeneration and suppressing cancer risk. But not all senescent cells self-destruct or are removed by the immune system, and the processes of clearance appear to slow down and become less efficient with age. The numbers of lingering senescent cells grow throughout the body, and the inflammatory signaling produced by these cells, useful in the short-term, becomes very harmful when sustained over months and years.

Today I'll point your attention to an open access review paper that discusses cellular senescence as a contributing cause of osteoporosis. It isn't the only contributing cause, but it appears sufficient in and of itself to cause the loss of bone mass and strength. Osteoporosis is, at the high level, an imbalance between the number and activity of cells building bone (osteoblasts) and the number and activity of cells breaking down bone (osteoclasts). Both osteoblasts and osteoclasts are continually active, and bone tissue is constantly remodeled. In youth, these processes of creation and destruction are in balance. The inflammatory signaling of senescent cells helps to disrupt that balance, tipping it in favor of osteoclast activity.

Senile Osteoporosis: The Involvement of Differentiation and Senescence of Bone Marrow Stromal Cells

Senile osteoporosis is an age dependent bone disorder occurring both in men and women, which has become a worldwide health concern. The functional change of bone marrow stromal cells (BMSCs) has been demonstrated to contribute to senile osteoporosis, showing as BMSCs differentiate into fewer osteoblasts, but more adipocytes, and BMSCs become senescent. Besides the critical involvement of BMSCs in senile osteoporosis, BMSCs are also a favorite cell source for cell therapy and have been applied for osteoporosis treatment. Therefore, uncovering the underlying mechanisms of function changes of BMSCs during senile osteoporosis is important not only for better understanding the involvement of BMSCs in senile osteoporosis, but also for manipulating them for clinical applications.

Recent findings demonstrate that numerous transcriptional factors, signaling pathways, epigenetic regulations and other factors play key roles in regulating the differentiation and senescence of BMSCs, the alteration of which contributes to senile osteoporosis. Runx2 and PPARγ are two key transcription factors that are responsible for osteogenic differentiation and adipogenic differentiation of BMSCs, respectively. Decreased Runx2 expression and increased PPARγ results in senile osteoporosis. NRF2 and FOXP1 are two transcription factors related to the senescence of BMSCs by regulating antioxidant responsive genes. They are decreased with age, thus, leads to BMSCs senescence and bone loss. BMP signaling, Wnt signaling, and Notch signaling pathways all show dual roles in regulating osteogenic and adipogenic differentiation of BMSCs. They function either by targeting the downstream transcription factors, such as Runx2, PPARγ, or by cross-talking with each other.

Recently, p53/p21 and p16/Rb signaling pathways have been demonstrated to be involved in the senescence of BMSCs, which is one main cause of senile osteoporosis. These signaling pathways are activated by DNA damage or reactive oxygen species (ROS) accumulation and finally lead to cell senescence. Besides, BMP signaling and Wnt signaling also participate in inducing senescence of BMSCs by inducing ROS, triggering DNA damage or interacting with p53/p21 signaling. Moreover, epigenetic regulation also plays important role in regulating differentiation and senescence of BMSCs. The epigenetic regulation, such as DNA methylation and histone acetylation, regulates the differentiation and senescence of BMSCs by regulating the expression of transcription factors or disturbing the binding of transcription factors to specific gene's promoter. These findings provide an understanding of the molecular mechanisms underlying the altered differentiation and senescence of BMSCs during senile osteoporosis and provide potential targets or methods for treating senile osteoporosis.

Direct transplantation of normal BMSCs and elimination of senescent BMSCs both efficiently treat senile osteoporosis. Transplantation of normal allogeneic BMSCs into aged mice shows both prevention and treatment effects on senile osteoporosis. In addition, modification of the differentiation ability of BMSCs through targeting some genes can be applied for treating senile osteoporosis. More recently, elimination of senescent BMSCs has been demonstrated to be an effective therapeutic method for treating senile osteoporosis. All these findings strongly demonstrate that BMSCs can be applied for clinical treatment of senile osteoporosis by directly transplanting normal BMSCs, modifying differentiation of BMSCs, or eliminating senescent BMSCs. However, present findings are obtained from animal studies. Further clinical trials are needed.

The primary mechanism by which most cancers kill patients is metastasis, the spread of cancerous cells from the original tumor to new locations throughout the body. If metastasis didn't exist, cancer would be a much more tractable problem, largely capable of being controlled via even the blunt approach of surgery. Research that might lead to ways to sabotage metastasis across many different types of cancer is thus of great interest. A number of possible approaches have emerged over the past decade or so, but none have as yet advanced to the point of practical application in the clinic.

Researchers have demonstrated that the most aggressive cancer cells use significant amounts of lipids as energy sources, and that cancer cells store lipids in small intracellular vesicles called 'lipid droplets'. Cancer cells loaded with lipids are more invasive and therefore more likely to form metastases. Researchers identified a factor called TGF-beta2 as the switch responsible for both lipid storage and the aggressive nature of cancer cells. Moreover, it appeared that the two processes were mutually reinforcing. In fact, by accumulating lipids, more precisely fatty acids, cancer cells build up energy reserves, which they can then use as needed throughout their metastatic course.

Already known was that the acidity found in tumours promotes cancer cells' invasion of healthy tissue. The process requires the detachment of the cancer cell from its original anchor site and the ability to survive under such conditions (which are fatal to healthy cells). The new finding: researchers demonstrated that this acidity promotes, via the same TGF-beta2 'switch', the invasive potential and formation of lipid droplets. These provide the invasive cells with the energy they need to move around and withstand the harsh conditions encountered during the process of metastatis.

Concretely, this research opens up new therapeutic avenues thanks to the discovery of the different actors involved in metastasis, as these actors can be targeted and combated. Researchers show that it is possible to reduce tumour invasiveness and prevent metastases using specific inhibitors of TGF-beta2 expression but also compounds capable of blocking the transport of fatty acids or the formation of triglycerides. Among the latter are new drugs that are being evaluated to treat obesity. Their indications could therefore be rapidly extended to counter the development of metastases, which is the major cause of death among cancer patients.

Link: https://www.eurekalert.org/pub_releases/2020-01/ucdl-pmb012220.php

Age-related macular degeneration is a common form of vision loss. It begins as a dry form, and progresses to a wet form as blood vessels inappropriately grow into damaged retinal tissue. Researchers have identified downregulation of Dicer1 as a factor in the progression of the condition, and here demonstrate that a gene therapy to increase expression of Dicer1 may form the basis for a therapy targeting both dry and wet stages of macular degeneration. That increased expression acts to block a significant cause of inflammation and cell death in retinal tissue.

Degeneration of the retinal pigmented epithelium (RPE) and aberrant blood vessel growth in the eye are advanced-stage processes in blinding diseases such as age-related macular degeneration (AMD), which affect hundreds of millions of people worldwide. Loss of the RNase DICER1, an essential factor in micro-RNA biogenesis, is implicated in RPE atrophy. However, the functional implications of DICER1 loss in choroidal and retinal neovascularization are unknown.

Deficiency of DICER1, an RNase that processes double-stranded and self-complementary RNAs including a majority of premature micro-RNAs (miRNAs) into their bioactive forms, is among the inciting molecular events implicated in atrophic AMD. DICER1 deficiency is implicated in RPE cell death in atrophic AMD due to accumulation of unprocessed Alu RNAs, which results in noncanonical activation of the NLRP3 inflammasome, an innate immune pathway resulting in RPE death.

We report that genetic suppression of Dicer1 in three independent mouse models manifests in the eye as focal RPE atrophy and aberrant choroidal and retinal neovascularization, and that DICER1 expression is reduced in a mouse model of spontaneous choroidal neovascular (CNV) lesions. Furthermore, we report that AAV-enforced expression of a DICER1 construct reduces spontaneous CNV in mice. In addition to expanding upon prior studies of DICER1 loss in atrophic AMD, these findings identify maintenance of outer retinal avascularity as another critical function of DICER1 in maintaining retinal homeostasis. This study also suggests that restoring DICER1 expression in the retina could itself be a viable therapeutic target for the treatment of AMD.

Link: https://doi.org/10.1073/pnas.1909761117

As illustrated in today's research commentary, all too many researchers continue to view aging as something distinct from age-related disease, and this inevitably leads to a poor approach to research and development. In this case, a rejection of the idea that rejuvenation is possible in principle at the present time. If one believes that aging and age-related disease are distinct, then one can also think that it is possible to age successfully, or age healthily. That we should split out the concepts of aging and disease, and only treat disease. This is all abject nonsense. There is no such thing as healthy aging or successful aging. There are processes of aging that can clearly be reversed, either actually or in principle. Too many people in positions of influence are producing irrational strategies for medical research under the belief that healthy aging is a viable goal.

Aging is by definition the accumulation of damage and dysfunction that raises mortality risk over time; it is a process of harm and loss. A "healthy" 80-year-old is in no way healthy by any objective measure. Can he sprint the way he used to? No. Is his hearing and eyesight the match of a youngster? No. Are his arteries damaged and distorted? Yes. Does he have a mortality risk that would raise eyebrows in a 20-year-old? Also yes. This is not health. This is a considerable progression towards the polar opposite of health.

To call any particular outcome of the damage and dysfunction at the roots of aging a disease is to draw an arbitrary line in the sand and say that some dysfunction is healthy, and won't be treated, while a little more dysfunction than that is unhealthy, and a disease that should be treated. Sadly this is exactly how medical science has progressed for all too long, even as the scientific understanding of aging needed for a better approach was assembled over the past century or more. The outcomes on either side of that arbitrary line in the sand (yes, you have clinical arthritis and will be treated, versus no, you have signs of progression towards clinical arthritis and come back later) all result from the same processes of damage taking place under the hood. This damage grows with time and leads inexorably to organ failure and death. Thus we should develop rejuvenation therapies to repair that damage, ideally long before it rises to the level of causing pathology. History teaches us that any other path is doomed to failure at worst and marginal, accidental gains at best.

Are We Ill Because We Age?

In the optic of geroscience, if aging becomes a treatable disease/process, it will be the duty of medical doctors to treat it. However, not everything which seems to be aging is aging. Over the history of gerontology and geriatrics, many processes previously thought to be part of aging are now considered not to be age-related, but an overlaying pathology. One of the best examples is anemia, which for decades was considered as a solid attribute of aging but now is considered related to various pathologies and not to aging itself. So, an older individual who does not have relevant underlying pathomechanisms would not have anemia even at 100 years of age or more. The same applies to hypertension, to sarcopenia, to kidney failure, and to cognitive impairment.

So again, what distinguishes aging from a disease conceptually? First, the extent of aging is systemic and complex while that of a disease is mostly limited. Aging is an inevitable, universal process (concerning all humans living long enough) while most diseases are associated with individuals' susceptibilities/vulnerabilities, and most of them, even chronic, are preventable. The most important cause of aging is time, while diseases usually have specific known causes. In other words, aging is irreversible and progressive while diseases are reversible and discontinuous. Finally, and most importantly, aging may be modulable but not treatable, while diseases are ultimately treatable even if we do not know presently how, which is only a question of progress of science. So many essential differences clearly speak against the notion that aging is "just another" disease.

we should ask how we would know if an anti-aging therapy really could slow aging. The problem is that most of our definitions are circular or impractical. At the most macro level, we might ask whether it extends lifespan or life expectancy. We might ask if we reduce the incidence or burden of age-related diseases (ARDs) with anti-aging interventions. However, it is possible we could do this by counteracting negative aspects of modern lifestyle (e.g., obesity), without affecting aging per se, and conversely that we might find interventions that slow aspects of aging without having much impact on ARDs. Lastly, we might ask whether anti-aging interventions have impacts on metrics of biological aging. If these metrics are specific metrics of the processes being treated, the reasoning becomes circular. For example, we could not prove that senolytics affect aging simply because they reduce the number of senescent cells. Higher level indicators of biological age, such as homeostatic dysregulation indices or the epigenetic clock, are slightly more promising metrics. However, even here there is a problem: these various indices are only poorly correlated with each other and are themselves based on various theories about what aging is. For example, if senolytics lower (rewind) the epigenetic clock, is this simply because the epigenetic profiles of senescent cells are different, and we have removed these cells from the mix? Or was there really an impact on aging in the remaining cells?

At this stage of our knowledge there is no place in medicine for anti-aging medicine understood as treating symptoms of aging when aging has already happened. However, there might be a place for interventions/modulations that would delay the occurrence of aging, when applied early in life, before any time-dependent processes had accumulated and aging symptoms show up. Scientists should recognize at this stage that we know a lot but not enough yet to translate the scientific discoveries in the field of gerontology to interventions into the older subjects. However, a new approach is needed and should be oriented at a systemic conceptualization of the aging process and not at the fragmentation of its different components.

Thus, better assessment of the biological aging against the chronological aging holds promises to be able (e.g., by significant biomarkers) to assess the physiological aging processes in their complexity and act on them specifically and jointly. The concept that aging does not always lead to ARD, but that the same processes may lead to either ARD or successful aging in older persons depending on the homeodynamics, will also help to individualize the interventions. Furthermore, the recognition that not everything occurring in aging is detrimental will help to design purposeful interventions to reinforce what is necessary and combat what IS detrimental. Finally, the recognition of aging as a lifelong process and that chronic diseases start early in life would help to design interventions very early in life having consequences on ARD. So, we should move from the aging as a disease concept to the aging as an adaptation, which may result in ARD or successful functional healthspan.

Senolytic drugs that selectively destroy senescent cells in aged tissues have performed quite well in animal studies of fibrosis in heart, lung, and kidney. The therapy reverses fibrosis in those tissues to a larger degree, and with greater reliably, than is the case for any other readily available approaches. Unfortunately small molecule senolytics are all tissue specific to varying degrees in their biodistribution and effects, and so the benefits are not universally realized throughout the body.

As an example of this point, researchers here show that uterine fibrosis and its consequences are unresponsive to dasatinib and quercetin senolytic treatment, though they do not determine whether the compounds reach the uterus to the same degree as is the case for the heart, lung, or kidneys. That leaves the question of exactly why this treatment is ineffective, poor biodistribution of the senolytics versus tissue-specific mechanistic differences in cellular senescence and fibrosis, to be answered at a later date.

The most obvious histological change in the aged uterus is the collagen deposition (fibrosis) in the muscle layers and stroma. Mechanisms involved in this uterine fibrosis remain unclear. Collagen deposition in tissues occurs as a result of chronic inflammatory processes involving several pathways: inflammatory interleukins, growth factors, caspases, oxidative stress products, and accumulation of senescent cells. Targeting senescent cells with senolytic drugs might slow down or prevent fibrosis processes in different tissues and organs. Currently, quercetin (Q) and dasatinib (D), administered alone or in combination (D+Q), are the most studied senolytic drugs. Different authors have reported anti-fibrotic effects of these drugs in tissues such as kidney, lung, and liver.

Studies about potential antifibrotic and senolytic effects of these drugs in the uterus are few, and there is no published study about effects of the D+Q combination on the uterus. It is important to mention that although these drugs alone have a senolytic potential, their combination selectively targets a broader range of senescent cell types than either agent alone. We investigated effects of aging and the senolytic drug combination of dasatinib plus quercetin (D+Q) on uterine fibrosis. Forty mice, 20 young females (03-months) and 20 old females (18-months), were analyzed.

The main morphological changes observed during the mice uterine aging were increased uterine volume and fibrosis. In our study, dilated uterus was observed in 35% of the old mice, with no cases observed in any young mice. Interestingly, the D+Q treatment did not reduce the prevalence of uterine dilatation in old mice. The main feature of the uterine fibrosis process is collagen deposition. Age-related fibrosis appears to be a slow and continuous process that might, over time, cause development of serious pathological complications, including those observed in our animals: a dilated uterus. Due to slow development of this age-related disease, D+Q senolytic therapy in the present protocol may not have been continued long enough for attenuating uterine collagen deposition.

Link: https://doi.org/10.18632/aging.102772

Researchers here report that upregulation of α-Klotho and TGFβR2 together, via gene therapy, can modestly reverse osteoarthritis in a rat model in which untreated animals progress to a more severe stage of the condition. Inhibiting TGF-β receptors such as TGFβR2 is known to suppress chronic inflammation, and likely functions by interfering in the inflammatory TGF-β signaling produced by senescent cells. The evidence for cellular senescence to drive the progression of osteoarthritis is quite compelling at this point. Meanwhile, α-Klotho declines with age and upregulation of this protein is known to improve regenerative capacity in some tissues.

Osteoarthritis is caused by gradual changes to cartilage that cushions bones and joints. During aging and repetitive stress, molecules and genes in the cells of this articular cartilage change, eventually leading to the breakdown of the cartilage and the overgrowth of underlying bone, causing chronic pain and stiffness. Previous research had pinpointed two molecules, αKLOTHO and TGF beta receptor 2 (TGFβR2), as potential drugs to treat osteoarthritis. αKLOTHO acts on the mesh of molecules surrounding articular cartilage cells, keeping this extracellular matrix from degrading. TGFβR2 acts more directly on cartilage cells, stimulating their proliferation and preventing their breakdown.

Researchers treated young, otherwise healthy rats with osteoarthritis with viral particles containing the DNA instructions for making αKLOTHO and TGFβR2. Six weeks after the treatment, rats that had received control particles had more severe osteoarthritis in their knees, with the disease progressing from stage 2 to stage 4. However, rats that had received particles containing αKLOTHO and TGFβR2 DNA showed recovery of their cartilage: the cartilage was thicker, fewer cells were dying, and actively proliferating cells were present. These animals' disease improved from stage 2 to stage 1, a mild form of osteoarthritis, and no negative side effects were observed.

Further experiments revealed 136 genes that were more active and 18 genes that were less active in the cartilage cells of treated rats compared to control rats. Among those were genes involved in inflammation and immune responses, suggesting some pathways by which the combination treatment works. To test the applicability of the drug combination to humans, the team treated isolated human articular cartilage cells with αKLOTHO and TGFβR2. Levels of molecules involved in cell proliferation, extracellular matrix formation, and cartilage cell identity all increased.

Link: https://www.salk.edu/news-release/drug-combo-reverses-arthritis-in-rats/

Macrophages are a type of innate immune cell, and like all immune cells are involved in a great many processes in the body, ranging from tissue regeneration to clearing out molecular waste and debris to destruction of pathogens. Macrophages, and the similar microglia of the central nervous system, adopt different phenotypes, known as polarizations, depending on environment and the task at hand. The M1 polarization is pro-inflammatory and focused on ingestion of pathogens and debris, while the M2 polarization is anti-inflammatory and focused on regeneration. These are broad buckets and as such not truly representative of the real complexity of types and behaviors in these cell populations, but they are helpful enough for researchers to consider therapies based on forcing macrophages to preferentially adopt one polarization over another.

Earlier work on macrophage polarizations in aging suggested that issues arise with a growth in M1 populations and reduction in M2 populations, mirroring the rising chronic inflammation of aging. Matters are more complicated and tissue specific than that, however. To pick one illustrative example, today's open access commentary looks at what is known of polarization in the aging of muscle tissue, where the opposite trend is observed. The collective activities of cells, like cell metabolism itself, is a ferociously complicated domain and varies widely from tissue type to tissue type within the body. How these aspects of our biology change with age is yet another layer of complexity atop that, and little of it is completely mapped and understood at the detail level. Simple points of intervention, or global changes that can be made safely, are few and far between.

Macrophages in skeletal muscle aging

Macrophage function is largely mediated by a unique process of polarization. Depending on local environmental cues, macrophages polarize to pro-inflammatory M1 or anti-inflammatory M2 subtypes. In skeletal muscle, polarized macrophages regulate injury repair or infection resolution. Upon injury, infiltrated monocytes polarize to M1 and secrete proinflammatory cytokines to facilitate the elimination of pathogens and the cleanup of tissue debris. Subsequently, M2 macrophages that are converted from M1 and recruited from surrounding muscles jointly suppress inflammation and promote growth factors and collagen synthesis that contribute to injury repair. Accordingly, the blocking of the M1 to M2 transition resulted in defective repair, and the depletion of macrophages severely compromised muscle repair.

Contrary to muscle repair, the role of macrophage involvement in skeletal muscle aging is poorly understood. To gain insight into the function of macrophages in skeletal muscle aging, we analyzed their polarization status in aging human skeletal muscle. Considering that skeletal muscle aging inevitably occurs even in individuals devoid of obvious injury or infection, we studied resident macrophages from healthy older individuals in order to focus on normal/natural aging. We found that most macrophages in human skeletal muscle were M2, and the number increased with age. In contrast, M1 macrophages were much fewer in number, and decreased with age.

We further observed that macrophages closely co-localize with adipocytes in intermuscular adipose tissue (IMAT), but not satellite cells (muscle stem cells). This co-localization suggested possible mechanisms for the M2 increase and the actions of increased M2 in aging skeletal muscle. Adipocytes have been shown to secrete M2-promoting Th2 cytokines and adiponectin, and M2 was indeed the major macrophage population in adipose tissues in lean but not obese mice. We infer that adipocytes in IMAT contribute to the extensive M2 polarization in normal skeletal muscle, and that increased IMAT in aging skeletal muscle in non-obese, healthy people may be responsible for the M2 increase.

In keeping with the evidence that M2 macrophages are capable of regulating collagen synthesis and adipogenesis, we observed that collagen mRNA levels were dramatically reduced in aged mouse skeletal muscle, but collagen protein levels were comparable between aged and young muscle. We inferred from this observation that increased M2 macrophages may contribute to the stable collagen protein level in muscle. Consistent with this notion, increased M2 macrophages in aged skeletal muscle were shown to promote muscle fibrosis in mice.

Regarding adipogenesis, a recent study showed that M2 macrophages suppress adipocyte progenitor cell proliferation in mouse adipose tissue, and that the depletion of M2 macrophages enhanced the generation of small adipocytes and improved insulin sensitivity. In skeletal muscle, it was shown that M2 macrophages elevate adipogenesis by fibro-adipogenic progenitors (FAPs)/ncb2015">fibro-adipogenic progenitors (FAPs). Thus, increased M2 macrophages may contribute to fibrosis and fat infiltration, the two major features of skeletal muscle aging, although their exact function remains elusive.

This open access commentary reflects a reasonable conservative position on the development of means to treat aging, which is that nothing can yet produce greater and more reliable results in humans than undertaking a better lifestyle. In this view, some combination of aerobic exercise, strength training, and calorie restriction robustly does more for most people than any of the other options on the table. Ten years ago I would have agreed. Now, however, I think it clear that senolytic therapies to selectively destroy senescent cells and some forms of mesenchymal stem cell transplantation, those capable of produce a significant amount of engraftment of the transplanted cells, can achieve greater benefits than lifestyle choices. We would need to see more work on NAD+ upregulation and mitochondrially targeted antioxidants to make the same claim there, while much of the rest of the present field seems unlikely to ever do as well as lifestyle interventions.

In modern times, inventing a drug that prevents the aging-linked decline in organ function, expands the years of life spent in good health, or even increases lifespan promises fame and fortune for the discoverer. Vitamins, anti-oxidants, resveratrol and other alleged sirtuin activators, caloric restriction, nicotinamide adenine dinucleotide (NAD+) and its biosynthetic precursors, young blood and growth and differentiation factor 11 (GDF 11), senolytics, rapamycin and rapalogs, metformin as well as numerous other compounds and treatments all were (or still are) considered as the magic bullet for "anti-aging" effects in the last couple of years.

However, for most, if not all of them, preclinical results in animal models were difficult to translate to humans, unexpected adverse effects in animals or humans were reported, and/or clinical trials showing any efficacy in healthy young and old individuals are still elusive. Importantly, aging per se is not recognized as a disease, and so-called "anti-aging" effects are often difficult to disentangle from disease prevention. For example, it is not entirely clear whether the beneficial outcome of caloric restriction in non-human primates is due to a reduction of numerous diseases observed in control-fed primates (whatever control levels mean in a laboratory context for these animals), or if true "anti-aging" effects were achieved.

In stark contrast to the currently proposed putative "anti-aging" drugs, a combination of various lifestyle-based approaches clearly achieves the best epidemiological risk profile for healthy aging, with minimal or no adverse effects. Moreover, some of these approaches, for example exercise training, are not only highly efficient in preventing certain chronic diseases, but also in the treatment of numerous pathologies. While it is true that the molecular basis of the health beneficial effect of exercise remains largely enigmatic, for as long as data about clinical efficacy and safety of exercise "mimetics" and "anti-aging" drugs are missing (and probably even beyond that), lifestyle-based interventions remain the mainstay approach to minimize the risk for diseases, reduce morbidity and mortality and most importantly, improve healthspan in aging. The old adage "use it or lose it" should thus serve as a reminder that regular physical activity is directly and strongly linked to health in the young and the elderly.

Link: https://doi.org/10.18632/aging.102741

In the publicity materials here, researchers discuss the recently published SASP Atlas, a fairly comprehensive map of the molecules secreted by senescent cells - the senescence-associated secretory phenotype (SASP). Cells become senescent at the end of their replicative lifespan, but also in response to wounding, DNA damage, a toxic environment, or the signals of senescent neighbors. Senescence is transient, in the sense that these cells should self-destruct or be destroyed by the immune system shortly after their creation. Unfortunately these processes become inefficient with age, leading to rising numbers of senescent cells throughout the body. When senescent cells are present in sizable numbers for long periods of time, the SASP becomes very harmful. It disrupts tissue function and produces chronic inflammation. It is an important contributing cause of aging.

Senescent cells, which stop dividing under stress, are long-recognized drivers of multiple diseases of aging. Mouse studies have shown that targeted removal of these cells and the inflammatory factors they secrete, known as the senescence-associated secretory phenotype (SASP), has beneficial results on multiple organ systems and functions. Success in the laboratory has given rise to companies and research projects aimed at developing either senolytics, drugs that clear senescent cells, or senomorphics, drugs that suppress the SASP. But drug development and clinical utilization require simple, reliable biomarkers to assess the abundance of senescent cells in human tissues.

Researchers have now extensively profiled the SASP of human cells and have generated a curated database available for use in the field, the SASP Atlas. "The stage is now set for the development of clinically-relevant biomarkers of aging. This will speed efforts to get safe and effective drugs into the clinic and, in the long term, could enable physicians to give patients a clear read-out of how well, or poorly, their various tissues and organs are aging. The complexity of the SASP, which is typically monitored by a few dozen secreted proteins, has been greatly underappreciated, and a small set of factors cannot explain the diverse phenotypes senescence produces in vivo."

The SASP Atlas as a comprehensive proteomic database of soluble and exosome SASP factors originating from multiple senescence inducers and cell types. Each profile consists of hundreds of largely distinct proteins, but also includes a 'core' subset of proteins elevated in all SASPs. "For the first time we have the capability of measuring the burden of senescent cells in vivo and making educated guesses on how they became senescent and how neighboring cells are being affected."

Link: https://www.buckinstitute.org/news/stage-is-set-to-develop-clinically-relevant-senescence-based-biomarkers-of-aging/

Chronic inflammation is an important aspect of aging, a process that stems from low-level biochemical damage and cellular dysfunction, and that then contributes to the progression of age-related disease and tissue dysfunction. Chronic inflammation sustained over years accelerates all of the common fatal age-related conditions: it disrupts tissue maintenance, and leads to fibrosis, immune dysfunction, and many more issues. The chronic inflammation of aging is important enough that beneficial therapies have been built on the basis of suppressing inflammation directly, without addressing its causes. Treatments that actually address the causes should be very much better at the end of the day, of course.

Interventions that have been demonstrated to slow aging in laboratory species tend to act to suppress the age-related increase in inflammation - they would have to, in order to achieve the outcome of a longer, healthier life in these animals. Calorie restriction is the best studied of these interventions, and a wide range of calorie restriction mimetic drugs have arisen from this field of research, compounds that mimic a fraction of the overall metabolic response to a lower intake of calories. Today's open access paper reviews what is known of the way in which mechanisms of the calorie restriction response act to reduce chronic inflammation and its impact on age-related disease.

A sizable fraction of the inflammation of aging arises from the presence of senescent cells. These cells grow in number with age, and their signaling produces a range of detrimental effects on surrounding tissue, of which chronic inflammation is just one - though, as noted here, an important one. Calorie restriction adopted in later life doesn't impact the burden of cellular senescence to anywhere near as great a degree as the use of senolytic drugs can achieve by selectively destroying senescent cells. That point is worth keeping in mind while looking over the paper noted here.

Control of Inflammation by Calorie Restriction Mimetics: On the Crossroad of Autophagy and Mitochondria

Under certain circumstances such as aging, there is a failure in the resolution mechanisms leading to the chronic activation of immune cells and persistent inflammation. This state of low-grade but chronic inflammation is known as inflammaging, and is characterized by increased levels of pro-inflammatory cytokines in the circulation. Notably, inflammaging is considered a risk factor for many age-related diseases. Even in certain tissues like the brain, that possesses a privilege protection against inflammation, certain signs of inflammation appear gradually with age, and this neuroinflammation can anticipate the appearance of some neurodegenerative diseases. In addition, the integrity of the intestinal barrier is compromised due to inflammatory stress during aging and contributes to the development of several diseases. Finding drugs that protect against inflammaging, the disruption of the intestinal barrier, and neuroinflammation should be a priority for geroscience in the next years.

Mitochondrial metabolism and autophagy are two of the most metabolically active cellular processes, playing a crucial role in regulating organism longevity. It is well known that an intense crosstalk exists between mitochondria and autophagosomes, and the activity or stress status of either one of these organelles may affect the other. A mitochondrial or autophagy decline compromises cellular homeostasis and induces inflammation. Furthermore, mitochondrial function and autophagy are key pathways controlling the activation of both the innate and the adaptive immune system. In the last decade, it has become evident that mitochondria are essential organelles that direct the fate of immune cells, giving rise to a new scientific discipline that is called immunometabolism. Moreover, the outcome of the inflammatory response can be controlled by modulating the metabolism of immune cells.

Calorie restriction (CR) is the oldest strategy known to promote healthspan, and a plethora of CR mimetics have been used to emulate its beneficial effects. Herein, we discuss how CR and CR mimetics, by modulating mitochondrial metabolism or autophagic flux, prevent inflammatory processes, protect the intestinal barrier function, and dampen both inflammaging and neuroinflammation. We outline the effects of some compounds classically known as modulators of autophagy and mitochondrial function, such as NAD+ precursors, metformin, spermidine, rapamycin, and resveratrol, on the control of the inflammatory cascade and how these anti-inflammatory properties could be involved in their ability to increase resilience to age-associated diseases.

Undergoing earlier menopause is a sign of a greater burden of age-related damage and dysfunction, so it should not be surprising to see that this correlates with a greater incidence of chronic disease in the years thereafter. People with a greater burden of cell and tissue damage tend to exhibit all of the manifestations of aging earlier than their less damaged peers. These variations in damage burden and consequences from individual to individual are near all the results of lifestyle choices, particularly smoking, weight, and exercise, and environmental factors such as exposure to chronic viral infection. Genetics plays only a small role until very late life, and even then it is outweighed by the choices made and the level of stress that the immune system has suffered over the years.

As life expectancy is now more than 80 years for women in high income countries, a third of a woman's life is spent after the menopause. It is known already that premature menopause, occurring at the age of 40 or younger, is linked to a number of individual medical problems in later life, such as cardiovascular disease and diabetes. However, there is little information about whether there is also an association between the time of natural menopause and the development of multiple medical conditions - known as multimorbidity.

Researchers used data on women who had joined the prospective Australian Longitudinal Study on Women's Health between 1946 and 1951. The women responded to the first survey in 1996 and then answered questionnaires every three years (apart from a two-year interval between the first and second survey) until 2016. The women reported whether they had been diagnosed with or treated for any of 11 health problems in the past three years: diabetes, high blood pressure, heart disease, stroke, arthritis, osteoporosis, asthma, chronic obstructive pulmonary disease, depression, anxiety, or breast cancer. Women were considered to have multimorbidity if they had two or more of these conditions.

During the 20 years of follow-up, 2.3% of women experienced premature menopause and 55% developed multimorbidity. Compared with women who experienced menopause at the age of 50-51 years, women with premature menopause were twice as likely to develop multimorbidity by the age of 60, and three times as likely to develop multimorbidity from the age of 60 onwards. "We found that 71% of women with premature menopause had developed multimorbidity by the age of 60 compared with 55% of women who experienced menopause at the age of 50-51. In addition, 45% of women with premature menopause had developed multimorbidity in their 60s compared with 40% of women who experienced menopause at the age of 50-51."

Link: https://www.eshre.eu/Press-Room/Press-releases-2020/menopause-and-multimorbitity

With the caveat that the behavior of cells in culture is not necessarily all that relevant to their behavior amidst the full complexities of living tissue, this study is an interesting initial exploration of the ways in which the cellular senescence of supporting cells in the brain might contribute to the progression of neurodegeneration. Senescent cells secrete a potent mix of inflammatory and other signaling; while they serve a useful purpose when present for a short time, not all are successfully destroyed. Their numbers grow with age, and the presence of these errant cells and their signaling is very harmful over the long term. Thus the development of senolytic therapies to selectively destroy senescent cells is a very promising line of work in the treatment of aging as a medical condition.

Neurodegeneration is a major age-related pathology. Cognitive decline is characteristic of patients with Alzheimer's and related dementias and cancer patients after chemotherapy or radiotherapy. A recently emerged driver of these and other age-related pathologies is cellular senescence, a cell fate that entails a permanent cell cycle arrest and pro-inflammatory senescence-associated secretory phenotype (SASP). Although there is a link between inflammation and neurodegenerative diseases, there are many open questions regarding how cellular senescence affects neurodegenerative pathologies.

Among the essential cell types in the brain, astrocytes are the most abundant population. Astrocytes retain proliferative capacity, and their functions are crucial for neuron survival. Astrocytes are critical for mediating ion homeostasis, growth factor responses and neurotransmitter functions in the brain. Previous studies showed that astrocyte dysfunction is associated with multiple neurodegenerative diseases. Importantly, senescent astrocytes were identified in aged and Alzheimer's disease brain tissue, and other studies identified several factors that are responsible for inducing senescence in astrocytes. These studies reported a link between an inflammatory environment and neurodegenerative diseases, but how astrocyte senescence might alter brain function in general remains unclear.

Here, we investigated the phenotype of primary human astrocytes made senescent by irradiation, and identified genes encoding glutamate and potassium transporters as specifically downregulated upon senescence. This down regulation led to neuronal cell death in co-culture assays. Unbiased RNA sequencing of transcripts expressed by non-senescent and senescent astrocytes confirmed that glutamate homeostasis pathway declines upon senescence. Genes that regulate glutamate homeostasis as well as potassium ion and water transport are essential for normal astrocyte function. Our results suggest a key role for cellular senescence, particularly in astrocytes, in excitotoxicity, which may lead to neurodegeneration including Alzheimer's disease and related dementias.

Link: https://doi.org/10.1371/journal.pone.0227887

Stress response mechanisms have been shown to be important in the way in which metabolism determines longevity in any given species. Short-lived species exhibit great plasticity of life span in response to stresses such as heat, cold, nutrient deprivation, and hypoxia. A mild or transient stress can trigger lasting upregulation of cell and tissue maintenance activities, leading to improved function and a slowed aging process. Most such stress responses converge on the processes of autophagy responsible for recycling unwanted or damaged protein machinery and cell structures.

One of numerous lines of inquiry in this part of the field of aging research is focused on hypoxia-inducible factors (HIFs), proteins that manage the response to hypoxia, the stress resulting from insufficient oxygen to supply cellular operations. HIFs are involved in many age-related conditions, but their relationship with aging and disease is a complicated one. In some cases inappropriate overactivation of HIFs is harmful, such as in cancerous tissue. In the case of aging as a whole, HIFs may be involved in a range of processes that are both helpful and harmful. Thus a more careful exploration is required in order to pick out possible points of intervention.

Hypoxia-Inducible Factor-1α: The Master Regulator of Endothelial Cell Senescence in Vascular Aging

Since the discovery of HIF-1α, several seminal works have identified the changes in HIF associated with age and the development of age-related disorders, including neurodegenerative diseases. Importantly, in 2009, researchers described HIF-1 as a longevity factor, demonstrating that HIF-1 stabilization is associated with a 30-50% increase in lifespan in nematodes. Several studies have shown that stabilization of HIF-1 increases longevity and healthspan through different pathways in Caenorhabditis elegans. These critical findings in worms yielded a new perspective on the study of HIF stabilization and lifespan among mammals. However, the stabilization of mammalian HIF-1α has been implicated in tumor growth and cancer development and may therefore be harmful. Consequently, a balance between the beneficial and detrimental effects of HIF is critical for homeostasis and depends on the involved components and their contribution to longevity.

Studies on skin, a tissue that is continuously exposed to intrinsic and extrinsic aging factors, have identified HIF-1α as a crucial determinant of skin homeostasis, especially in epidermal aging and wound healing. Results have reported that the loss of epidermal HIF-1α accelerates epidermal aging and affects re-epithelialization in humans and mice. Notably, significant elevations in both hypoxia-inducible transcription factors HIF-1α and HIF-1β gene expression have also been found in the gingival tissues of aged animals, even though these tissues were deemed clinically healthy. In a model of limb ischemia in mice, HIF-1 was found to mediate angiogenesis and, therefore, has been proposed to contribute to the pathological aging process.

HIF is not only a transcriptional factor that regulates tissue oxygenation (including angiogenesis and vascular remodeling) but also controls redox balance, inflammation, and glucose metabolism to eventually maintain cellular homeostasis. According to current knowledge, the age-dependent impairment of HIF-1α induction leads to diminished vascular responses to limb ischemia and less effective wound healing. Some evidence shows the functionally important expression of HIF-1α among ischemic limb mice. It has been demonstrated that the abundance of the HIF-1α protein is decreased in ischemic tissues from aged mice and has also been linked with the downregulation of genes encoding angiogenic growth factors. Another vital player of vascular aging, which is positively regulated by HIF-1, is vascular endothelial growth factor (VEGF), a central mediator of angiogenesis. During aging, there is a defect in HIF-1 activity, yielding VEGF expression reduction and leading to the impairment of angiogenesis in response to the ischemia model.

Recently, we found that HIF-1α is involved in p53, p16, cyclin D1, and lamin B1-mediated senescence in vascular endothelial cells (ECs). Moreover, senescent ECs failed to express HIF-1α, and the microvesicles released by these cells were unable to carry HIF-1α. In another study, HIF-1α was found to play a critical regulatory role in vascular inflammation among macrophages after intimal injury through limiting excessive vascular remodeling. The mechanism by which macrophage-derived HIF-1α mediated this effect is still unknown. Considering these findings, HIF-1α may represent a possible therapeutic target in vascular diseases, especially in vascular aging.

Mitochondria are the power plants of the cell. A herd of these bacteria-like organelles in every cell manufacture the chemical energy store molecules that are used to power cellular processes. Mitochondrial function declines with age throughout the body. Evidence suggests that this is due to changes in mitochondrial dynamics that inhibit the quality control mechanisms of mitophagy that are responsible for recycling worn and damaged mitochondria. This loss of miochondrial function is well known to contribute to the progression of neurodegenerative conditions, as the brain is an energy-hungry organ, making this an important aspect of aging to target for reversal.

Mitochondrial health is vital for cellular and organismal homeostasis, and mitochondrial defects have long been linked to the pathogenesis of neurodegenerative diseases such as Alzheimer's, Parkinson's, ALS, Huntington's, and others. However, it is still unclear whether cellular mechanisms required for the maintenance of mitochondrial integrity and function are deficient in these diseases, thus exacerbating mitochondrial pathology. The quality control of mitochondria involves multiple levels of strategies to protect against mitochondrial damage and maintain a healthy mitochondrial population within cells. In neurons, mitophagy serves as a major pathway of the quality control mechanisms for the removal of aged and defective mitochondria through lysosomal proteolysis. The molecular and cellular mechanisms that govern mitophagy have been extensively studied in the past decade. However, mitophagy deficit has only been recognized recently as a key player involved in aging and neurodegeneration.

Given the fact that mitochondrial deficit is clearly linked to neuronal dysfunction and the exacerbation of disease defects, protection of mitochondrial function could be a practical strategy to promote neuroprotection and modify disease pathology. Mitochondrially targeted antioxidants have been proposed. In particular, the antioxidant MitoQ, a redox active ubiquinone targeted to mitochondria, has been examined and demonstrated to have positive effects in multiple models of aging and neurodegenerative disorders. Importantly, mitophagy could be another promising target for drug discovery strategy. Therefore, further detailed studies to elucidate mitophagy mechanisms not only advance our understanding of the mitochondrial phenotypes and disease pathogenesis, but also suggest potential therapeutic strategies to combat neurodegenerative diseases.

Link: https://doi.org/10.3390/cells9010150

Chronic inflammation in brain tissue is thought to be important in the progression of neurodegenerative conditions such as Alzheimer's disease. Some factions within the research community theorize that chronic inflammation driven by dysfunctional microglia and other supporting cells in the brain is the important cause of Alzheimer's, not the early accumulation of amyloid-β. Even as it becomes inflammatory with advancing age, the immune system continues to perform necessary functions, however. So any approach to addressing the issue must be fairly selective. An example is the use of senolytic drugs capable of passing the blood-brain barrier in order to destroy senescent microglia and astrocytes, a strategy that, in mouse models, has been shown to reverse the tau pathology characteristic of the later stages of Alzheimer's disease.

While there is consensus that the immune system is intimately involved in Alzheimer's disease (AD), there is considerable debate over which aspects of inflammation are harmful and contribute to degeneration, and which are protective and may prevent cognitive decline. Furthermore, it has yet to be established which components of the immune system actively play a role in pathology and which are just a consequence of disease. Gliosis, or increased numbers of activated astrocytes and microglia are a hallmark feature of neuroinflammation. However, past descriptions of this phenomenon, namely just "reactive" or "increased gliosis" are vastly oversimplified. Recent evidence highlights altered glia-specific pathways in post-mortem AD tissue and in mouse models of AD, suggesting that glial responses are much more heterogeneous and complex than previously thought.

While neuroinflammation can promote efficient clearance of amyloid-β and neuronal debris it can also accelerate disease by causing neuronal and glial cell death. This inflammatory balance is highly orchestrated and understanding how to regulate these responses is key to developing effective therapeutics for AD. The initiation of an immunological reaction can be beneficial and critical, allowing for a burst of glial activity to protect and repair the site of damage, and to clear toxic species or dysfunctional synapses. For example, in response to adverse conditions, microglia will undergo morphological changes, accompanied by the release of a storm of molecular mediators that increases clearances of amyloid-β. Furthermore, various types of non-neuronal cells are recruited to the site to assist in repairing the damage and consolidating excessive inflammation. These reparative processes are beneficial, yet may also have harmful consequences such as sustained cytokine release which can become toxic to neuronal cells. Therefore, understanding the specific cellular roles and inflammatory reactions in AD is of vital importance.

Link: https://doi.org/10.3389/fnagi.2019.00337

One must always be careful in the interpretation of studies of aging in which essential biological processes are disrupted. There are any number of ways to disrupt essential biological functions to produce all sorts of consequent damage. But damage that isn't relevant to the normal processes of aging can nonetheless produce results that look very much like age-related conditions. Thus the details matter greatly. Here researchers suppress autophagy in mice in order to gain greater insight into its role in aging, and suggest that there might be reasons for caution in the development of therapies to boost autophagy in old people - though again, the details matter greatly in any interpretation of this work.

Autophagy is the name given to a collection of cellular maintenance processes that work to recycle damaged protein machinery and structures. Autophagy declines with age, and this loss may be of greatest relevance when it comes to removal of worn and dysfunctional mitochondria. Mitochondrial function falters with age, which causes issues throughout the body, particularly in energy-hungry tissues such as the brain and muscle. This appears to be connected to a reduced effectiveness of mitochondrial autophagy, though the causes of this issue are still being investigated.

It is well known that many of the interventions known to slow aging in mice involve upregulation of autophagy, and some, like calorie restriction, will only slow aging and extend life if autophagy is functional. It is at present reasonable to conclude that autophagy is an important portion of the way in which the operation of metabolism steers the outcome of aging, but data resulting from the practice of calorie restriction in humans strongly suggests that the magnitude of the benefits that would result from therapeutic upregulation of autophagy just isn't as large as we'd all like it to be - though perhaps the upregulation just needs to be larger. We shall see in the years ahead, as biotech startups such as Selphagy Therapeutics make progress on clinical development of this class of therapy.

Temporal inhibition of autophagy reveals segmental reversal of ageing with increased cancer risk

Autophagy is an evolutionarily conserved bulk cellular degradation system that functions to breakdown and recycle a wide array of cytoplasmic components from lipids, proteins, and inclusion bodies, to whole organelles (e.g. mitochondria). Importantly a reduction in autophagic flux (the rate at which autophagosomes form and breakdown cellular contents) is associated with increasing age in mammals. Evidence from lower organisms suggests that autophagy inhibition can negate the positive-effects of regimens that extend lifespan, such as calorie restriction, rapamycin supplementation, and mutations in insulin signalling pathways.

In mice, the constitutive promotion of autophagy throughout lifetime has been shown to extend health- and life-span in mammalian models. These studies have provided hitherto missing evidence that autophagic flux can impact on mammalian longevity and supports the notion that the pharmacological promotion of autophagy may extend health-, and potentially life-span, in humans. However, whether a reduction in autophagy is sufficient to induce phenotypes associated with ageing, and whether these effects can be reversed by restoring autophagy has to date not been addressed. Considering that the therapeutic window for pharmacological intervention to counteract ageing, and age-related diseases, will be later in life (as opposed to from conception), after autophagic flux has declined, it is critical to understand how the temporal modulation (inhibition and restoration) of autophagy may impact on longevity and health.

To address these questions, we use two doxycycline (dox) inducible shRNA mouse models that target the essential autophagy gene Atg5 to demonstrate that autophagy inhibition in young adult mice is able to drive the development of ageing-like phenotypes and reduce longevity. Importantly we confirm that the restoration of autophagy is associated with a substantial restoration of health- and life-span, however this recovery is incomplete. Notably the degree of recovery is segmental, being dependent on both the tissue and metric analysed. A striking consequence of this incomplete restoration is that autophagy restored mice succumb to spontaneous tumour formation earlier and at an increased frequency than control mice, a phenotype not observed during autophagy inhibition alone. As such our studies indicate that despite the significant benefit, autophagy reactivation may also promote tumorigenesis in advanced ageing context.

Researchers here propose that the skin is a significant source of the systemic chronic inflammation that is observed in older individuals. Setting aside the range of other mechanisms that contribute to inflammation to only consider the accumulation of senescent cells with age, and the fact that these errant cells are a potent source of inflammatory signaling, this proposition doesn't seem unreasonable. The skin is a sizable organ, after all, and even if it produces senescent cells at much the same pace as the rest of the body, it will still represent a large and quite distributed pool of such cells, positioned to delivery their inflammatory signals throughout the body.

Increasing evidence points to a provocative role of sustained, sub-clinical inflammation, often termed "inflammaging," in the development of these chronic disorders. In support of this notion, chronologically aged humans (≥50 years) display elevated circulating levels of pro-inflammatory cytokines, particularly IL-6, IL-1β, and TNFα. Moreover, subjects with chronic cutaneous inflammatory diseases, such as psoriasis and eczematous dermatitis, also display an increased prevalence of aging-associated disorders, including atherosclerotic cardiovascular disease, obesity, and type 2 diabetes. Though anti-inflammatory regimens, such as inhibitors of IL-1βα and TNFα, as well as methotrexate, have been deployed in the management of these aging-associated disorders, the outcomes of treatments with these agents have been inconclusive.

While many chronologically aged humans merely display marked evidence of inflammation, they nonetheless display elevated circulating levels of cytokines, suggesting that one or more, as yet identified organs, could account for the aging-associated increase in circulating cytokines. It seems reasonable to postulate that the responsible organs must be large enough to sustain such an increase in circulating cytokines, even without noticeable inflammation. Although the musculoskeletal system is the largest organ in humans, most chronologically aged humans display no evidence of musculoskeletal inflammation.

Other relatively large organs to be considered include the skin, intestines, lungs, and liver. The skin weighs about 20 lbs (with an additional, variable contribution from subcutaneous adipose tissues), while the weights of the intestines, lungs, and liver represent ≈7.5, 5.0 and 3.3 lbs, respectively. Because of their relatively lesser size, inflammation of the lungs, intestines, and liver likely would not only need to be apparent, but also sustained if any of these organs could account for the increase in circulating levels of cytokines. Yet again, the majority of otherwise normal aged humans display few clinical signs or symptoms of inflammation in these organs. Hence, it seems unlikely that they could contribute substantially to "inflammaging" unless multiple organs simultaneously exhibit mild inflammation. Notably, the aged skin commonly exhibits signs and symptoms of inflammation, such as pruritus and senile xerosis.

Because of its relatively large size, we hypothesized that the skin could be an important contributor to the elevated levels of circulating cytokines in chronologically aged humans, despite the fact that it typically displays little evidence of inflammation. Not only its size, but also its unique anatomic site, serving as the interface between the body and external environment, supports our hypothesis. In this site, it is continuously exposed to external physical and chemical stressors, which themselves can provoke inflammation, even as other less-exposed organs remain quiescent. In addition, chronologically aged humans display alterations in several key epidermal functions, each of which can provoke low-grade, chronic inflammation in the skin.

Link: https://doi.org/10.2147/CIA.S235595

The authors of this open access review paper discuss what is known of the age-related failure of the immune system, with a focus on the consequences for viral infection and vaccination effectiveness. The elderly suffer greatly because the immune system falters in its ability to protect against pathogens, a dysfunction that has numerous root causes. The atrophy of the thymus, reducing the supply of new T cells to a trickle; the disruption of hematopoietic stem cell function, reducing the pace of production of all immune cells; the fibrosis of lymph nodes, rendering it hard for immune cells to coordinate with one another; the accumulation of broken and harmful immune cell populations absent a supply of undamaged reinforcements. Potential strategies exist to address all of these issues; they must just be brought to realization by the research and development communities.

Immunosenescence is a major cause of increased incidence and severity of viral infections in the elderly, and contributes to impaired immunogenicity and efficacy of vaccines. Understanding the biological basis for age-associated alterations in viral immunity and vaccine immunogenicity is a challenge with substantial clinical importance. Subsequently, the use of systems biology approaches in combination with computational model systems will be crucial to understand the complexity of age-associated changes in the immune system by identifying molecular networks that orchestrate immunity to vaccinations in humans and potentially define correlates of protection.

Given the plastic nature of aging and rapidly growing field of systems biology, molecular profiling of the aging-related changes is increasingly being examined at a single cell level by high-throughput omics technologies, including genomics, metagenomics, transcriptomics, and metabolomics. Specially, aging of the immune cells is affected by changes in homeostasis via cytokine levels, and by modifications in the metabolic pathways. Caloric restrictions (CR) affected a marked improvement in the maintenance and/or production of naïve T cells and the consequent preservation of TCR repertoire diversity. Furthermore, CR also improved T cell function and reduced production of inflammatory cytokines by memory T cells, suggesting that CR can delay T cell senescence and potentially contribute to extended lifespan by reducing susceptibility to infectious diseases.

A key area for future exploration in the immunosenescence field is the role of the secondary lymphoid organs as a critical partner in the development and function of the aging human immune system. It will be important to analyze age-related changes in secondary lymphoid organs, lymph nodes and spleen, given the aging-associated decrease in the size of lymph nodes. Lymph nodes not only serve as the key initiating region of the immune response, but they also play an important role in maintaining naive lymphocytes.

Next, investigation of how extracellular vesicles (EVs) are linked to aging could be a promising area of interest. EVs are membrane-bound vesicles released by multiple cell types that include immune cells. Evidence from cellular models suggests that exosomes released by macrophages from older are more pro-inflammatory than those released by macrophage from younger. In particular, mRNA levels of IL-6 and IL-12, but not TNF-α, in macrophage-derived exosomes were significantly higher in serums of older subjects. Given that EVs play an important role in immune cell network and cellular senescence, the profiles of secretome and the function of senescent immune cells will soon be revealed as the EV research field progresses.

Link: https://doi.org/10.4110/in.2019.19.e37

Today's research materials are representative of numerous initiatives aiming to produce taxonomies of the biochemistry of aging, to catalog the observed variations. Yet, with the exception of a very small number of unlucky souls bearing rare harmful mutations, we all age for the same underlying reasons. The same processes of metabolism produce the same forms of cell and tissue damage, leading to the same downstream dysfunctions and the same ultimately fatal age-related conditions. Yes, there is some variation in outcome. For all that aging is a universally similar process of multiple interacting forms of damage, some portions of its consequences progress modestly more rapidly or modestly more slowly from individual to individual, a distribution of outcomes that largely results from lifestyle choices and random happenstance, rather than from genetic variation.

Thus many researchers are interested in this distribution, perhaps more so than in doing something about the challenge of aging, the death and suffering it causes. Given this view of the situation, I would say that somewhat more scientific effort goes into cataloging the differences between individuals than is merited. Examining long-lived people, with the goal of producing interventions that might make more people live incrementally longer in good health, is a terrible strategy, when compared with the alternative of directly addressing the common causes of aging, which might make everyone live considerably longer in good health. Nonetheless, despite the great potential of rejuvenation biotechnology based on repair of the damage that causes aging, there is a lot more funding and interest in the research community for far less promising lines of work.

'Ageotypes' provide window into how individuals age

Researchers profiled a group of 43 healthy men and women between the ages of 34 and 68, taking extensive measurements of their molecular biology at least five times over two years. The researchers determined that people generally age along certain biological pathways in the body: metabolic, immune, hepatic (liver) and nephrotic (kidney). People who are metabolic agers, for example, might be at a higher risk for diabetes or show signs of elevated hemoglobin A1c, a measure of blood-sugar levels, as they grow older. People with an immune ageotype, on the other hand, might generate higher levels of inflammatory markers or be more prone to immune-related diseases as they age. But the ageotypes are not mutually exclusive, and a metabolic ager could also be an immune ager, for example.

Just because an individual falls into one or more of the four ageotypes - metabolic, immune, hepatic and nephrotic - doesn't mean that they're not also aging along the other biological pathways. The ageotype signifies the pathways in which increases in aging biomarkers are most pronounced. Perhaps most exciting - and surprising - is that not everyone in the study showed an increase in ageotype markers over time. In some people, their markers decreased, at least for a short period, when they changed their behavior. They still aged, but the overall rate at which they did so declined, and in some cases aging markers decreased. In fact, the team saw this phenomenon occur in a handful of important clinical molecules, including hemoglobin A1c and creatine, a marker for kidney function, among a small subset of participants.

In that subset, there were individuals who made lifestyle changes to slow their aging rate. Among those who exhibited decreased levels of hemoglobin A1c, many had lost weight, and one made dietary changes. Some who saw a decrease in creatine, indicating improved kidney function, were taking statins. In other cases, exactly why rates of aging markers waned was unclear. For some people, there were no obvious behavioral changes, yet the team still saw a decreased rate of aging along their ageotype pathways. There was also a handful of people that maintained a slower-than-average aging rate throughout the entire study. How or why is still a mystery.

Personal aging markers and ageotypes revealed by deep longitudinal profiling

The molecular changes that occur with aging are not well understood. Here, we performed longitudinal and deep multiomics profiling of 106 healthy individuals from 29 to 75 years of age and examined how different types of 'omic' measurements, including transcripts, proteins, metabolites, cytokines, microbes, and clinical laboratory values, correlate with age. We identified both known and new markers that associated with age, as well as distinct molecular patterns of aging in insulin-resistant as compared to insulin-sensitive individuals. In a longitudinal setting, we identified personal aging markers whose levels changed over a short time frame of 2-3 years. Further, we defined different types of aging patterns in different individuals, termed 'ageotypes', on the basis of the types of molecular pathways that changed over time in a given individual. Ageotypes may provide a molecular assessment of personal aging, reflective of personal lifestyle and medical history, that may ultimately be useful in monitoring and intervening in the aging process.

The decline of the vascular system with age takes numerous forms, such as a loss of capillary density, stiffening of blood vessel walls leading to raised blood pressure and increased rupturing of small vessels, and leakage of the blood-brain barrier that wraps blood vessels in the central nervous system. This vascular degeneration is a distinct process from the accumulation of metabolic waste, such as amyloid-β, that characterizes neurodegenerative diseases. Age-related conditions tend to have numerous distinct causes that interact over time to make one another worse, and this is certainly true of the aging of the brain.

Three new studies add to growing evidence that damaged blood vessels wreak havoc on the brain, but not by exacerbating amyloid-β (Aβ) deposition. One found no correlation between intracerebral atherosclerosis and overall amyloid plaque burden in cognitively normal older adults. Another reported that midlife atherosclerosis in the carotid artery upped future risk of vascular dementia, but not Alzheimer's disease (AD). A third found that white-matter hyperintensities - a proxy for damage to small vessels in the brain - had no bearing on future changes in AD biomarkers.

"These studies can all be interpreted to support the hypothesis that vascular risk influences the risk for development of cognitive impairment and dementia principally via non-amyloidogenic pathways. They provide further evidence for, and are compatible with, the growing body of evidence that the timing of vascular risk also matters, with midlife being the most sensitive period. They all suggest that cerebrovascular disease and AD affect cognitive decline through distinct pathways."

On their own, faulty blood vessels in the brain can cause cognitive impairment and dementia. Blood-vessel disease is also thought to contribute to the clinical symptoms of AD, since people with Alzheimer's often have vascular pathology along with amyloid plaques and neurofibrillary tangles. Regardless of whether vascular dysfunction has an additive or synergistic relationship with AD pathology in influencing cognitive decline, the crucial point is that good blood vessel health benefits the brain. A person's vascular risk is highly modifiable by way of lifestyle choices or, if need be, medication.

Link: https://www.alzforum.org/news/research-news/vascular-dysfunction-taxes-cognition-not-amyloid-ad

Meaningful progress towards the control of cancer, ending it as a major threat to life and health, will be led by programs that can produce very broadly applicable treatments. That means therapies that can be applied to many (or even all) cancers with minimal differences in configuration or need for further per-cancer development. There are hundreds of cancer subtypes, but only so many researchers, and only so much funding for research and development: development of highly specific therapies is just not an effective path forward.

Examples of the most promising lines of work with broad application include the OncoSenX suicide gene therapy targeting p53 expression, interference in telomere lengthening, and blocking immune inhibitors such as CD47 that cancer cells use to evade the immune system. Researchers here report on another possible approach, a very broad cell surface signature of cancer that might be used to build chimeric antigen receptor T cell immunotherapies that can be applied to a very wide range of cancers indeed.

T-cell therapies for cancer - where immune cells are removed, modified and returned to the patient's blood to seek and destroy cancer cells - are the latest paradigm in cancer treatments. The most widely-used therapy, known as CAR-T, is personalised to each patient but targets only a few types of cancers and has not been successful for solid tumours, which make up the vast majority of cancers. Researchers have now discovered T-cells equipped with a new type of T-cell receptor (TCR) which recognises and kills most human cancer types, while ignoring healthy cells. This TCR recognises a molecule present on the surface of a wide range of cancer cells as well as in many of the body's normal cells but, remarkably, is able to distinguish between healthy cells and cancerous ones, killing only the latter.

Conventional T-cells scan the surface of other cells to find anomalies and eliminate cancerous cells - which express abnormal proteins - but ignore cells that contain only "normal" proteins. The scanning system recognises small parts of cellular proteins that are bound to cell-surface molecules called human leukocyte antigen (HLA), allowing killer T-cells to see what's occurring inside cells by scanning their surface. HLA varies widely between individuals, which has previously prevented scientists from creating a single T-cell-based treatment that targets most cancers in all people. The new study describes a unique TCR that can recognise many types of cancer via a single HLA-like molecule called MR1. Unlike HLA, MR1 does not vary in the human population - meaning it is a hugely attractive new target for immunotherapies.

T-cells equipped with the new TCR were shown, in the lab, to kill lung, skin, blood, colon, breast, bone, prostate, ovarian, kidney and cervical cancer cells, while ignoring healthy cells. To test the therapeutic potential of these cells in vivo, the researchers injected T-cells able to recognise MR1 into mice bearing human cancer and with a human immune system. This showed "encouraging" cancer-clearing results which the researchers said was comparable to CAR-T therapy in a similar animal model.

Link: https://www.cardiff.ac.uk/news/view/1749599-discovery-of-new-t-cell-raises-prospect-of-universal-cancer-therapy

In today's open access research materials, the authors report that upregulation of the gene expression of an identified marker of aging, ELOVL2, can improve visual function in aging mice. Normally, expression of ELOVL2 declines with age, and consequent effects on visual function may involve the role of ELOVL2 in production of long-chain omega-3 and omega-6 polyunsaturated acids. These metabolites are in high demand in retinal cells, and lowered levels may well cause a sizable fraction of age-related dysfunction.

Any discussion of this change in ELOVL2 expression and visual function is interesting in the context of why degenerative aging takes place. It is clearly the case that considerable dysregulation of cellular metabolism takes place with age. The proximate cause of this degeneration of function is changes in the epigenetic regulation of gene expression, the pace of production of various proteins essential to cell function. In near all cases it is quite obscure as to why exactly these epigenetic changes take place - researchers are far more interested in identifying changes than in the much more arduous work of understanding the full context of any given change. The underlying damage of aging is well catalogued, such as in the SENS view of aging, but linking this damage through a long chain of downstream consequences to specific age-related functional consequences is a sizable project, still in its very earliest stages.

Researchers Identify Gene with Functional Role in Aging of Eye

A lengthy-named gene called Elongation of Very Long Chain Fatty Acids Protein 2 or ELOVL2 is an established biomarker of age. Researchers found that an age-related decrease in ELOVL2 gene expression was associated with increased DNA methylation of its promoter. Methylation is a simple biochemical process in which groups of carbon and hydrogen atoms are transferred from one substance to another. In the case of DNA, methylation of regulatory regions negatively impacts expression of the gene. When researchers reversed hypermethylation in vivo, they boosted ELOVL2 expression and rescued age-related decline in visual function in mice.

ELOVL2 is involved in production of long-chain omega-3 and omega-6 polyunsaturated fatty acids, which are used in several crucial biological functions, such as energy production, inflammation response, and maintenance of cell membrane integrity. The gene is found in humans as well as mice. In particular, ELOVL2 regulates levels of docosahexaenoic acid or DHA, a polyunsaturated omega-3 fatty acid abundantly found in the brain and retina. DHA is associated with a number of beneficial effects. Notably, its presence in photoreceptors in eyes promotes healthy retinal function, protects against damage from bright light or oxidative stress and has been linked to improving a variety of vision conditions, from age-related macular (AMD) degeneration to diabetic eye disease and dry eyes.

The lipid elongation enzyme ELOVL2 is a molecular regulator of aging in the retina

Methylation of the regulatory region of the elongation of very-long-chain fatty acids-like 2 (ELOVL2) gene, an enzyme involved in elongation of long-chain polyunsaturated fatty acids, is one of the most robust biomarkers of human age, but the critical question of whether ELOVL2 plays a functional role in molecular aging has not been resolved. Here, we report that Elovl2 regulates age-associated functional and anatomical aging in vivo, focusing on mouse retina, with direct relevance to age-related eye diseases.

We show that an age-related decrease in Elovl2 expression is associated with increased DNA methylation of its promoter. Reversal of Elovl2 promoter hypermethylation in vivo through intravitreal injection of 5-Aza-2'-deoxycytidine (5-Aza-dc) leads to increased Elovl2 expression and rescue of age-related decline in visual function. Mice carrying a point mutation C234W that disrupts Elovl2-specific enzymatic activity show electrophysiological characteristics of premature visual decline, as well as early appearance of autofluorescent deposits, well-established markers of aging in the mouse retina. Finally, we find deposits underneath the retinal pigment epithelium in Elovl2 mutant mice, containing components found in human drusen, a pathologic hallmark of age related macular degeneration.

These findings indicate that ELOVL2 activity regulates aging in mouse retina, provide a molecular link between polyunsaturated fatty acids elongation and visual function, and suggest novel therapeutic strategies for the treatment of age-related eye diseases.

Delivery of exosomes derived from stem cell populations has been demonstrated to improve recovery from injury in numerous studies and human applications. The interesting aspect of this demonstration in stroke recovery in pigs is that exosomes from neural stem cells provoke greater functional recovery without improving some of the structural changes that are normally associated with greater mortality and loss of function.

Researchers have presented brain imaging data for a new stroke treatment that supported full recovery in swine, modeled with the same pattern of neurodegeneration as seen in humans with severe stroke. The researchers report the first observational evidence during a midline shift - when the brain is being pushed to one side - to suggest that a minimally invasive and non-operative exosome treatment can now influence the repair and damage that follow a severe stroke.

Exosomes are considered to be powerful mediators of long-distance cell-to-cell communication that can change the behavior of tumor and neighboring cells. The results of the study echo findings from other recent studies using exosome technology. Many patients who suffer stroke exhibit a shift of the brain past its center line-the valley between the left and right part of the brain. Lesions or tumors will induce pressure or inflammation in the brain, causing what typically appears as a straight line to shift. "Based on results of the exosome treatment in swine, it doesn't look like lesion volume or the effects of a midline shift matter nearly as much as one would think. This suggests that, even in some extremely severe cases caused by stroke, you're still going to recover just as well."

Trauma from an acute stroke can happen quickly and can cause irreversible damage almost immediately. Data from the team's research showed that non-treated brain cells near the site of the stroke injury quickly starved from lack of oxygen and died - triggering a lethal action of damage signals throughout the brain network and potentially compromising millions of healthy cells. However, in brain areas treated with exosomes that were taken directly from cold storage and administered intravenously, these cells were able to penetrate the brain and interrupt the process of cell death.

Link: https://news.uga.edu/exosomes-promote-remarkable-recovery-in-severe-stroke/

Researchers here note a novel mechanism by which exosomes might cause issues following a stroke. Exosomes are a form of intracellular communication, membrane-bound packages of molecules that are released and taken up by cells in large numbers. Researchers are usually concerned with the way in which exosome cargo affects the behavior of cells once the exosomes are taken up, but here they note changes in exosome structure following a stroke that leads them to clump and block blood vessels. This is an interesting mechanism, and it will be equally interesting to see how the research community chooses to try to address it.

Researchers have found that after stroke, exosomes - nanosized biological suitcases packed with an assortment of cargo that cells swap, like proteins and fats - traveling in the blood get activated and sticky and start accumulating on the lining of blood vessels. Like a catastrophic freeway pileup, platelets, also tiny cells that enable our blood to clot after an injury, start adhering to the now-sticky exosomes, causing a buildup that can effectively form another clot, further obstruct blood flow to the brain and cause additional destruction.

One thing traveling exosomes typically aren't is sticky. Rather, much like our real suitcases, they have a smooth label that marks their intended destination. But when these external destination tags become inexplicably sticky following a stroke, not only do exosomes not reach their destination, they can worsen stroke outcome. In a bit of a perfect storm, the scientists have shown in both stroke models and human blood vessels that exosomes cruising through the blood then pick up RGD, the unique and normally sticky peptide sequence, arginine-glycine-aspartate, which is key to the pileup that can cause additional brain damage.

More typically, exosomes carry a negligible amount of RGD, a protein that's important in holding together the extracellular matrix that helps cells connect and form tissue. In the aftermath of a stroke, cells and the extracellular matrix both get damaged, and sticky RGD is effectively set free. Platelets normally aren't exposed to RGD, which should mostly be sequestered in the extracellular matrix, so they become angry, activated and also sticky in response.

Another piece of this sticky situation is that a receptor called αvβ3. Avβ3 also is found on the lining of blood vessels and naturally binds to sticky RGD as part of its role with the extracellular matrix. The new stroke study shows the RGD carrying exosomes also target these receptors. In fact, when scientists gave antibodies to αvβ3, the binding to the blood vessel lining was blocked. A bottom line of the new work is that RGD sequences are a key contributor to the secondary damage from stroke.

Link: https://jagwire.augusta.edu/sticky-situation-inside-blood-vessels-can-worsen-stroke-damage/

The J.P. Morgan Healthcare conference runs every year in San Francisco, a big draw for the biotech industry, and many organizations take the opportunity to host events at the same time. Among these, the SENS Research Foundation has for the past few years hosted a pitch day in which biotech companies in the longevity industry, largely startups, present to that portion of the Bay Area investor community interested in funding the treatment of aging as a medical condition. I was there to present on progress at Repair Biotechnologies, and took some notes on the other companies as they talked about their work.

Kimera Labs

Kimera Labs is a fairly established company working on exosome therapeutics and diagnostics, deriving the exosomes used in therapy from cultured stem cells. They have been around for 10 years or so, and started selling exosomes in 2014. They are primarily concerned with regenerative medicine applications, accelerating regeneration from severe injury via exosome delivery to produce faster healing without scar formation. Kimera Labs exosomes have been used to treat about 30,000 patients. The founder views the effects of stem cell exosomes as being a stimulation of growth signaling that is characteristic of embryonic development.

Viscient Biosciences

Viscient Biosciences works on 3D bioprinting of human tissues for drug discovery and validation, allowing for development programs that are, in their earlier stages, more cost-effective than those that must rely on animal studies. For example, they create liver organoids arrayed by the hundred on plates that are used in the processes of drug screening and testing. The company is founded by the former Organovo CEO. While they are not currently working on rejuvenation, the principals want to take their work into that realm of drug discovery.

OncoSenX

OncoSenX is the spin-out from Oisin Biotechnologies that applies the Entos Pharmaceuticals fusogenic lipid nanoparticle platform to the task of selectively destroying cancer cells. These lipid nanoparticles are non-toxic, and one can thus employ very large doses without provoking immune reactions, widespread off-target cell death, or other issues. This is a big improvement over past generations of lipid nanoparticles. The DNA machinery carried by the lipid nanoparticles triggers the destruction of cells expressing the tumor suppressor gene p53. It doesn't matter if p53 is mutated and disabled, as is the case in many cancers, as the platform targets the earliest stages of the gene expression of p53, not the presence of p53 itself. The founder shared data from recent studies in immunocompetent mouse models of tumor development, showing that this approach results in a 100% rate of tumor clearance, a substantially better performance than checkpoint inhibitors can achieve in the same models.

Underdog Pharmaceuticals

Underdog Pharmaceuticals is one of the SENS Research Foundation spinout companies. The staff there work on removal of 7-ketocholesterol via the use of carefully designed cyclodextrin molecules that bind to it and carry it to the liver for excretion. 7-ketocholesterol is a form of persistent metabolic waste that has no useful role in the body; removing all of it would be a good thing. This toxic compound is important in the progression of atherosclerosis, but is also probably relevant to a range of other age-related conditions.

Turn.bio

Turn.bio is one of a growing number of groups working on forms of cellular reprogramming to reverse the epigenetic changes and loss of cell function that take place with aging. The Turn.bio approach uses mRNA delivery to achieve partial reprogramming, to shock cells over a few days into reversing their age-related epigenetic changes, without pushing them into abandoning their adult phenotype and function. The company presented gene expression profile data obtained from the use of their therapy in vitro, in which cells exhibited a shift to more youthful phenotypes without changing cell identity. In vivo they have assessed, for example, the impact of their treatment on muscle regeneration, showing lasting improvement in muscle regeneration in aged mice. They are also in the process of assessing delivery of their therapy to the retina to reduce age-related decline in visual function.

Gero

Gero is one of the present crop of AI-based drug discovery groups, using machine learning to speed up identification of therapeutics that might influence aging. They have produced results based on mouse and human data, and have identified a range of drug candidates, largely existing drugs that might be repurposed. They have tested these drugs in mice to assess slowing or reversal of aspects of aging; they view their approach as reducing damage, and think that clearance of senescent cells is probably an important factor in the results they are achieving in mice. The founders are now collaborating with Brian Kennedy in Singapore, and have moved there from their start in Russia.

Nemalife

Nemalife automates the process of screening interventions in C. elegans nematode worms, often used in early stage research in aging. Their product uses microfluidic chips to form a tiny habitat for C. elegans, combined with scanning technology and software, which results in a compact desktop device in which one can run this sort of study cost-effectively. Their differentiator is the small size of their system, which uses lesser amounts of reagents in comparison to other automation for C. elegans studies developed in recent years.

AgeX Therapeutics

Michael West took the floor to talk about about a relatively new subsidiary of AgeX Therapeutics called Reverse Bioengineering, which joins the other companies now working on applications of cell reprogramming. He noted that the cellular rejuvenation that occurs during reproduction, in the early development of the embryo, is the process that inspires these efforts. The AgeX staff are not just interested in changing the state of cells to make them younger, but also in making embryonic and embryonic-like cells older in phenotype. This artificial aging of cell phenotype has applications in producing cell lines and engineered tissues, to ensure that the cells are in the right state for adult function. The company is working on delivery of reprogramming therapeutics via exosomes as well as more traditional approaches. As to why regeneration is turned off in adults versus during embryonic development: the consensus is that this is a cancer risk reduction strategy, selected for by evolution. Cancers exhibit embryonic-like DNA methylation, they represent an inappropriate reversion to embryonic growth and regeneration, but these mechanisms are there to be exploited in a more controlled fashion.

Volumetric

Volumetric commercializes an advance in 3D bioprinting, a system that can incorporate blood vessel networks in the printed tissue that are sufficient to support larger tissue sizes. This has long been the roadblock that prevents serious work on whole organ engineering. This company is indeed aiming at the production of entire organs for transplantation, built from patient cells. They see the roadmap to that goal as starting with 3D printers, then the development of more advanced bioinks, then the creation of small engineered tissue models with complex architecture, and finally the creation of whole organs. Companies such as Volumetric will produce products at each stage that will support this progression; Volumetric is already selling the creation of engineered tissue models as a service.

712 North

712 North is focused on small molecule manipulation of mitochondrial pathways around OPA1, to promote either greater mitochondrial fission or fusion in order to treat specific conditions. More fusion can help some neurodegenerative conditions, while more fission might be the basis for cancer therapies. The company is initially looking at the inherited condition of autosomal dominant optic atrophy, in which there is OPA1 mutation. Looking ahead, OPA1 function changes in Alzheimer's disease in ways that produce results that look similar to those of the inherited condition in the optic nerve. Separately, there is evidence for OPA1 manipulation to reverse tau pathology in mouse models. This all further points to the importance of mitochondrial function in many conditions.

Qalytude

Qalytude is an adaptation of an existing business model for an easy online process to obtain prescription medications. The service uses physician and pharmacy networks to allow people interested in treating aging to obtain metformin, NAD+ patches, rapamycin, the senolytic therapy of dasatinib and quercetin, and so forth. They started with metformin, which I personally think people should not waste their time with, and are moving on to the other options. It is the provision of senolytics to the public at large that is the important part of their program, to my eyes at least. Given a subscriber community, the founders want to expand to conduct studies and gather health data.

Oisin Biotechnologies

Most of the readership here should be familiar with Oisin Biotechnologies, the first company to use the Entos Pharmaceuticals fusogenic lipid nanoparticle suicide gene therapy, in this case to target senescent cells for destruction. They see targeting cells based on their internal patterns of gene expression as the next stage in the evolution of cell targeting: more precise and adaptable than past technologies. The non-toxic lipid nanoparticles can be introduced throughout the body in high doses without side-effects, and the payload only triggers in cells that express p16, a characteristic sign of cellular senescence. The founders showed the full data for the mouse life span study that completed last year, and noted that treated mice didn't just live longer, but also exhibited increased bone density as measured via DEXA scans. They also showed good safety data from a small study carried out in companion animal dogs.

Leucadia Therapeutics

Leucadia Therapeutics works towards reversing the age-related decline in drainage of cerebrospinal fluid through the cribriform plate in the skull. In their model, this is a primary cause of Alzheimer's disease, as it allows metabolic waste to build up in the olfactory bulb where the condition starts. The founder discussed their animal data: they occluded the cribriform plate in ferrets, and as a consequence these animals suffered olfactory bulb degeneration and other aspects of Alzheimer's-like pathology. The company is presently focused on generating large amounts of human CT scan data, to produce an assay that determines who will progress from mild cognitive impairment to Alzheimer's, based an analysis of the state of the cribriform plate. Leucadia will then use the scanned population to determine who will benefit from a small medical device implanted in the cribriform plate to restore drainage of cerebrospinal fluid, and launch a clinical trial.

Repair Biotechnologies

Repair Biotechnologies is the company that I founded with Bill Cherman to work on regeneration of the thymus to address immunosenescence and reversal of atherosclerosis. We are continuing our path of preclinical development. I presented on recent progress in both of these programs, such as mouse data for improved immune function following upregulation of FOXN1 in the thymus, and visualizations of resistance to foam cell formation in a macrophage cell line that expresses enzymes capable of breaking down cholesterol.

Retrotope

Retrotope carries out human studies of treatment with deuterium loaded fatty acids, which are more stable and resistant to oxidative damage than the usual hydrogen-based fatty acids found in the body. The deuterium is very precisely placed - has to be in exactly the right place to avoid toxicity while increasing stability. When delivered as a therapy, replacing a modest percentage of the native fatty acids, these more stable fatty acids greatly reduce lipid peroxidation. The company has carried out clinical trials in an inherited infant neurodegenerative condition, caused by mutation in PLA2G6, and demonstrated reversal of this form of neurodegeneration. PLA2G6 is also implicated in Parkinson's disease, interestingly. The company has run clinical trials in Friedrich's Ataxia patients with good results, and obtained initial human data for progressive supranuclear palsy, showing reversal of the condition in three subjects.

Revel Pharmaceuticals

Revel Pharmaceuticals aims to commercialize glucosepane cross-link breakers based on the work funded by the SENS Research Foundation at the Spiegel Lab at Yale. The candidate enzymes were found via mining bacterial populations for species that can metabolize glucosepane, the primary basis for harmful persistent cross-links in humans. Collagen does not turn over all that much in adults, and these molecules get linked together or have their structure detrimentally altered via glucosepane cross-links. Cross-links accumulate steadily over time, from age 20 onwards, rising to pathological levels in later life. The founder noted that there have been trials of cross-link breaker small molecules in the past, but as of yet there are no successfully approved products.

Maia Biotechnology

Maia Biotechnology produces what they term telomerase-mediated therapeutics to target telomeres. This is perhaps the first group to attempt commercial development of a near universal cancer therapy based on suppressing tumor growth via interfering in telomerase and telomere function in cancer cells. They have developed a DNA sequence called THIO that, once introduced into cells, is incorporated into telomeres by telomerase activity. THIO sabotages cell function once present in telomeres, causing cell death. The founders presented in vitro data showing cell death in various cancers cell lines when exposed to THIO. THIO also combines well with PD-1 checkpoint inhibitors, when tested in mouse models of cancer, producing much better results than either on its own - actually completely clearing the tumors.

Myelin is the sheathing of nerves, essential to their function. Excessive loss produces disabling and ultimately fatal conditions such as multiple sclerosis, but we all lose myelin integrity to some degree as a consequence of the damage and dysfunction of degenerative aging. This most likely contributes to cognitive decline and other age-related issues. A number of different approaches have been identified to boost the operation of the normal maintainance processes that remyelinate nerves, such as FGF21 upregulation, or increasing the size of remyelinating cell populations. Here, researchers discover another possible trigger that might force greater remyelination. While the work aims at treatment of conditions such as multiple sclerosis, successful remyelination therapies should in principle be useful for anyone in the later stages of aging.

Researchers have found that by genetically switching off a receptor activated by blood proteins, named Protease Activated Receptor 1 (PAR1), the body switches on regeneration of myelin, a fatty substance that coats and protects nerves. "Myelin regeneration holds tremendous potential to improve function. We showed when we block the PAR1 receptor, neurological healing is much better and happens more quickly. In many cases, the nervous system does have a good capacity for innate repair. This sets the stage for development of new clinically relevant myelin regeneration strategies."

Myelin acts like a wire insulator that protects electrical signals sent through the nervous system. Demyelination, or injury to the myelin, slows electrical signals between brain cells, resulting in loss of sensory and motor function. Sometimes the damage is permanent. Demyelination is found in disorders such as MS, Alzheimer's disease, Huntington's disease, schizophrenia, and spinal cord injury. Thrombin is a protein in blood that aids in healing. However, too much thrombin triggers the PAR1 receptor found on the surface of cells, and this blocks myelin production. Oligodendrocyte progenitor cells capable of myelin regeneration are often found at sites of myelin injury, including demyelinating injuries in multiple sclerosis.

The research focused on two mouse models. One was an acute model of myelin injury and the other studied chronic demyelination, each modeling unique features of myelin loss present in MS, Alzheimer's disease, and other neurological disorders. Researchers genetically blocked PAR1 to block the action of excess thrombin. The research not only discovered a new molecular switch that turns on myelin regeneration, but also discovered a new interaction between the PAR1 receptor and a very powerful growth system called brain derived neurotropic factor (BDNF).

Significantly, the researchers found that a current FDA-approved drug, vorapaxar, that inhibits the PAR1 receptor also showed ability to improve myelin production in cells tested in the laboratory. "It is important to say that we have not and are not advocating that patients take this inhibitor at this time. We have not used the drug in animals yet, and it is not ready to put in patients for the purpose of myelin repair. Using cell culture systems, we are showing that this has the potential to improve myelin regeneration."

Link: https://newsnetwork.mayoclinic.org/discussion/mayo-clinic-research-discovers-a-molecular-switch-for-repairing-central-nervous-system-disorders/

Researchers have been investigating the role of sestrin in longevity in lower animals such as flies and nematodes for some years now. Upregulation extends life, downregulation shortens life, and initial investigations suggested that the effect operates through the usual stress response mechanisms involved in life extension in short-lived species. Researchers here establish that sestrin in flies and sestrin-1 in mice are necessary for many of the benefits of exercise, and upregulation of sestrin mimics the effects of exercise on metabolism. There is also other published research in mice from recent years to support this role for sestrin-1 in mammals, in that expression of this gene is upregulated by exercise and also improves the operation of the cellular maintenance processes of autophagy.

One promising therapeutic intervention to impede age-related functional decline is endurance exercise. Endurance training induces remodeling in muscle tissue that alters the metabolic health of the entire organism. Evidence from humans and model organisms strongly suggests that endurance exercise has substantially protective effects on various indices of healthspan. These changes are often thought to be at least partially mediated by exercise-induced upregulation of AMP-activated protein kinase (AMPK) and the insulin-AKT pathway.

Sestrins are small stress-inducible proteins that are found throughout the animal kingdom. Mammals express three Sestrins (Sesn1-3), while Drosophila and C. elegans express one Sestrin orthologue. Once induced, Sestrins coordinate metabolic homeostasis by regulating multiple signaling pathways. Through its intrinsic oxidoreductase activity and by regulating autophagy, Sestrin can function as an antioxidant to reduce oxidative damage in cells. Importantly, while Sestrins downregulate TORC1/S6K signaling, they strongly activate TORC2/AKT signaling.

Here, using Sestrin-deficient fly and mouse models, we show that Sestrins play a critical role in mediating chronic exercise adaptations and exercise benefits. Genetic ablation of Sestrins prevents organisms from acquiring metabolic benefits of exercise and improving their endurance through training. Conversely, Sestrin upregulation mimics both molecular and physiological effects of exercise, suggesting that it could be a major effector of exercise metabolism.

Link: https://doi.org/10.1038/s41467-019-13442-5

In today's open access paper, the authors argue that a downward trend in normal human body temperature recorded by physicians over the past 150 years is real, rather than being an artifact of changing approaches to measurement. Taking that as settled, though I'm sure there is plenty of room left to debate the point, one might then ask why this trend exists and what it might imply.

Over the past few centuries, both life expectancy at birth and adult life expectancy have risen steadily, the former more profoundly than the latter due to sizable reductions in childhood mortality. The majority of these gains in adult life expectancy have been the result of improved control over infectious disease, reducing the burden placed on the immune system over the long term by both chronic and passing infections. The authors of this paper pull from a number of sources to suggest that this burden of chronic infection is the source of raised body temperature, due to inflammation.

Does a lowered body temperature in and of itself cause differences in human longevity, or do the effects of chronic inflammation on the pace of immune aging far outweigh it? Human data is supportive of the idea that lower body temperature correlates with greater longevity, but not definitively so. The practice of calorie restriction lowers core body temperature in the course of slowing aging in mammals. But is body temperature actually an important mechanism in comparison to the others involved in chronic infection and calorie restriction? I would guess no, given what I've seen of the literature on these topics.

Decreasing human body temperature in the United States since the industrial revolution

In 1851, the German physician Carl Reinhold August Wunderlich obtained millions of axillary temperatures from 25,000 patients in Leipzig, thereby establishing the standard for normal human body temperature of 37°C. A compilation of 27 modern studies, however, reported mean temperature to be uniformly lower than Wunderlich's estimate. Recently, an analysis of more than 35,000 British patients with almost 250,000 temperature measurements, found mean oral temperature to be 36.6°C.

In this study, we analyzed 677,423 human body temperature measurements from three different cohort populations spanning 157 years of measurement and 197 birth years. We found that men born in the early 19th century had temperatures 0.59°C higher than men today, with a monotonic decrease of -0.03°C per birth decade. Temperature has also decreased in women by -0.32°C since the 1890s with a similar rate of decline (-0.029°C per birth decade). Although one might posit that the differences among cohorts reflect systematic measurement bias due to the varied thermometers and methods used to obtain temperatures, we believe this explanation to be unlikely.

The question of whether mean body temperature is changing over time is not merely a matter of idle curiosity. Human body temperature is a crude surrogate for basal metabolic rate which, in turn, has been linked to both longevity (higher metabolic rate, shorter life span) and body size (lower metabolism, greater body mass). We speculated that the differences observed in temperature between the 19th century and today are real and that the change over time provides important physiologic clues to alterations in human health and longevity since the Industrial Revolution.

Resting metabolic rate is the largest component of a typical modern human's energy expenditure, comprising around 65% of daily energy expenditure for a sedentary individual. Heat is a byproduct of metabolic processes, the reason nearly all warm-blooded animals have temperatures within a narrow range despite drastic differences in environmental conditions. Over several decades, studies examining whether metabolism is related to body surface area or body weight, ultimately, converged on weight-dependent models. Since US residents have increased in mass since the mid-19th century, we should have correspondingly expected increased body temperature. Thus, we interpret our finding of a decrease in body temperature as indicative of a decrease in metabolic rate independent of changes in anthropometrics.

Although there are many factors that influence resting metabolic rate, change in the population-level of inflammation seems the most plausible explanation for the observed decrease in temperature over time. Economic development, improved standards of living and sanitation, decreased chronic infections from war injuries, improved dental hygiene, the waning of tuberculosis and malaria infections, and the dawn of the antibiotic age together are likely to have decreased chronic inflammation since the 19th century. For example, in the mid-19th century, 2-3% of the population would have been living with active tuberculosis. Although we would have liked to have compared our modern results to those from a location with a continued high risk of chronic infection, we could identify no such database that included temperature measurements. However, a small study of healthy volunteers from Pakistan - a country with a continued high incidence of tuberculosis and other chronic infections - confirms temperatures more closely approximating the values reported by Wunderlich.

In summary, our investigation indicates that humans in high-income countries have changed physiologically over the last 200 birth years with a mean body temperature 1.6% lower than in the pre-industrial era. The role that this physiologic 'evolution' plays in human anthropometrics and longevity is unknown.

This is an interesting study; you'll have to actually look at the open access paper to see the meat of it, which is the various graphs showing the changes in relative population size of different microbe families in the gut that take place with age. A great deal of work on the gut microbiome and its role in health and aging is presently taking place in the scientific community; researchers have identified a number of beneficial metabolites that are produced by classes of microbe that decline with age. Further, the gut microbiome becomes ever more inflammatory with age. The size of these effects on health might be in the same ballpark as those of regular exercise, but the reasons why changes take place are not yet fully understood. The causative mechanisms seem fairly clear in and of themselves, meaning declining immune function, changes in diet, and so forth, but how they interact and which are primary and which are secondary is yet to be firmly resolved.

We obtained RNA sequencing data of subjects ranging from newborns to centenarians from a previous study, and summarized the data into a relative abundance matrix of genera in all the samples. Without using the age information of samples, we applied an unsupervised algorithm to recapitulate the underlying aging progression of microbial community from hosts in different age groups and identify genera associated to this progression. Literature review of these identified genera indicated that for individuals with advanced ages, some beneficial genera are lost while some genera related with inflammation and cancer increase.

A few genera were previously implicated in the literature, such as Oxalobacter, Butyrivibrio, Lactobacillus which have been experimentally demonstrated to be associated with aging, as well as Prevotellaceae which has been highlighted with lower presence in the gut microbiota of centenarians. The abundances of some other genera increased with respect to aging, but decreased in the extremely elderly subjects. Among these genera, Lactobacillus species are commonly used as probiotics. Oscillospira species have been frequently reported as enriched in lean subjects compared to the obese subjects, and are central to the human gut microbiota for degrading fibers. Oxalobacter is responsible for degrading oxalate in the gut. It has been experimentally demonstrated appearing in the gut of almost all young individuals, but these bacterium may later be lost during aging.

Prevotellaceae is commonly found in the gastric system of people who maintain a diet low in animal fats and high in carbohydrates and is lost in centenarians. Researchers also found that there was an increased abundance of Prevotellaceae in the guts of healthy people compared with people with Parkinson's disease. Parascardovia is a genus of Bifidobacteriaceae, which has been shown to provide health-promoting benefits to the host. Butyrivibrio species have been experimentally proved as butyrate producing bacteria, and butyrate is a preferred energy source for colonic epithelial cells and is thought to play an important role in maintaining colonic health in humans. Overall, the decrease of these beneficial genera in the elderly age groups, especially centenarians, maybe manifestation of or causal associations to decline of health in those age groups.

Link: https://doi.org/10.1186/s12866-019-1616-2

That cancer mortality is declining at a time in which the aged segment of the population is growing, and ever more people are overweight and obese, is a testament to (a) improved prevention (largely fewer people smoking, which has a sizable impact on lung cancer incidence and severity) and (b) the ever increasing efficacy of modern cancer treatments, particularly immunotherapies. These newer cancer therapies are still in the comparatively early stages of evolution as a technology platform, and we should expect these gains to continue. The immunotherapies of the 2030s will be very impressive in comparison to those deployed today.

The cancer death rate declined by 29% from 1991 to 2017, including a 2.2% drop from 2016 to 2017, the largest single-year drop in cancer mortality ever reported. The steady 26-year decline in overall cancer mortality is driven by long-term drops in death rates for the four major cancers - lung, colorectal, breast, and prostate, although recent trends are mixed. The pace of mortality reductions for lung cancer - the leading cause of cancer death - accelerated in recent years.

Overall cancer death rates dropped by an average of 1.5% per year during the most recent decade of data (2008-2017), continuing a trend that began in the early 1990s and resulting in the 29% drop in cancer mortality in that time. The drop translates to approximately 2.9 million fewer cancer deaths than would have occurred had mortality rates remained at their peak. Continuing declines in cancer mortality contrast with a stable trend for all other causes of death combined, reflecting a slowing decline for heart disease, stabilizing rates for cerebrovascular disease, and an increasing trend for accidents and Alzheimer's disease.

Lung cancer death rates have dropped by 51% (since 1990) in men and by 26% (since 2002) in women, with the most rapid progress in recent years. For example, reductions in mortality accelerated from 3% per year during 2008-2013 to 5% per year during 2013-2017 in men and from 2% to almost 4% in women. However, lung cancer still accounts for almost one-quarter of all cancer deaths, more than breast, prostate, and colorectal cancers combined.

The most rapid declines in mortality occurred for melanoma of the skin, on the heels of breakthrough treatments approved in 2011 that pushed one-year survival for patients diagnosed with metastatic disease from 42% during 2008-2010 to 55% during 2013-2015. This progress is likewise reflected in the overall melanoma death rate, which dropped by 7% per year during 2013-2017 in people ages 20 to 64, compared to declines during 2006-2010 (prior to FDA approval of ipilimumab and vemurafenib) of 2%-3% per year in those ages 20 to 49 and 1% per year in those ages 50 to 64. Even more striking are the mortality declines of 5% to 6% in individuals 65 and older, among whom rates were previously increasing.

Link: https://pressroom.cancer.org/CancerStats2020

The materials here report on efforts to screen for small molecule compounds that can reduce the age-related decline of mitochondrial function observed in neurons - and indeed throughout the body. Screening the contents of compound libraries is a process that might sound simple, and conceptually it is, but it is a complex task to build a cost-effective system and supporting logistics to screen for a novel outcome. In this case the outcome is a reversal of at least some degree of reduced mitochondrial function in neurons from old tissue, as well as improvement in important aspects of neural function.

Every cell contains a herd of a few hundred mitochondria, the distant descendants of ancient symbiotic bacteria, evolved to become fully integrated component parts of the cell. They still replicate like bacteria, can fuse and split and pass around pieces of their protein machinery, and contain a small remnant genome. Mitochondria have many roles, but are primarily responsible for producing adenosine triphosphate (ATP), chemical energy store molecules that are used to power cellular processes. This is a fairly energetic activity that has the side-effect of producing reactive oxidative molecules that damage cell structures; in a normal, youthful metabolism this is entirely compensated for by repair processes, and is in fact used as a signal. For example, it enables some of the benefits of exercise by linking increased energy production to increased cell maintenance and muscle tissue growth. Age-related disruption of ATP production is particularly important in energy-hungry tissues such as the brain and muscles. Less energy means loss of function, and in the case of the brain that contributes meaningfully to the progression of neurodegenerative conditions.

The evidence of recent years suggests that the proximate cause of the problem is changes in gene expression that impair the balance between mitochondrial fission and fusion, which in turn promotes the presence of large and damaged mitochondria that are challenging for the cellular maintenance process of mitophagy to recycle. Everything goes downhill from there. Approaches such as mitochondrially targeted antioxidants and NAD+ upregulation, both shown to modestly slow aging in laboratory species and improve tissue function in human trials, may produce their benefits in large part because they change mitochondrial behavior in ways that allow mitophagy to function more efficiently, clearing out damaged and dysfunctional mitochondria.

Compounds protect brain cells' energy organelle from damage linked to Alzheimer's, ALS, Parkinson's

A new screening platform has enabled scientists to discover a set of drug-like compounds that may powerfully protect brain cells from dangerous stresses found in Alzheimer's and other neurodegenerative diseases. The screening platform allows researchers for the first time to rapidly test libraries of thousands of molecules to find those that provide broad protection to mitochondria in neurons. Mitochondria are tiny oxygen reactors that supply cells with most of their energy. They are especially important for the health and survival of neurons. Mitochondrial damage is increasingly recognized as a major factor, and in some cases a cause, for diseases of neuronal degeneration such as Alzheimer's, Parkinson's, and ALS.

The scientists, in an initial demonstration of their platform, used it to rapidly screen a library of 2,400 compounds, from which they found more than a dozen that boost the health of neuronal mitochondria and provide broad protection from stresses found in neurodegenerative disorders. The researchers are now testing the most potent of these mitochondria-protectors in animal models of Alzheimer's, amyotrophic lateral sclerosis, and other diseases, with the ultimate goal of developing one or more into new drugs. "It hasn't yet been emphasized in the search for effective therapeutics, but mitochondrial failure is a feature of many neurodegenerative disorders and something that must be corrected if neurons are to survive. So I'm a big believer that finding mitochondria-protecting molecules is the way to go against these diseases."

Neuron-based high-content assay and screen for CNS active mitotherapeutics

Impaired mitochondrial dynamics and function are hallmarks of many neurological and psychiatric disorders, but direct screens for mitotherapeutics using neurons have not been reported. We developed a multiplexed and high-content screening assay using primary neurons and identified 67 small-molecule modulators of neuronal mitostasis (MnMs). Most MnMs that increased mitochondrial content, length, and/or health also increased mitochondrial function without altering neurite outgrowth. A subset of MnMs protected mitochondria in primary neurons from amyloid-β toxicity, glutamate toxicity, and increased oxidative stress. Some MnMs were shown to directly target mitochondria.

The top MnM also increased the synaptic activity of hippocampal neurons and proved to be potent in vivo, increasing the respiration rate of brain mitochondria after administering the compound to mice. Our results offer a platform that directly queries mitostasis processes in neurons, a collection of small-molecule modulators of mitochondrial dynamics and function, and candidate molecules for mitotherapeutics.

Researchers here investigate the relationship between the protein complex mTORC1 and the aging of intestinal stem cells, leading to loss of function in the intestine. mTORC1 signaling increases with age in intestinal tissue and leads to exhaustion of the stem cell pool, as downstream mechanisms are triggered to suppress proliferation of these cells. Naturally, mTOR or mTORC1 inhibitors are capable of reducing this effect, though one should always compare all things related to mTOR with the effects of calorie restriction before becoming too excited by new findings. Calorie restriction acts to inhibit mTOR signaling, and the size of the health benefits that it provides should guide expectations as to the bounds of the possible for therapies that inhibit mTORC1.

Nutrient malabsorption is common among the elderly, and often causes anemia and other illnesses. Nutrients are absorbed by the intestinal villi, which are composed of a layer of intestinal epithelial cells (IECs) and the lamina propria, and the absorption activity is affected by the size and density of villi. The epithelial layer is renewed every 4-5 days by intestinal stem cells (ISCs), which generate transient amplifying (TA) progenitor cells that later differentiate into absorptive or secretory cells. It has been reported that the number and regenerative activities of ISCs are decreased in 17 to 24-month-old mice, yet whether aging affects villus function and how villus aging is controlled remain less well understood.

mTOR, a sensor of nutrients and growth factors, is a central regulator of aging and a target for lifespan and healthspan extension. mTOR forms mTORC1 and mTORC2 complexes, and mTORC1 activation promotes cell proliferation by increasing global protein synthesis and other anabolic processes. mTORC1 signaling has been shown to be required for IEC proliferation during homeostasis and regeneration, including regeneration mediated by quiescent ISCs. In addition, several studies have shown that diet restriction promotes ISC expansion via mTORC1 signaling, although conflicting results have been reported regarding the exact roles played by mTORC.

The current genetic study reveals that mTORC1, which is hyperactivated in IECs, especially ISCs and TA cells of aged mice, drives villus aging by inhibiting ISC and progenitor cell proliferation through amplifying the MKK6-p38-p53 stress response pathway. This leads to ISC exhaustion and decreases in villus size and density. The natural function of the mTOR-MKK6-p38 MAPKs-p53 pathway may be to balance mTORC1-induced overgrowth and protect cells from runaway proliferation and oncogenic transformation, which is consistent with the concept that aging acts as an anti-hyperplasia mechanism.

Targeting p38 MAPK or p53 prevents or rescues ISC and villus aging and nutrient absorption defects. Inhibition of mTORC1 with rapamycin for only 1.5 months partially restored the structure and function of intestinal villi in old mice. These findings reveal that mTORC1 drives aging by augmenting a prominent stress response pathway in gut stem cells and identify p38 MAPK as an anti-aging target downstream of mTORC1.

Link: https://doi.org/10.1038/s41467-019-13911-x

I can't say that I think the data presented in the research noted here merits quite the degree of the attention that it has been given in the popular science press. It is interesting, but not compelling if its role is to be evidence for a lack of correlation between amyloid-β and cognitive decline. When thinking about the early stages of loss of cognitive function, in which changes are small and subtle, one might have to consider other factors such as vascular dysfunction or other neurodegenerative conditions with quite different mechanisms that could produce these effects. The interplay and relative importance of the field of mechanisms at this stage of aging is far from clear. Nonetheless, the present mood of the scientific community and its onlookers is that of a growing revolt against the amyloid cascade hypothesis of Alzheimer's disease, so research that ties into that mood receives attention.

There has been a longstanding belief among neuroscientists, backed by scientific evidence, that beta-amyloid, a protein that can clump together and form sticky plaques in the brain, is the first sign of Alzheimer's disease. The amyloid hypothesis, as it is often referred to, suggests an archetypal cascade in which β-amyloid in the brain initiates the acceleration of tau pathology, which in turn drives neurodegeneration and associated cognitive symptoms. However, now a new study is challenging the current hypothesis, with data suggesting that subtle thinking and memory differences may come before, or happen alongside, the development of amyloid plaques that can be detected in the brain.

"Our research was able to detect subtle thinking and memory differences in study participants and these participants had faster amyloid accumulation on brain scans over time, suggesting that amyloid may not necessarily come first in the Alzheimer's disease process. Much of the research exploring possible treatments for Alzheimer's disease has focused on targeting amyloid. But based on our findings, perhaps that focus needs to shift to other possible targets."

The study involved 747 people with an average age of 72. After adjusting for age, education, sex, genetic risk for Alzheimer's disease, and amyloid level at the start of the study, researchers found people with subtle thinking and memory differences had a more rapid accumulation of amyloid compared to people with normal thinking and memory skills. On a test that uses a dye to measure amyloid levels, where the average level was 1.16 for participants with subtle thinking and memory difficulties, amyloid levels in this group increased by .03 above and beyond the amyloid changes in those with normal thinking and memory skills over four years. People with subtle differences also had faster thinning of the entorhinal cortex, a brain region that is impacted very early in Alzheimer's disease.

On the other hand, researchers also found that, while people with mild cognitive impairment had more amyloid in their brains at the beginning of the study, they did not have faster accumulation of amyloid when compared to those with normal thinking and memory skills. However, they did have faster thinning of the entorhinal cortex as well as brain shrinkage of the hippocampus. "From prior research, we know that another biomarker of Alzheimer's disease, a protein called tau, shows a consistent relationship with thinking and memory symptoms. Therefore, more research is needed to determine if tau is already present in the brain when subtle thinking and memory differences begin to appear."

Link: https://www.genengnews.com/news/the-alzheimers-chicken-and-egg-dilemma/

The activities of mTOR are well researched, given that mTOR inhibition slows aging in a number of species. This is one of the more prominent areas of research and development to emerge from the study of beneficial stress responses such as that produced by the practice of calorie restriction. The mTOR protein participates in cellular metabolism through a pair of protein complexes, and much of the work to date has focused on the protein complex mTORC1 rather than mTORC2.

The present consensus (though not unchallenged) is that general inhibition of mTOR, such as via the use of rapamycin, is problematic because harmful effects arise from inhibition of mTORC2, offsetting the benefits due to inhibition of mTORC1. Certainly, it is the case that inhibiting mTORC2 alone shortens lifespan in laboratory animals, while inhibiting mTORC1 alone slows aging and extends life. Thus the development of drugs based on this research has focused on specific inhibition of mTORC1; several companies have a pipeline of small molecule therapies in later stage trials.

Researchers here show that increased mTORC2 activity boosts autophagy and improves cardiac function in middle-aged flies, suggesting that the current industry of mTORC1 inhibition will soon enough be joined by an industry of mTORC2 upregulation. I remain unconvinced that the effect sizes in humans resulting from upregulated autophagy will be large enough to merit the strong focus placed on this line of research and development, at a time in which most work on more promising rejuvenation therapies continues to languish in comparison, but we shall see how it all turns out soon enough.

Study of cardiac muscles in flies might help you keep your heart young

The researchers' approach starts with autophagy, a cellular "cleanup process" that removes and recycles damaged proteins and organelles. The autophagy process slows with age, which can lead to the weakening of cardiac muscles. The research team looked at a key genetic pathway conserved in virtually all organisms on Earth related to autophagy that balances organism growth with nutrient intake. This pathway, called mechanistic target of rapamycin (or mTOR), has long been linked to tissue aging. One of two complexes that underlie the mTOR pathway, referred to as mTORC2, decreases with age as autophagy declines. But the researchers found that transgenically boosting mTORC2 strengthens heart muscles of older fruit flies. "Boosting the complex almost fully restored heart function."

The discovery that enhancing mTORC2 slows the decline of the critical autophagy process could have big implications for how doctors treat patients with heart disease, one of the leading causes of the death. While flies and humans might seem to be worlds apart evolutionarily, the two species' hearts age in a similar fashion. By middle age, cardiac muscles in both species tend to contract with less strength and regularity.

TGFB-INHB/activin signaling regulates age-dependent autophagy and cardiac health through inhibition of MTORC2

Age-related impairment of macroautophagy/autophagy and loss of cardiac tissue homeostasis contribute significantly to cardiovascular diseases later in life. MTOR (mechanistic target of rapamycin kinase) signaling is the most well-known regulator of autophagy, cellular homeostasis, and longevity. The MTOR signaling consists of two structurally and functionally distinct multiprotein complexes, MTORC1 and MTORC2. While MTORC1 is well characterized but the role of MTORC2 in aging and autophagy remains poorly understood.

Here we identified TGFB-INHB/activin signaling as a novel upstream regulator of MTORC2 to control autophagy and cardiac health during aging. Using Drosophila heart as a model system, we show that cardiac-specific knockdown of INHB/activin-like protein daw induces autophagy and alleviates age-related heart dysfunction, including cardiac arrhythmias and bradycardia. Interestingly, the downregulation of daw activates TORC2 signaling to regulate cardiac autophagy. Activation of TORC2 alone through overexpressing its subunit protein rictor promotes autophagic flux and preserves cardiac function with aging. In contrast, activation of TORC1 does not block autophagy induction in daw knockdown flies. Lastly, either daw knockdown or rictor overexpression in fly hearts prolongs lifespan, suggesting that manipulation of these pathways in the heart has systemic effects on longevity control.

Healthier lifestyle choices are called healthier lifestyle choices for a reason: they do improve health over the long term. That translates to a reduced risk of suffering any of the common age-related diseases, and a noteworthy delay in their incidence when they do occur. Per the epidemiological research noted here, the difference between healthy and unhealthy lifestyles amounts to eight to ten more years of life free from the common chronic diseases of aging.

Researchers looked at 34 years of data from 73,196 women and 28 years of data from 38,366 men participating in, respectively, the Nurses' Health Study and the Health Professionals Follow-up Study. Healthy diet was defined as a high score on the Alternate Healthy Eating Index; regular exercise as at least 30 minutes per day of moderate to vigorous activity; healthy weight as a body mass index of 18.5-24.9 kg/m2; and moderate alcohol intake as up to one serving per day for women and up to two for men.

They found that women who practiced four or five of the healthy habits at age 50 lived an average of 34.4 more years free of diabetes, cardiovascular diseases, and cancer, compared to 23.7 healthy years among women who practiced none of these healthy habits. Men practicing four or five healthy habits at age 50 lived 31.1 years free of chronic disease, compared to 23.5 years among men who practiced none. Men who were current heavy smokers, and men and women with obesity, had the lowest disease-free life expectancy.

"Previous studies have found that following a healthy lifestyle improves overall life expectancy and reduces risk of chronic diseases such as diabetes, cardiovascular disease, and cancer, but few studies have looked at the effects of lifestyle factors on life expectancy free from such diseases. This study provides strong evidence that following a healthy lifestyle can substantially extend the years a person lives disease-free."

Link: https://www.eurekalert.org/pub_releases/2020-01/htcs-hlh010620.php

The gut microbiome produces a range of metabolites that are beneficial to health, though this production slackens with age for reasons that are still being explored. In recent years, researchers have demonstrated in mice that the short-chain fatty acids butyrate, acetate, and propionate are produced by gut microbes and have beneficial effects on brain function, such as by improving the pace of neurogenesis. Given this, it is a reasonable proposition to think that supplementation with these compounds might incrementally improve recovery from stroke or other form of brain injury. Researchers here show that to be the case in mice, and investigate the mechanisms by which these compounds beneficially alter the behavior of cells in injured areas of the brain.

Recovery after stroke is a multicellular process encompassing neurons, resident immune cells, and brain-invading cells. Stroke alters the gut microbiome which in turn has considerable impact on stroke outcome. However, the mechanisms underlying gut-brain interaction and implications for long-term recovery are largely elusive. Here, we tested the hypothesis that short-chain fatty acids (SCFA), key bioactive microbial metabolites, are the missing link along the gut-brain axis and might be able to modulate recovery after experimental stroke.

SCFA supplementation in the drinking water of male mice significantly improved recovery of affected limb motor function. Using in vivo wide-field calcium imaging, we observed that SCFA induced altered contralesional cortex connectivity. This was associated with SCFA-dependent changes in dendritic spine and synapse densities. RNA-sequencing of the forebrain cortex indicated a potential involvement of microglial cells in contributing to the structural and functional re-modelling. Further analyses confirmed a substantial impact of SCFA on microglial activation, which depended on the recruitment of T cells to the infarcted brain.

Previous studies have shown a bi-directional communication along the gut-brain axis after stroke. Stroke alters the gut microbiota composition, and in turn, microbiota dysbiosis has a substantial impact on stroke outcome by modulating the immune response. However, until now the mediators derived from the gut microbiome affecting the gut-immune-brain axis and the molecular mechanisms involved in this process were unknown. Here, we demonstrate that SCFA - fermentation products of the gut microbiome - are potent and pro-regenerative modulators of post-stroke neuronal plasticity at various structural levels. We identified that this effect was mediated via circulating lymphocytes on microglial activation. These results identify SCFA as a missing link along the gut-brain axis and as a potential therapeutic to improve recovery after stroke.

Link: https://doi.org/10.1523/JNEUROSCI.1359-19.2019

Clearing amyloid-β from the brain has failed to reverse Alzheimer's disease in patients, and this unfortunate outcome is slowly - all too slowly - producing a change in direction in the mainstream of Alzheimer's research. One possible conclusion is that amyloid-β is simply the wrong target, and this has led to a great deal of alternative theorizing in recent years. Even so, the consensus remains that amyloid-β does play a significant role in the condition, albeit not enough of a role in the later stages of Alzheimer's to allow anti-amyloid therapies to work. The jury remains out on whether early reduction in amyloid-β aggregation can postpone Alzheimer's - i.e. whether this aggregation actually a causative mechanism or whether it is a side-effect of the actual cause, such as chronic inflammation driven by persistent infection.

A currently popular view is that the mechanistic evidence continues to suggest that amyloid-β is important, and thus it should be targeted - but not in isolation, as the past decade or two of failed trials amply demonstrate that removal of only amyloid-β is not sufficient. The conclusion is that there must also be reductions in tau aggregation, perhaps treatment of cerebrovascular dysfunction, suppression of inflammation in the brain, and so forth. Along these lines, today's open access research is a demonstration of a combination immunotherapy in mice that targets both amyloid-β and tau. Absent stunning success in some of the more radical new directions in Alzheimer's research, such as restoring drainage of cerebrospinal fluid, we will likely see such combination immunotherapies tested in humans in the near future.

Testing a MultiTEP-based combination vaccine to reduce Aβ and tau pathology in Tau22/5xFAD bigenic mice

Alzheimer's disease (AD) is a complex and multifactorial disease involving genetic and environmental risk factors that together lead to the progressive accumulation of two hallmark pathologies: β-amyloid plaques and neurofibrillary tangles (NFTs). Although many clinical trials have aimed to reduce β-amyloid and, more recently, to target the accumulation of tau that drives NFT formation, debate remains regarding which of these pathologies represents the most tractable target, and the precise timing for these potential treatments.

Recent longitudinal analyses demonstrated evidence of synergism between Aβ and phosphorylated tau (p-tau) suggesting these pathologies may interact to trigger the progression from amnestic mild cognitive impairment (MCI) subjects to AD dementia. PET imaging studies suggest that Aβ deposits start decades before dementia onset, and may or may not precede tau pathology, with the latter correlating better with symptom onset and the degree of dementia.

According to the modified amyloid cascade model, primary age-related tauopathy (PART) develops universally as a function of aging and, by itself, produces no or only mild cognitive symptoms. Aβ deposition occurs independently in the neocortex and induces or facilitates the spread of pathological tau, perhaps by promoting the production of pathological tau strains. Pathological tau is directly associated with neurodegeneration, which in turn drives cognitive decline. In this model of AD, Aβ does not directly cause cognitive symptoms but is still central to disease pathogenesis as a dominant driver of downstream pathological processes including tau pathology.

This synergistic model suggests that combinatorial/multi-target therapies directed at the accumulation of both amyloid and tau pathologies may be more effective in the treatment of AD than previously tested unimodal approaches. Recently, we demonstrated that the combination of AV-1959R and AV-1980R vaccines targeting Aβ and tau, respectively, induced robust antibody responses against various forms of both Aβ and tau pathological molecules in wildtype mice.

Here, we tested the therapeutic efficacy of co-formulated vaccines targeting Aβ and tau administered simultaneously in combination with AdvaxCpG adjuvant in the Tau22/5xFAD (T5x) mouse model of AD that develops highly aggressive Aβ and tau pathology. T5x mice immunized with a mixture of Aβ- and tau-targeting vaccines generated high Aβ- and tau-specific antibody titers that recognized senile plaques and neurofibrillary tangles in human AD brain sections. Production of these antibodies in turn led to significant reductions in the levels of soluble and insoluble total tau, and hyperphosphorylated tau as well as insoluble Aβ42, within the brains of T5x mice.

Researchers here report on the use of a combination of a brain-computer interface and functional electrical stimulation of muscles to bypass damage leading to paralysis of the hand, allowing some degree of restored function. The approach was demonstrated in non-human primates in which nerves connecting the hand to the brain were damaged via surgery. Competition in approaches to the problem of nervous system damage is a good thing, but one would hope that this class of application of brain-computer interface is largely made irrelevant by future advances in regenerative medicine.

Paralysis following stroke is a leading cause of long-term motor disability. Brain machine interfaces (BMIs) can transform cortical activity into control signals for an external device, such as a robotic arm or computer cursor, and may provide a solution for restoring lost function. Bypassing the damaged pathway using brain-controlled functional electrical stimulation (FES) to regain volitional control of the paralysed limb is promising for restoring lost motor function. Brain-controlled FES works as an "artificial" neural pathway by creating a causal relationship between brain activity and an evoked limb movement. However, subjects may be required to learn a novel causal input-output relationship to control the paralysed limb.

Disruption of descending pathways, as can result from stroke, results in a lost connection between the brain and target muscles. Functional recovery in such a situation is characterised by substantial reorganisation in the structure and function of the damaged brain. Thus, our nervous system shows remarkable flexibility to adapt to novel neuromotor mappings. How the brain incorporates a novel "artificial" neural pathway into volitional limb control within the surviving cortical areas remains largely unclear.

In the present study, we generated a model of chronic hemiparalysis in the extremities caused by subcortical stroke in monkeys. We then employed an artificial cortico-muscular connection (ACMC) to connect the preserved cortical areas to muscles beyond the damaged site. Specific neural oscillations in the cortical area were detected contingent to the input and converted into electrical stimulation delivered to the muscles in real time. We demonstrated that, despite damage to subcortical areas, a flexible change in the neural oscillations controlling the ACMC was observed in a targeted manner throughout an extensive sensorimotor area. Thus, monkeys that experienced a subcortical stroke could rapidly learn to regain lost volitional control of a paralysed hand.

Link: https://doi.org/10.1038/s41467-019-12647-y

Some fraction of what we think of as cardiovascular aging is in fact due to the lack of exercise that is so very prevalent in our society of comfort and machineries of transport, rather than due to inexorable underlying processes of aging. Those processes certainly exist, and ultimately cut down even the fittest individuals, but failing to maintain fitness in later life does tend make the outcomes of aging worse. Studies of the sort noted here are a way to assess how large the burden of a lack of fitness might be, at least when it comes to cardiovascular function. The researchers took a collection of people who are training to run a marathon for the first time, and quantified the improvements that take place in cardiovascular metrics over the course of this effort.

Aging increases aortic stiffness, contributing to cardiovascular risk even in healthy individuals. Aortic stiffness is reduced through supervised training programs, but these are not easily generalizable. The purpose of this study was to determine whether real-world exercise training for a first-time marathon can reverse age-related aortic stiffening. Untrained healthy individuals underwent 6 months of training for the London Marathon.

Assessment pre-training and 2 weeks post-marathon included central (aortic) blood pressure and aortic stiffness using cardiovascular magnetic resonance distensibility. Biological "aortic age" was calculated from the baseline chronological age-stiffness relationship. Change in stiffness was assessed at the ascending aorta (Ao-A) and descending aorta at the pulmonary artery bifurcation (Ao-P) and diaphragm (Ao-D).

A total of 138 first-time marathon completers (age 21 to 69 years, 49% male) were assessed, with an estimated training schedule of 6 to 13 miles/week. At baseline, a decade of chronological aging correlated with a decrease in Ao-A, Ao-P, and Ao-D distensibility by 2.3, 1.9, and 3.1 x 10^-3 mm/Hg, respectively. Training decreased systolic and diastolic central (aortic) blood pressure by 4 mmHg and 3 mmHg. Descending aortic distensibility increased (Ao-P: 9%; Ao-D: 16%), while remaining unchanged in the Ao-A. These translated to a reduction in "aortic age" by 3.9 years and 4.0 years (Ao-P and Ao-D, respectively). Benefit was greater in older, male participants with slower running times.

Link: https://doi.org/10.1016/j.jacc.2019.10.045

There are many situations in which it might be advantageous to deliver large numbers of immune cells into a patient, to set them to work as reinforcements for the native immune cell populations. It is technically feasible to grow and then introduce into a patient twice as many - or ten times as many, or even more - of some classes of immune cell as are normally present in the body at any given time. At the moment, therapies of this nature are largely focused on treating cancers, such as the approach pioneered by LIfT Biosciences. That the transferred immune cells come from a donor rather than being generated from a sample of patient cells is actually helpful in terms of their ability to attack a cancer.

For other potential applications, however, it will usually be less helpful to have immune cells from person A introduced into person B. The downsides, in that the immune cells are foreign and can thus attack healthy tissue or spur inflammatory responses from native cells, can outweigh the benefits. Nonetheless, in the research materials noted below, scientists use this approach in the treatment of the later stages of sepsis resulting from infection. This is a life-threatening condition in which older individuals fare far worse than younger individuals. Older patients have a higher risk of sepsis, and lower odds of survival, particularly at the point at which the immune system becomes overwhelmed by a population of pathogens replicating beyond its ability to control.

In a perfect world, it would be possible to generate cost-effective populations of immune cells that can be introduced into any patient as a way to reinforce the immune response for a time. This would either mean a much cheaper approach than presently exists to the production patient-matched cells using reprogramming techniques, or a way to generate cell lines that are not recognized as being foreign to the body, no matter who they are provided to. Approaches to both of these options are at various stages of development in the research community and in biotech companies.

Finding a new way to fight late-stage sepsis

Cells called macrophages are one of the first responders in the immune system, with the job of "eating" invading pathogens. However, in patients with sepsis, the number of macrophages and other immune cells are lower than normal and they don't function as they should. In this study, researchers collected monocytes from the bone marrow of healthy mice and cultured them in conditions that transformed them into macrophages. The lab also developed vitamin-based nanoparticles that were especially good at delivering messenger RNA, molecules that translate genetic information into functional proteins.

The scientists, who specialize in messenger RNA for therapeutic purposes, constructed a messenger RNA encoding an antimicrobial peptide and a signal protein. The signal protein enabled the specific accumulation of the antimicrobial peptide in internal macrophage structures called lysosomes, the key location for bacteria-killing activities. From here, researchers delivered the nanoparticles loaded with that messenger RNA into the macrophages they had produced with donor monocytes, and let the cells take it from there to "manufacture" a new therapy.

After seeing promising results in cell tests, the researchers administered the cell therapy to mice. The mouse models of sepsis in this study were infected with multidrug-resistant Staphylococcus aureus and E. coli and their immune systems were suppressed. Each treatment consisted of about 4 million engineered macrophages. Controls for comparison included ordinary macrophages and a placebo. Compared to controls, the treatment resulted in a significant reduction in bacteria in the blood after 24 hours - and for those with lingering bacteria in the blood, a second treatment cleared them away.

Vitamin lipid nanoparticles enable adoptive macrophage transfer for the treatment of multidrug-resistant bacterial sepsis

Sepsis, a condition caused by severe infections, affects more than 30 million people worldwide every year and remains the leading cause of death in hospitals. Moreover, antimicrobial resistance has become an additional challenge in the treatment of sepsis, and thus, alternative therapeutic approaches are urgently needed. Here, we show that adoptive transfer of macrophages containing antimicrobial peptides linked to cathepsin B in the lysosomes (MACs) can be applied for the treatment of multidrug-resistant bacteria-induced sepsis in mice with immunosuppression.

The MACs are constructed by transfection of vitamin C lipid nanoparticles that deliver antimicrobial peptide and cathepsin B (AMP-CatB) mRNA. The vitamin C lipid nanoparticles allow the specific accumulation of AMP-CatB in macrophage lysosomes, which is the key location for bactericidal activities. Our results demonstrate that adoptive MAC transfer leads to the elimination of multidrug-resistant bacteria, including Staphylococcus aureus and Escherichia coli, leading to the complete recovery of immunocompromised septic mice. Our work provides an alternative strategy for overcoming multidrug-resistant bacteria-induced sepsis and opens up possibilities for the development of nanoparticle-enabled cell therapy for infectious diseases.

There are many overlapping mechanisms involved in the age-related loss of stem cell function in muscle tissue that leads to loss of muscle mass and strength. To name a few: the mitochondrial dysfunction that occurs in all tissues, or the chronic inflammation produced by senescent cells and the aging immune system. The authors of this open access review paper choose to divide approaches to treatment of loss of muscle stem cell function, whether compensatory or actual rejuvenation, into those that affect stem cells versus those that affect the stem cell niche. Research has suggested that the fact that muscle stem cell populations become less active with age is more a matter of changes in the niche and systemic signaling rather than inherent damage to the stem cells themselves, but these changes must still originate in damage elsewhere in tissue.

Ex vivo manipulations of aged satellite cells have proven to be effective strategies to reverse some of the intrinsic alterations limiting their regenerative potential. These manipulations include genetic interventions to silence p16INK4a expression, thereby restoring quiescence and regenerative capacity to the aged satellite cell. Similarly, ex vivo pharmacological inhibition of p38 MAPK signaling decreases the expression of cell-cycle inhibitors, such as p16INK4a, and restores asymmetric division in satellite cells, contributing to enhanced regenerative potential of aged satellite cells in muscle transplantation experiments.

In vivo, local and systemic interventions have also shown promise in reversing age-related satellite cell defects. For example, systemic pharmacological treatments to restore basal autophagy flux preserved quiescence and muscle stem cell regenerative capacity in old muscles. Similarly, systemic delivery of oxytocin restores age-related regenerative capacity in old muscles, promoting satellite cell activation and proliferation, while systemic delivery of WISP1 during a regenerative event improves myogenic commitment and regenerative success. Moreover, systemic delivery of exogenous α-Klotho improves muscle stem cell bioenergetics and improves regenerative capacity in aged animals.

Rejuvenating interventions able to target the whole organism have also a positive impact on satellite cell function during aging. Successful interventions include caloric restriction, rapamycin treatment, supplementation with the NAD+ precursor nicotinamide riboside, senescent cell ablation, and in vivo reprogramming. These studies anticipate the existence of common hallmarks of aging associated with satellite cell loss of function in old animals, which can be considered common targets for intervention. Consistently, targeting chronic inflammation (a shared feature of several age-related pathologies) through systemic treatment with an inhibitor of NFκB activation improves myogenic function in aged satellite cells.

Link: https://doi.org/10.1111/febs.15182

Over longer timescales involving large-scale funding, meaningful progress only occurs in those lines of research and development that enjoy broad public support and understanding. While it is the case that small groups of philanthropists and visionaries are those who do the hard (and largely unacknowledged) work to create new possibilities, of those options, only those that are welcomed and desired by the masses are brought into reality. In the matter of rejuvenation therapies, we presently stand somewhere in an awkward transition phase in which the experts are largely convinced, but the public remains largely ignorant or skeptical. Given that the research community is resolved to build ways to treat aging as a medical condition, and a related biotech industry is forming, we'll see ever more examples of advocacy aimed at educating the public, in order to obtain support for bigger and broader programs that will advance the state of the art in this field of medicine.

It's not your imagination - the world is graying. In fact, by 2050, the global population age 65 and older is projected to nearly triple, to 1.5 billion. With this aging population, it will be more important than ever to reduce the burden of age-related disease. In the future, science will allow us to intervene in the aging process to make this a reality. It's imperative to keep our older population healthy and independent as long as possible. As this population grows, we'll need to provide help to increasing numbers of older people who are no longer independent. It will be a huge challenge for us as a society in the next 20 or 30 years.

Aging is a biological and physiological process like any other. We can learn how it works - how cells and molecules create what we see as "aging" in a person. Aging can be beautiful, but it is also the number-one risk factor or driver of most of the medical problems that we treat in adults: cancer, diabetes, dementia, Alzheimer's disease, cardiovascular disease, strokes, and heart attacks. The crazy thing is we can manipulate the aging process. We can adjust it. We can treat it. None of this is science fiction anymore. It's all science fact, right up to the part where people are conducting clinical trials of drugs that treat complex health problems through targeting molecular aging mechanisms. In geroscience, we seek to understand the relationship between aging, disease, and quality of life. The promise of this field is that by intervening in the process of aging, we could slow, prevent, delay, or reduce the risk of all sorts of diseases - all at the same time.

When visiting your primary physician in 2050, you'll have your aging mechanism risk factors checked, and you'll probably have preventive treatments. For example, we'll treat your senescent (old, inactive) cells or your autophagy (the process by which your body removes old, damaged proteins). If something is amiss in your risk factors, then we'll make adjustments. It'll just become part of regular preventive medicine.

Link: https://www.ucsf.edu/magazine/aging-optional

As a class of therapy to treat the mitochondrial dysfunction of age, mitochondrially targeted antioxidants are fairly advanced in their progression towards widespread use. MitoQ is classified as a supplement, and has been shown to improve cardiovascular function in older people. Plastinquinones such as SkQ1 have a fair-sized literature of animal studies and are approved for use in inflammatory eye diseases in Russia. They are going through clinical trials in Europe for a range of conditions. The mitochondrially targeted antioxidant of interest today is SS-31, which has been under clinical development for some years, and, as for SkQ1, has a fair sized literature of animal studies. In today's open access paper, researchers report on the mechanisms by which SS-31 produces improvement of mitochondrial function in an animal model of heart failure.

Mitochondria are the powerplants of the cell, conducting energetic chemical operations that result in the production of ATP, an energy store molecule used to power cellular processes. A side-effect of mitochondrial function is the generation of oxidative molecules that can produce all sorts of damage as they react with molecular machinery throughout the cell. This is consistently and constantly repaired, and even treated as a form of signaling, in the normal course of affairs. As aging progresses, greater levels of this oxidative stress occur, and mitochondria become dysfunctional in ways that can be helped by dialing back the presence of oxidative molecules in the mitochondrial themselves.

The normal sort of antioxidants sold in supplement stores have no useful effect on this problem, and in fact are counterproductive. They don't soak up oxidizing molecules in mitochondria and they do soak up the oxidizing molecules elsewhere, suppressing the benefits that arise from oxidative signaling. Hence the existence of mitochondrially targeted antioxidants.

In animal studies, mitochondrially targeted antioxidants have been shown to be beneficial in numerous age-related conditions that feature mitochondrial oxidative stress and dysfunction, which is most conditions of aging, in fact. As is the case for approaches to NAD+ upregulation targeted at improving mitochondrial function, the effect size isn't as large as one might like, but it is hard to argue with the data showing that reductions in mitochondrial oxidative stress improve cardiovascular function in humans. In animal models, a wider range of age-related conditions can be improved via delivery of this class of therapy, but it remains to be seen how many will translate well to the human case.

Reduction of Elevated Proton Leak Rejuvenates Mitochondria in the Aged Cardiomyocyte

Mitochondria are both the primary source of organismal energy and the major source of cellular reactive oxygen species (ROS) and oxidative stress during aging. Aged cardiac mitochondria are functionally changed in redox balance and are deficient in ATP production. Numerous reported studies have focused on redox stress and ROS production in aging. However, in its simplistic form, the free radical theory of aging has become severely challenged.

While more attention has been placed on mitochondrial electron leak and consequent free radical generation, proton leak is a highly significant aspect of mitochondrial energetics, as it accounts for more than 20% of oxygen consumption in the liver and 35% to 50% of that in muscle in the resting state. There are two types of proton leak in the mitochondria: 1) constitutive, basal proton leak, and 2) inducible, regulated proton leak , including that mediated by uncoupling proteins (UCPs). In skeletal muscle, a majority of basal proton conductance has been attributed to adenine nucleotide translocase (ANT). Although, aging-related increased mitochondrial proton leak was detected in the mouse heart, kidney, and liver by indirect measurement of oxygen consumption in isolated mitochondria, direct evidence of functional impact remains to be further investigated. Moreover, the exact site and underlying mechanisms responsible for aging-related mitochondrial proton leak are unclear.

SS-31 (elamipretide) binds to cardiolipin-containing membranes and improves cristae curvature. Prevention of cytochrome c peroxidase activity and release has been proposed as its major basis of activity. SS-31 is highly effective in increasing resistance to a broad range of diseases, including heart ischemia reperfusion injury, heart failure, neurodegenerative disease, and metabolic syndrome. In aged mice, SS-31 ameliorates kidney glomerulopathy and brain oxidative stress and has shown beneficial effects on skeletal muscle performance. We have recently shown that administration of SS-31 to 24 month old mice for 8 weeks reverses the age-related decline in diastolic function, increasing the E/A ratio from just above 1.0 to 1.22, restoring this parameter 35% towards that of young (5 month old) mice. However how SS-31 benefits and protects aged cardiac cells remains unclear.

In this report we investigated the effect and underlying mechanism of action of SS-31 on aged cardiomyocytes, especially on the mitochondrial proton leak. Using the naturally aged rodent model we provided direct evidence of increased proton leak as the primary energetic change in aged mitochondria. We further show that the inner membrane protein ANT1 mediates the augmented proton entry in the old mitochondria. Most significantly, we demonstrate that SS-31 prevents the proton entry and rejuvenates mitochondrial function through direct association with ANT1 and stabilization of the ATP synthasome.

Calorie restriction is the most studied of methods to slow aging and extend healthy life in laboratory species. Most of the diverse life extending interventions tested in these species are in fact ways to trigger some of the same mechanisms observed to be involved in calorie restriction. Cellular responses to stress, such as low levels of nutrients or heat, converge on mechanisms such as upregulation of the maintenance processes of autophagy, leading to better cell and tissue function. In short-lived species this can have quite large effects on life span, but that effect size diminishes greatly for longer-lived species such as our own. Mice live 40% longer when on a calorie restricted diet, but while we humans exhibit similar short-term health benefits, we only live a few additional years at most when practicing calorie restriction.

Epistasis analyses using mutant strains in lower organisms such as Caenorhabditis elegans (C. elegans) have revealed genes required for the effects of calorie restriction (CR), referred to here as CR genes, and the signal pathways mediating the effects of CR. In C. elegans, a number of genes such as aak-2, daf-16, skn-1, clk-1, and pha-4 have been reported to be associated with the life-prolonging effect of CR. Some of these genes also mediate the effects of CR in mice. Previous studies also reported that mutations of single genes (referred to here as longevity genes) can extend lifespan even in ad libitum feeding animals.

Many of these genes can be functionally categorized into genes associated with nutrient sensing or metabolic responses. Among these gene mutations, reduction- or loss-of-function mutations of genes in the growth hormone (GH)-insulin-like growth factor-1 (IGF-1) signaling consistently extend lifespan in a range of organisms. Since CR is known to decrease the plasma concentration of GH and IGF-1, the GH-IGF-1 pathway is considered an evolutionary conserved pathway for longevity and a main aspect of the mechanism of CR.

Thus far, a total of 112 CR genes in yeast, 62 in nematode, 27 in drosophila, and seven in mice have been identified . Among these genes, forkhead box protein O 3 (Foxo3) and sirtuin 1 (Sirt1) genes are common in mice, nematodes, and flies. CR and longevity gene models have elucidated signal pathways for the extension of lifespan, although the signal pathways are context dependent.

Link: https://doi.org/10.3390/nu11123068

Researchers here demonstrate that a gene therapy able to force an increase in the size of neural stem cell populations improves neurogenesis and cognitive function in old mice. Stem cell populations are balanced in activation and replication versus quiescence as a way to sustain their function over time, though in many old tissues this becomes biased towards quiescence, and there is consequently too little creation of new daughter somatic cells to support tissue function. Still, too much sustained replication could also be harmful in the longer term, causing losses and damage to the stem cell population. Nonetheless, one could reasonably argue that short term upregulation of stem cell replication will act to enhance brain tissue function in a fairly lasting way, via delivery and integration of new neurons into brain tissue.

Researchers wanted to investigate if increasing the number of stem cells in the brain would help in recovering cognitive functions, such as learning and memory, that are lost during ageing. The research group stimulated the small pool of neural stem cells that reside in the brain in order to increase their number and, as a result, to also increase the number of neurons generated by those stem cells. To achieve this goal, researchers used a gene therapy to produce overexpression of the cell cycle regulators Cdk4/cyclinD1. Surprisingly, additional neurons could survive and form new contacts with neighbouring cells in the brain of old mice.

Next, the scientists examined a key cognitive ability that is lost, similarly in mice and in humans, during ageing: navigation. It is well known that individuals learn to navigate in a new environment in a different way depending on whether they are young or old. When young, the brain can build and remember a cognitive map of the environment but this ability fades away in older brains. As an alternative solution to the problem, older brains without a cognitive map of the environment need to learn the fixed series of turns and twists that are needed to reach a certain destination. While the two strategies may superficially appear similar, only a cognitive map can allow individuals to navigate efficiently when starting from a new location or when in need of reaching a new destination.

Would boosting the number of neurons be sufficient to counteract the decreasing performance of the brain in navigation and slow down this ageing process? The answer is "yes": old mice with more stem cells and neurons recovered their lost ability to build a map of the environment and remembered it for longer times making them more similar to young mice. Even better, when neural stem cells were stimulated in the brain of young mice, cognitive impairments were delayed and memory was better preserved over the entire course of the animal natural life. In young individuals, a brain area called the hippocampus is crucial for remembering places and events, and is also responsible for creating maps of new environments. However, old individuals use other structures that are more related to the development of habits. It was very interesting to see that adding more neurons in the hippocampus of old mice allowed them to use strategies typical of young animals.

Link: https://tu-dresden.de/tu-dresden/newsportal/news/verjuengungskur-fuers-gehirn-zusaetzliche-stammzellen-verbessern-lernen-und-gedaechtnis-von-alten-maeusen

Alzheimer's disease is a condition characterized by amyloid aggregation, chronic inflammation in brain tissue, and tau aggregation, these aspects of the condition progressing at different paces and interacting with one another in complex ways that are yet to be fully understood. Amyloid aggregation is widely thought to be the initial, triggering pathology. Tau aggregation is found in the later stages of Alzheimer's disease, once cell death begins in earnest, and the evidence suggests that this form of pathology is driven by chronic inflammation in the brain. Removal of senescent supporting cells in the brain, thereby reducing inflammatory signaling, can reverse tau aggregation in mouse models of the condition, for example.

The failure of treatments that clear amyloid aggregates to improve patient outcomes in clinical trials has led to a growing debate over how the various aspects of Alzheimer's disease fit together to produce the progression from mild cognitive impairment to full blown dementia. Perhaps amyloid is a side-effect of chronic inflammation, or simply no longer important to the progression of the condition once matters have progressed to the point of sustained inflammation and tau aggregation. Researchers are now looking more closely at addressing chronic inflammation and tau aggregation either instead of or in addition to clearance of amyloid. The evidence, such as that noted below, continues to support this change in strategy.

Alzheimer 'tau' protein far surpasses amyloid in predicting toll on brain tissue

Many researchers are now taking a second look at tau protein, once dismissed as simply a "tombstone" marking dying cells, and investigating whether tau may in fact be an important biological driver of Alzheimer's disease. In contrast to amyloid, which accumulates widely across the brain, sometimes even in people with no symptoms, autopsies of Alzheimer's patients have revealed that tau is concentrated precisely where brain atrophy is most severe, and in locations that help explain differences in patients' symptoms (in language-related areas vs. memory-related regions, for example).

"No one doubts that amyloid plays a role in Alzheimer's disease, but more and more tau findings are beginning to shift how people think about what is actually driving the disease. Still, just looking at postmortem brain tissue, it has been hard to prove that tau tangles cause brain degeneration and not the other way around. One of our group's key goals has been to develop non-invasive brain imaging tools that would let us see whether the location of tau buildup early in the disease predicts later brain degeneration."

Researchers recruited 32 participants with early clinical stage Alzheimer's disease, all of whom received PET scans using two different tracers to measure levels of amyloid protein and tau protein in their brains. The participants also received MRI scans to measure their brain's structural integrity, both at the start of the study, and again in follow-up visits one to two years later.

The researchers found that overall tau levels in participants' brains at the start of the study predicted how much degeneration would occur by the time of their follow up visit (on average 15 months later). Moreover, local patterns of tau buildup predicted subsequent atrophy in the same locations with more than 40 percent accuracy. In contrast, baseline amyloid-PET scans correctly predicted only 3 percent of future brain degeneration. "Seeing that tau buildup predicts where degeneration will occur supports our hypothesis that tau is a key driver of neurodegeneration in Alzheimer's disease."

Prospective longitudinal atrophy in Alzheimer's disease correlates with the intensity and topography of baseline tau-PET

β-Amyloid plaques and tau-containing neurofibrillary tangles are the two neuropathological hallmarks of Alzheimer's disease (AD) and are thought to play crucial roles in a neurodegenerative cascade leading to dementia. Both lesions can now be visualized in vivo using positron emission tomography (PET) radiotracers, opening new opportunities to study disease mechanisms and improve patients' diagnostic and prognostic evaluation.

In a group of 32 patients at early symptomatic AD stages, we tested whether β-amyloid and tau-PET could predict subsequent brain atrophy measured using longitudinal magnetic resonance imaging acquired at the time of PET and 15 months later. Quantitative analyses showed that the global intensity of tau-PET, but not β-amyloid-PET, signal predicted the rate of subsequent atrophy, independent of baseline cortical thickness. Additional investigations demonstrated that the specific distribution of tau-PET signal was a strong indicator of the topography of future atrophy at the single patient level and that the relationship between baseline tau-PET and subsequent atrophy was particularly strong in younger patients.

This data supports disease models in which tau pathology is a major driver of local neurodegeneration and highlight the relevance of tau-PET as a precision medicine tool to help predict individual patient's progression and design future clinical trials.

There is plenty of evidence from epidemiological studies of human populations for correlations between physical fitness and a slower age-related decline in brain structure and function. The research community turns out new studies of this nature on a regular basis, and the work here is a representative example of the type. While studies in humans usually cannot say anything about causation, animal studies of exercise and fitness very clearly show that exercise improves cognitive function over the course of aging, slowing the declines of age.

A new study provides new evidence of an association between cardiorespiratory fitness and brain health, particularly in gray matter and total brain volume - regions of the brain involved with cognitive decline and aging. Brain tissue is made up of gray matter, or cell bodies, and filaments, called white matter, that extend from the cells. The volume of gray matter appears to correlate with various skills and cognitive abilities.

The researchers found that increases in peak oxygen uptake were strongly associated with increased gray matter volume. The study involved 2,013 adults from two independent cohorts. Participants were examined in phases from 1997 through 2012. Cardiorespiratory fitness was measured using peak oxygen uptake and other standards while participants used an exercise bike. MRI brain data also was analyzed.

The results suggest cardiorespiratory exercise may contribute to improved brain health and decelerate a decline in gray matter. The most striking feature of the study is the measured effect of exercise on brain structures involved in cognition, rather than motor function. "This provides indirect evidence that aerobic exercise can have a positive impact on cognitive function in addition to physical conditioning. Another important feature of the study is that these results may apply to older adults, as well. There is good evidence for the value of exercise in midlife, but it is encouraging that there can be positive effects on the brain in later life as well."

Link: https://newsnetwork.mayoclinic.org/discussion/keep-exercising-new-study-finds-its-good-for-your-brains-gray-matter/

Most interventions that increase longevity in short-lived laboratory species, such as the nematodes used here, are just different ways of influencing the same underlying stress response mechanisms. Thus they don't tend to synergize well with one another. There are exceptions, however, and here researchers demonstrate a strong synergy between mutations in insulin and TOR signaling. It is worth noting that the fivefold life extension achieved here is only half of the present record for nematodes. Very short-lived species like this one exhibit great plasticity of life span in response to interventions, far greater than is the case for mammals, particularly long-lived mammalian species such as our own. We should not expect enormous gains to result from the same approach in humans, even given that the underlying mechanisms of insulin and TOR signaling are surprisingly similar in nematodes and mammals.

Researchers have identified synergistic cellular pathways for longevity that amplify lifespan fivefold in C. elegans, a nematode worm used as a model in aging research. The research draws on the discovery of two major pathways governing aging in C. elegans, which is a popular model in aging research because it shares many of its genes with humans and because its short lifespan of only three to four weeks allows scientists to quickly assess the effects of genetic and environmental interventions to extend healthy lifespan.

Because these pathways are "conserved," meaning that they have been passed down to humans through evolution, they have been the subject of intensive research. A number of drugs that extend healthy lifespan by altering these pathways are now under development. The discovery of the synergistic effect opens the door to even more effective anti-aging therapies.

The new research uses a double mutant in which the insulin signaling (IIS) and TOR pathways have been genetically altered. Because alteration of the IIS pathways yields a 100 percent increase in lifespan and alteration of the TOR pathway yields a 30 percent increase, the double mutant would be expected to live 130 percent longer. But instead, its lifespan was amplified by 500 percent.

Link: https://mdibl.org/press-release/mdi-biological-scientists-identify-pathways-that-extend-lifespan-by-500-percent/

Ultimately, the treatment of aging as a medical condition must include ways to either repair or replace damaged stem cell populations. This is a monumental task, given the sizable number of distinct types of stem cell in the body, but there is progress towards replacement via cell therapy in the case of a few of the better studied and characterized stem cell populations. Arguably the most advanced of this work is focused on replacement of hematopoietic stem cells, the stem cell population responsible for generating blood and immune cells. This is fortunate, as the decline of these stem cells has a profound detrimental effect on the immune system, and the age-related decline of immune function is an important contribution to the frailty of older individuals. Improving hematopoietic function in older individuals is one of the necessary steps that must be taken to reverse immunosenescence.

Transplantation of hematopoietic stem cells, in the form of bone marrow transplantation, has been an ongoing concern for decades, and there has consequently been a great deal of research into the biochemistry of these stem cells, as well as how to move towards therapies that deliver just hematopoietic stem cells rather than tissue. It is now possible to produce patient matched stem cells using reprogramming techniques, potentially eliminating many of the serious issues of rejection and autoimmunity that make hematopoietic stem cell transplant as presently practiced a procedure with significant risk. The major blocking challenge at the moment is how to ensure that enough of the transplanted cells engraft in the bone marrow niches and survive to produce a steady supply of blood and immune cells. This issue has yet to be robustly solved, despite a few promising demonstrations in animal models.

Hematopoietic Differentiation of Human Pluripotent Stem Cells: HOX and GATA Transcription Factors as Master Regulators

Hematopoiesis is a complex process through which hematopoietic stem cells (HSCs) generate all the cell types found in the blood. This originates during the early stages of embryonic development and continues in the bone marrow (BM) throughout adulthood to preserve homeostasis in the blood system. The interest in the expansion and production of HSCs has increased in recent years. After the derivation of human embryonic stem cells (ESCs) and the discovery of cellular reprogramming, much effort has been devoted to obtain HSCs and mature blood cells from human pluripotent stem cells (PSCs).

In addition to their unlimited, yet-to-be realized, therapeutic potential, human PSCs make a very useful tool that can be utilized to understand the signaling pathways involved in hematopoiesis. Recently, long term engraftment and multi-lineage differentiation of hPSCs-derived hematopoietic progenitor cells was achieved after screening large numbers of potential transcription factors that were activated in vivo following transplantation in mice. Ideally, the generation of functional HSCs with the same capacity in vitro would allow deep interrogation of the differentiation process, and, eventually, the generation of therapeutic grade cells.

Human PSCs represent a promising versatile source of cells for regenerative medicine. The fact that they could be derived from patients' somatic cells and undergo clonal expansion in culture makes them ideal for the regeneration of the blood system. Their potential with regard to treating genetic blood disorders could be augmented when combined with genome editing techniques.

However, two main hurdles limit the translation of induced pluripotent stem cell (iPSC) derived HSCs into cellular therapies. First, the generation of functional iPSC-derived HSCs capable of long-term engraftment and full reconstitution of the blood system. Second, the long-term safety of the generated cells. HSCs derived from iPSCs remain transcriptionally and epigenetically distinct from cord blood HSCs. The impact of these differences on the safety and functionality of the generated HSCs is yet to be investigated.

A rising level of TGF-β has long been associated with numerous aspects of aging. More modern research has shown it to encourage cells to become senescent. Further, TGF-β is an important component of the inflammatory mix of signals secreted by senescent cells, making it a part of the mechanism by which senescent cells can encourage their neighbors to also become senescent. When senescent cells fail to clear quickly, as happens in older individuals, this leads to a feedback loop of continually rising chronic inflammation and ever greater numbers of senescent cells. This is an important contribution to degenerative aging and the progressive failure of tissue and organ function throughout the body.

TGF-β exerts diverse functions by modulating the expression of downstream target genes via transcriptional and post-transcriptional mechanisms as well as protein modulation in a context-dependent manner. Importantly, the downstream targets of TGF-β signaling include many regulators involved in multiple aspects of aging processes, such as cell proliferation, cell cycle regulation, the production of reactive oxygen species (ROS), DNA damage repair, telomere regulation, unfolded protein response (UPR), and autophagy. Due to a large overlap between the two pathways, TGF-β signaling exhibits multifaceted crosstalk with aging processes. At the cellular level, TGF-β signaling has been shown to play an important role in cellular senescence and stem cell aging. Furthermore, the alteration of TGF-β signaling pathways has been frequently observed in various age-related diseases, including cardiovascular disease, Alzheimer's disease (AD), osteoarthritis, and obesity.

TGF-β has been shown to have dual functions in cancer biology: An early tumor suppressor and a late tumor promoter. The cytostatic effects of TGF-β are mediated by inducing the cyclin-dependent kinase inhibitors p15Ink4b, p21, and p27, and by suppressing several proliferation factors including c-Myc. This suggests a senescence promoting role of TGF-β under normal conditions and also coincides with the tumor suppressing role of cell senescence. TGF-β has been shown to induce or accelerate senescence and senescence-associated features in various cell types. In addition, the TGF-β-mediated accumulation of senescent cells has been suggested in idiopathic pulmonary fibrosis (IPF).

In addition to the cytostatic mechanisms, the senescence-promoting role of TGF-β might be explained by the effects on other modulators of senescent phenotypes. TGF-β reportedly induces ROS production in the mitochondria in several cell types. In addition, TGF-β suppresses telomerase activities by downregulating the expression of telomerase reverse transcriptase (TERT) in various cell types. Further, the senescence-associated secretory phenotype (SASP) yields the production and secretion of various signaling molecules, importantly including TGF-β. Thus, TGF-β is secreted as one of the SASP factors and can induce and maintain senescent phenotype and age-related pathological conditions in an autocrine/paracrine manner.

Link: https://doi.org/10.3390/ijms20205002

There is a growing focus on inflammation in the brain as an important factor in the progression of neurodegenerative disease. One result is greater thought given to therapeutic strategies involving the suppression of inflammatory signaling, akin to the approaches used to control inflammatory autoimmune conditions such as rheumatoid arthritis. I would wager that this is probably not as good a strategy as removing senescent glial cells in the brain, and thus removing their sizable contribution to inflammatory signaling, given the animal data in support of that approach, but it will certainly be attempted in the years ahead.

Inflammation is initiated as the body's immune cells activate inflammatory cascades to prevent tissue damage from injury or infiltrating antigens. Within the central nervous system, microglia, known as 'the brain's immune cells,' interact with astrocytes and neurons by assuming phagocytic phenotypes and releasing inflammatory cytokines. This can cause neurodegeneration, phagocytosis of synapses, diminished neural function, microglial activation, inflammatory cytokine release, and further microglial activation until threat to the neural environment abates. Activation of astrocytes, termed astrogliosis, also occurs as part of the inflammatory process.

When acute, this neuroinflammatory response is necessary and even beneficial to the neural environment in eliminating pathogens or aiding brain repair. However, when extreme threats to the neural environment such as protein aggregates (i.e., lewy bodies, neurofibrillary tangles) accumulate in the brain and protractedly sustain inflammation, continuous gliosis and apoptosis can occur as a result of unregulated inflammatory cytokine release. Continuity of this activated state results in chronic inflammation, which is implicated in virtually all neurological disorders, including Alzheimer's disease, Parkinson's disease, and ALS.

Overexpression of tumor necrosis factor-α (TNF-α), a proinflammatory cytokine with a central role in microglial activation, has been associated with neuronal excitotoxicity, synapse loss, and propagation of the inflammatory state. Thalidomide and its derivatives, termed immunomodulatory imide drugs (IMiDs), are a class of drugs that inhibit TNF-α production. Due to their multi-potent effects, several IMiDs, including thalidomide, lenalidomide, and pomalidomide, have been repurposed as drug treatments for diseases such as multiple myeloma and psoriatic arthritis. Preclinical studies of currently marketed IMiDs, as well as novel IMiDs, support the development of IMiDs as therapeutics for neurological disease. IMiDs have a competitive edge compared to similar anti-inflammatory drugs due to their blood-brain barrier permeability and high bioavailability, with the potential to alleviate symptoms of neurodegenerative disease and slow disease progression.

Link: https://doi.org/10.3389/fcell.2019.00313

I'm pleased to see that the Revel Pharmaceuticals founders have finally sorted out a seed round to fund their work; the establishment of this startup has been in progress for a few years now, and some of us were beginning to think it a lost cause. Revel Pharmaceuticals is the biotech startup established to develop glucosepane cross-link breaker drugs based on work carried out by the Spiegel Lab at Yale. That team, supported by the SENS Research Foundation, first developed a means to synthesize glucospane, and then found bacterial enzymes that can break down glucosepane cross-links.

Glucosepane is the most prevalent form of cross-link observed in aged human tissues, hardy compounds that build up slowly over time as a side-effect of the normal operation of cellular metabolism, and are somewhere between challenging and impossible for even a youthful biochemistry to break down. We humans are just not equipped with the biochemical tools for the job. Cross-linking occurs when structural molecules of the extracellular matrix are linked to one another via bonds with a glucosepane compound, or other only short-lived and thus less harmful molecules, restricting their movement. This is a form of molecular damage that causes loss of elasticity in skin and blood vessel walls, among many other negative effects. The latter is quite serious, the starting point for hypertension, cardiovascular disease, and many other ultimately fatal issues.

The enzymes discovered at the Spiegel Lab and now under development at Revel Pharmaceuticals are a starting point for the development of a therapy that can break down glucosepane cross-links. In my view, breaking persistent cross-links will be as important to achieving rejuvenation in humans as the development of senolytics to destroy senescent cells. A similarly sized industry should arise given one group to light the path, many companies working towards therapies. I hope that the example of one company setting forth on this road to commercial development will soon enough inspire others to follow with their own approaches to the challenge.

Kizoo Technology Capital leads seed round financing at REVEL Pharmaceuticals

For the past 10 years, Yale Professors David Spiegel and Jason Crawford have been working on tools to enable the development of glucosepane-cleaving drugs. Kizoo Technology Capital investors say now is the time to advance this groundbreaking research toward the clinic and are leading funding of a new company, Revel Pharmaceuticals Inc., founded by Drs. David Spiegel, Jason Crawford, and Aaron Cravens. Kizoo leads the seed financing round at Revel, with Oculus co-founder Michael Antonov participating. SENS Research Foundation provided funding to the Yale GlycoSENS group for several years.

The long-lived collagen proteins that give structure to our arteries, skin, and other tissues are continuously exposed to blood sugar and other highly reactive molecules necessary for life. Occasionally, these sugar molecules will bind to collagen and form toxic crosslinks that alter the physical properties of tissues and cause inflammation. As a result, tissues slowly stiffen with aging, leading to rising systolic blood pressure, skin aging, kidney damage, and increased risk of stroke and other damage to the brain. Perhaps the most important of these Advanced Glycation End-product (AGE) crosslinks is a molecule called glucosepane. Revel is developing therapeutics that can cleave glucosepane crosslinks thus maintaining and restoring the elasticity of blood vessels, skin, and other tissues, and preventing the terrible effects of their age-related stiffening.

The Yale group's first major milestone - the first complete synthesis of glucosepane - was highly recognized when published. Since then progress has been rapid, with development of glucosepane binding antibodies and discovery of therapeutic enzyme candidates capable of breaking up glucosepane crosslinks. Revel will build upon this progress by advancing the first GlycoSENS therapeutics into the clinic.

"This is truly a first. Revel will open an entirely new category in repairing a significant damage of aging - crosslinking of collagen. Glucosepane crosslinks may cause not only wrinkles on your face but also lead to age-related rising blood pressure and possibly stroke. Collagen is the infrastructure of our bodies - in every tissue, supporting cellular function and health - but with aging, this critical molecular infrastructure accumulates damage. By clearing out this damage, we can restore tissue function and repair the body. Revel is one of only a few companies taking a repair-centric approach to treat diseases of aging and one day our AGE-cleaving therapeutics will undo this damage at the molecular level."

Fibrosis is an impairment of normal tissue maintenance resulting in scar-like deposits that disrupt tissue structure and function. A growing body of evidence shows that the presence of senescent cells can cause the fibrosis that is characteristic of age-related dysfunction in organs such as the heart, lungs, and kidneys. Of particular interest are the animal studies of recent years demonstrating that clearance of senescent cells can reverse fibrosis. There is no medical technology presently in widespread clinical use that can reliable and significantly reverse fibrosis, and thus some of the first human trials for senolytic therapies capable of selectively destroying senescent cells are targeting fibrotic diseases of the lung and kidney.

Despite the good evidence linking senescent cells to the development of fibrosis in aging organs, the specific molecular mechanisms by which inflammatory senescent cell signaling causes fibrosis remain unclear. In the open access paper noted here, researchers report on progress towards a better understanding in the matter of lung fibrosis. The specific mechanisms implicated are already known to be involved in heart fibrosis as well, so it may be the case that there is just the one link between cellular senescence and fibrosis that applies to all tissues.

Fibrosis is a shared pathological characteristic of many fatal lung diseases, such as idiopathic pulmonary fibrosis (IPF), which exhibits epithelial cell senescence and abundant foci of highly activated pulmonary fibroblasts. To date, there is no effective cure for these fibrotic diseases, as there is an incomplete understanding of the pathogenesis. In the progression of IPF, epithelial cell senescence has been demonstrated to occur in IPF and experimental lung fibrosis models. However, the underlying mechanism between epithelial cell senescence and pulmonary fibroblast activation remain to be elucidated.

In our study, we demonstrated that Nanog, as a pluripotency gene, played an essential role in the activation of pulmonary fibroblasts. In the progression of IPF, senescent epithelial cells could contribute to the activation of pulmonary fibroblasts via the senescence-associated secretory phenotype (SASP). Cell-cell contact between epithelial cells and fibroblasts appears to be essential in signalling cascades and important for wound repair. Pulmonary fibroblasts co-cultured with senescent epithelial cells expressed higher levels of collagen I, vimentin, and α-SMA, suggesting that senescent epithelial cells could effectively induce the activation of pulmonary fibroblasts.

We found that activated pulmonary fibroblasts exhibited aberrant activation of Wnt/β-catenin signalling and elevated expression of Nanog. Further study revealed that the activation of Wnt/β-catenin signalling was responsible for senescent epithelial cell-induced Nanog phenotype in pulmonary fibroblasts. Thus the targeted inhibition of epithelial cell senescence or Nanog could effectively suppress the activation of pulmonary fibroblasts and impair the development of pulmonary fibrosis, indicating a potential for the exploration of novel anti-fibrotic strategies.

Link: https://doi.org/10.18632/aging.102613

Autologous mesenchymal stem cell therapies involve obtaining cells from patient fat tissue or bone marrow, expanding or purifying the cells in culture, and introducing them back into the patient in order to produce benefits. The precise methodology used matters enormously, and these therapies vary widely in their effects and reliability, even between clinics that are ostensibly performing the same procedure. One issue, among many, is that cells isolated from an old patient are less effective than those from young patients. In part that is because steps taking place in culture that involve older cells will produce fewer viable cells and more senescent cells. Any approach that improves these numbers will tend to improve the therapy, whether that is achieved via culling senescent cells, partial reprogramming, or preventing cells from becoming senescent.

The beneficial functions of mesenchymal stem cells (MSCs) decline with age, limiting their therapeutic efficacy for myocardial infarction. Macrophage migration inhibitory factor (MIF) promotes cell proliferation and survival. We investigated whether MIF overexpression could rejuvenate aged MSCs and increase their therapeutic efficacy in myocardial infarction. Young and aged MSCs were isolated from the bone marrow of young and aged donors. Young MSCs, aged MSCs, and MIF-overexpressing aged MSCs were transplanted into the peri-infarct region in a rat myocardial infarction model.

Aged MSCs exhibited a lower proliferative capacity, lower MIF level, greater cell size, greater senescence-associated-β-galactosidase activity, and weaker paracrine effects than young MSCs. Knocking down MIF in young MSCs induced cellular senescence, whereas overexpressing MIF in aged MSCs reduced cellular senescence. MIF rejuvenated aged MSCs by activating autophagy, an effect largely reversed by the autophagy inhibitor 3-methyladenine.

MIF-overexpressing aged MSCs induced angiogenesis and prevented cardiomyocyte apoptosis to a greater extent than aged MSCs, and had improved heart function and cell survival more effectively than aged MSCs four weeks after myocardial infarction. Thus, MIF rejuvenated aged MSCs by activating autophagy and enhanced their therapeutic efficacy in myocardial infarction, suggesting a novel MSC-based therapeutic strategy for cardiovascular diseases in the aged population.

Link: https://doi.org/10.18632/aging.102592

The gut microbiome changes with age. This affects health in part because beneficial microbial populations produce metabolites, such as butyrate, that act to stimulate helpful processes in the body and brain, such as neurogenesis. Many of these populations tend to decline in later life, for reasons that include dietary shifts, immune system decline, and a range of other processes that, taken as a whole, are poorly understood.

The work here, placing gut microbes from old mice into germ-free mice that have no gut microbes, provides a different viewpoint on the beneficial nature of butyrate production by the gut microbiome, and on the processes that might be balancing different populations of microbes. The young germ-free mice are no doubt possessed of immune systems better able to keep harmful populations in check, and can thus benefit even when transplanted with a mixed bag of harmful and helpful microbes from old mice. It would be interesting to see how old germ-free mice fared under the same circumstances; less well, I suspect.

A number of possible approaches to treatment exist for age-related changes in the gut microbiome, including supplementation with those metabolites for which production is known to be lost with age, delivery of a more youthful mix of gut microbes via fecal transplantation, and more adventurous treatments such as immunization against flagellin. None are yet all that close to widespread use, even though some are technically straightforward to implement.

Bacteria in the gut may alter ageing process

Researchers transplanted gut microbes from old mice (24 months old) into young, germ-free mice (6 weeks old). After eight weeks, the young mice had increased intestinal growth and production of neurons in the brain, known as neurogenesis. The team showed that the increased neurogenesis was due to an enrichment of gut microbes that produce a specific short chain fatty acid, called butyrate. Butyrate is produced through microbial fermentation of dietary fibres in the lower intestinal tract and stimulates production of a pro-longevity hormone called FGF21, which plays an important role in regulating the body's energy and metabolism. As we age, butyrate production is reduced. The researchers then showed that giving butyrate on its own to the young germ-free mice had the same adult neurogenesis effects.

The team also explored the effects of gut microbe transplants from old to young germ-free mice on the functions of the digestive system. With age, the viability of small intestinal cells is reduced, and this is associated with reduced mucus production that make intestinal cells more vulnerable to damage and cell death. However, the addition of butyrate helps to better regulate the intestinal barrier function and reduce the risk of inflammation. The team found that mice receiving microbes from the old donor gained increases in length and width of the intestinal villi - the wall of the small intestine.

"It is intriguing that the microbiome of an aged animal can promote youthful phenotypes in a young recipient. This suggests that the microbiota with aging have been modified to compensate for the accumulating deficits of the host and leads to the question of whether the microbiome from a young animal would have greater or less effects on a young host. The findings move forward our understanding of the relationship between the microbiome and its host during ageing and set the stage for the development of microbiome-related interventions to promote healthy longevity."

Neurogenesis and prolongevity signaling in young germ-free mice transplanted with the gut microbiota of old mice

The gut microbiota evolves as the host ages, yet the effects of these microbial changes on host physiology and energy homeostasis are poorly understood. To investigate these potential effects, we transplanted the gut microbiota of old or young mice into young germ-free recipient mice. Both groups showed similar weight gain and skeletal muscle mass, but germ-free mice receiving a gut microbiota transplant from old donor mice unexpectedly showed increased neurogenesis in the hippocampus of the brain and increased intestinal growth.

Metagenomic analysis revealed age-sensitive enrichment in butyrate-producing microbes in young germ-free mice transplanted with the gut microbiota of old donor mice. The higher concentration of gut microbiota-derived butyrate in these young transplanted mice was associated with an increase in the pleiotropic and prolongevity hormone fibroblast growth factor 21 (FGF21). An increase in FGF21 correlated with increased AMPK and SIRT-1 activation and reduced mTOR signaling. Young germ-free mice treated with exogenous sodium butyrate recapitulated the prolongevity phenotype observed in young germ-free mice receiving a gut microbiota transplant from old donor mice. These results suggest that gut microbiota transplants from aged hosts conferred beneficial effects in responsive young recipients.

Researchers here provide evidence to support a role for cellular senescence in the progression of atrial fibrillation. You might recall a recent study showing that this heart condition is driven by fibrosis, which is a good reason to suspect that the presence of senescent cells may be a causative mechanism. There is a good amount of data from recent years to show that the inflammatory signaling produced by lingering senescent cells in aged tissues causes fibrosis, and that targeted removal of these errant cells can reverse fibrosis. Given that age-related fibrosis is a feature of many degenerative conditions of the lungs, heart, kidneys and other organs, and that there is presently little that that existing clinical medicine can do to turn back fibrosis, it is good news indeed that senolytic therapies to clear senescent cells may step up to fill this gap.

Atrial fibrillation (AF) is associated with increased mortality due mainly to heart failure and embolic complications. AF is well known to occur more frequently with increasing age and is linked to vascular aging. During AF, inflammation, apoptosis, endothelial dysfunction, and platelet activation contribute to creating a prothrombotic state and promoting atrial remodeling. While the link between aging and thrombogenicity is well established, the cellular and molecular mechanisms are still under consideration.

Premature cellular senescence is an irreversible form of cell cycle arrest that can be triggered by various cellular stresses, including DNA damage, oxidative stress, and oncogene activation. It is characterized by the acquisition of a proinflammatory and prothrombotic profile. Senescent cells are found in aged tissues where they remain metabolically active but are unable to proliferate despite the presence of mitogens.

In AF, the role of senescence in atrial remodeling and the development of a prothrombotic state remains unclear. Using a model of atrial endothelial cells, we recently demonstrated that thrombin, a key determinant of thrombogenicity during atrial fibrillation, promotes atrial endothelial cells senescence and the acquisition of the senescence-associated secretory phenotype, characterized by enhanced expression levels of vascular cell adhesion molecule (VCAM)-1, tissue factor (TF), transforming growth factor (TGF-β), and metalloproteinases (MMP-2 and MMP-9).

In this study, we investigated the link between AF and senescence markers through the assessment of protein expression in the tissue lysates of human appendages from patients in AF, including paroxysmal (PAF) or permanent AF (PmAF), and in sinus rhythm (SR). The major findings of the study indicated that the progression of AF is strongly related to the human atrial senescence burden as determined by p53 and p16 expression. The stepwise increase of senescence (p53, p16), prothrombotic (TF), and proremodeling (MMP-9) markers observed in the right atrial appendages of patients in SR, PAF, and PmAF points toward multiple interactions in the human atrium that enhance the senescence burden, atrial extracellular matrix remodeling, thrombogenicity, and other putative mediators involved in the progression of AF.

Link: https://doi.org/10.3390/jcm9010036

Research into the application of regenerative medicine techniques to regrowth of hair has been ongoing for some time. In principle, the hair follicle is a structure that could be engineered and implanted, or existing follicles induced to restored activity in some way. In practice this is challenging, and most forms of progressive hair loss are far from fully understood at the level of cellular biochemistry in the hair follicle: there is no great guarantee that generating or providing new follicles would have the desired effect, given the surrounding environment and its signaling.

Up to date, treatments for hair loss (alopecia) include pharmacological and surgical (autologous hair transplant) interventions. Although hair restoration surgery is nowadays the most effective method, donor hair follicles (HFs) scarcity is often its major limitation. Besides, pharmacological treatments still not fully satisfy the patient's needs and entail drastic side effects. Thus, the limited efficacy and possible side effects of the current treatments have fostered the search for alternative therapeutic solutions, capable of generating unlimited number of HFs de novo.

Of note, stem cell-based tissue engineering is emerging as the most thriving approach, aiming to reconstruct HFs in vitro to replace lost or damaged HFs as a consequence of disease, injury, or aging. HF bioengineering approaches are based on the accumulated knowledge on reciprocal epithelial-mesenchymal (EM) interactions controlling embryonic organogenesis and postnatal HF cyclic growth. However, despite recent progress in the field, clinical applications of tissue engineering strategies for hair loss are still missing. Neogenesis of human follicles derived from cultured HF dermal cells has not been successfully achieved yet.

A regenerative medicine therapy for human hair loss will only be successfully achieved when HF are formed de novo following implementation of in vitro bioengineered structures into the patient's bald scalp. Importantly, although from a scientific perspective studies have achieved and reported HF regeneration from human cells, the caveats are whether (a) there is any mouse contribution in HF neogenesis from human bioengineered structures transplanted into mouse skin, and (b) human bioengineered structures will generate HF that besides growing/cycling also mimetic natural hair type and are responsive to physiological stimuli.

Moreover, significant limitations may further hamper an operational clinical solution for hair loss. First, bioengineered hair reconstruction will imply large-scale production of cell-based structures and the development of well-defined culture expansion media for clinical usage. Robust culture systems that allow stem cell expansion while maintaining their intrinsic properties are still missing. Second, even if generation of functional and cycling HF units is achieved, a huge gap still exists until the conception of a clinically relevant bioengineered product that responds to physiological stimuli (eg, neuronal stimuli) and aesthetic context (hair type, density, pigmentation, and orientation).

Link: https://doi.org/10.1002/sctm.19-0301

A biomarker of aging is a a way to measure biological age, the burden of cell and tissue damage and consequent dysfunction. A biomarker that permitted the robust, quick, and cheap assessment of biological age would greatly speed up development of rejuvenation therapies. It would allow for rapid and cost-effective tests of many interventions, and the best interventions would quickly rise to prominence. At present the rigorous assessment of ways to intervene in the aging process is slow and expensive, as there is little alternative but to run life span studies. Even in mice that is prohibitively costly in time and funds for most research and development programs.

One of the more severe consequences of this state of affairs is that it takes a long time and sizable expense to weed out the less effective approaches to treatment. That this is a problem is well recognized by the scientific community, and many varied biomarkers of aging are presently under development. Perhaps the best known are the various forms of epigenetic clock, weighted algorithmic combinations of the status of DNA methylation sites that correlate with age and mortality risk. There are other approaches, though, such as combining simple measures of decline such as grip strength or inflammatory markers in blood tests. That class of methodology is explored in today's open access paper, with the focus specifically on measures adopted by the clinical community to assess frailty.

One of the concerns with the epigenetic clock, and for similar efforts using levels of blood proteins, is that it is quite unclear as to what exactly is being measured. The relationship with age and mortality emerges from the data, and it is then up to the research community to establish mechanistic connections between specific epigenetic changes and underlying processes of aging. It is quite possible that these biomarkers do not reflect all of the mechanisms of aging, and thus any use of them to assess a specific approach to rejuvenation would have to be carefully validated in parallel with the development of that therapy. This somewhat defeats the point of the exercise. When building a biomarker based on frailty indices, as here, there is at least a greater degree of confidence that it comprehensively touches on all of the contributions to aging, and we would thus expect any viable rejuvenation therapy to make a difference to the measure of age.

Age and life expectancy clocks based on machine learning analysis of mouse frailty

Biological age is an increasingly utilized concept that aims to more accurately reflect aging in an individual than the conventional chronological age. Biological measures that accurately predict health and longevity would greatly expedite studies aimed at identifying novel genetic and pharmacological disease and aging interventions. Any useful biometric or biomarker for biological age should track with chronological age and should serve as a better predictor of remaining longevity and other age-associated outcomes than does chronological age alone, even at an age when most of a population is still alive. In addition, its measurement should be non-invasive to allow for repeated measurements without altering the health or lifespan of the animal measured.

In humans, biometrics and biomarkers that meet at least some of these requirements include physiological measurements such as grip strength or gait, measures of the immune system, telomere length, advanced glycosylation end-products, levels of cellular senescence, and DNA methylation clocks. DNA methylation clocks have been adapted for mice but unfortunately these clocks are currently expensive, time consuming, and require the extraction of blood or tissue.

Frailty index assessments in humans are strong predictors of mortality and morbidity, outperforming other measures of biological age including DNA methylation clocks. Frailty indices quantify the accumulation of up to 70 health-related deficits, including laboratory test results, symptoms, diseases, and standard measures such as activities of daily living. The number of deficits an individual shows is divided by the number of items measured to give a number between 0 and 1, in which a higher number indicates a greater degree of frailty. The frailty index has been recently reverse-translated into an assessment tool for mice which includes 31 non-invasive items across a range of systems. The mouse frailty index is strongly associated with chronological age, correlated with mortality and other age-related outcomes, and is sensitive to lifespan-altering interventions. However, the power of the mouse frailty index to model biological age or predict life expectancy for an individual animal has not yet been explored.

In this study, we tracked frailty longitudinally in a cohort of aging male mice from 21 months of age until their natural deaths and employed machine learning algorithms to build two clocks: FRIGHT (Frailty Inferred Geriatric Health Timeline) age, designed to model chronological age, and the AFRAID (Analysis of Frailty and Death) clock, which was modelled to predict life expectancy. FRIGHT age reflects apparent chronological age better than the frailty index alone, while the AFRAID clock predicts life expectancy at multiple ages. These clocks were then tested for their predicitve power on cohorts of mice treated with interventions known to extend healthspan or lifespan, enalapril and methionine restriction. They accurately predicted increased healthspan and lifespan, demonstrating that an assessment of non-invasive biometrics in interventional studies can greatly accelerate the pace of discovery.

Hypertension, raised blood pressure, is very damaging to tissues and organ function throughout the body. It significantly increases the pace at which capillaries rupture, leading to small areas of cell death. The loss of function adds up, particularly in the brain, where this damage shows up as white matter lesions in imaging. The study here illustrates the damage done, and reinforces the message that control of blood pressure is very important for long term health. It has already been shown to reduce mortality, and the work here gives some insight into the mechanisms by which this reduction occurs.

It's been estimated that approximately two-thirds of people over the age of 75 may have damaged small blood vessels in the brain which are visible as bright white lesions on brain imaging. Prior research evidence has linked increased amounts of these white matter lesions in the brain with cognitive decline, limited mobility such as a slower walking speed, increased incidence of falls, and even increased stroke risk.

A clinical trial, followed 199 hypertension patients 75 years of age and older for 3 years. Throughout that time, researchers tracked the potential benefits of using an intensive anti-hypertensive medication treatment regimen to garner a 24-hour systolic blood pressure target of less than 130 mmHg compared to standard control (approximately 145 mmHg). As part of the INFINITY (Intensive Versus Standard Ambulatory Blood Pressure Lowering to Prevent Functional Decline In the Elderly) study, researchers assessed the older adults' mobility, cognitive function, their brain's white matter progression with magnetic resonance imaging (MRI), and tracked the occurrence of any adverse events.

While the researchers did not identify any significant differences in cognitive outcomes or walking speed between the two study groups, they did observe a significant reduction in the accumulation of brain white matter disease in those receiving the intensive treatment for blood pressure control. In fact, after three years, the accrual of white matter lesions in the brain were reduced by up to 40% in the those patients receiving the intensive blood pressure therapy compared to those who were on standard therapy. Further, study participants on the intensive therapy had a lower rate of cardiovascular events including heart attack, stroke, and hospitalization from heart failure than those on standard therapy.

Link: https://today.uconn.edu/2019/10/aggressive-blood-pressure-control-benefits-brains-older-adults/

This accelerometer study retells a familiar story, in that more active individuals have a lower rate of mortality in later life. In human studies it is challenging to move beyond simple correlation between these two pieces of data - is it that more robust people who were going to live longer anyway have a greater tendency to exercise, or is it that exercise produces benefits to health? The animal studies are quite definitive, however, in showing that exercise improves long term health and reduces incidence of age-related disease, even if it doesn't tend to increase overall life span in the same robust way that calorie restriction does.

Physical activity (PA) is an important determinant of health worldwide. It is estimated that inactivity causes 9% of premature mortality, approximately 5.3 million deaths a year. Although noncommunicable diseases (NCDs) that can be prevented by PA are associated with a higher proportion of deaths in high-income countries, high mortality rates due to these diseases are also observed in middle- or low-income countries, along with important mortality from communicable diseases.

Several studies have described an existing relationship between PA in older adults and the risk of all-causes mortality. These studies differ concerning PA assessment, length of follow-up, ethnicity, age at baseline, stratification variables, and other aspects, making comparison difficult. Newer literature with objectively measured PA using accelerometers suggests that increasing light physical activity (LPA) may also be important for reducing mortality in adults and older adults. This study aims to overcome some of the previous gaps in the scientific literature by evaluating the relationship between PA, measured by accelerometry and questionnaire, and risk of all-cause mortality in community-dwelling older adults from a Southern Brazilian city.

A representative sample of older adults (≥60 y) were enrolled in 2014. From the 1451 participants interviewed in 2014, 145 died (10%) after a follow-up of an average 2.6 years. Men and women in the highest tertile of overall PA had on average a 77% and 92% lower risk of mortality than their less active counterparts. The highest tertile of LPA was also related to a lower risk of mortality in individuals of both sexes (74% and 91% lower risk among men and women, respectively). Moderate to vigorous physical activity (MVPA) statistically reduced the risk of mortality only among women. Self-reported leisure-time PA was statistically associated with a lower risk of mortality only among men.

Link: https://doi.org/10.1111/jgs.16180

Mutational damage to nuclear DNA occurs constantly in all cells, and not all of it is successfully repaired. Setting aside recent evidence for cycles of damage and repair to cause epigenetic changes characteristic of aging, most unrepaired mutational damage has no meaningful consequence. It occurs in somatic cells that have few cell divisions left, so will not spread, and these cells will die or become senescent and be destroyed once they reach the Hayflick limit. It occurs in genes that are not active in the tissue in question, so even in long-lived somatic cells that do not replicate, such as those of the central nervous system, most mutations will be irrelevant to function.

So how might this process significantly affect tissue function and health? Firstly, mutations or combinations of mutations to a small number of important genes can make a cell cancerous, leading to unfettered replication and a tumor if not stopped by the immune system. Secondly, mutations that take place in a stem cell or progenitor cell can spread widely into tissue, and if they happen to change function in some way, that might contribute to age-related decline. There is no good evidence for the size of this effect, however. A first step on the way towards gathering that evidence is mapping the extent of somatic mutation and its clonal expansion in aged tissues, a project that is still ongoing in the research community.

Should somatic mutation turn out to be an important contributing cause of aging, what can be done about it? Targeted destruction of damaged cells might be off the table, given the size of the mutated cell population, and in any case there is the question of how to identify an enormous number of different stochastic mutations in order to trigger a suicide gene therapy or similar in only the desired cells. This is not a simple proposition. Periodic replacement of stem cell populations seems the most viable of options, as it would make the necessary gene therapy a somewhat easier prospect - it only has to be accomplished in the transplanted stem cells, rather than throughout the body. But again, identifying and fixing tens of thousands of broken genes, even in a petri dish, is certainly not a near term prospect. Indeed, viable methods of robustly replacing stem cell populations are still only in the earliest stages of development at this time. These are tools of the 2030s and 2040s, building atop a much more developed industry of gene therapy and regenerative medicine.

The somatic mutation landscape of the human body

In humans, somatic mutations play a key role in senescence and tumorigenesis. Pioneering work on somatic evolution in cancer has led to the characterization of cancer driver genes and mutation signatures; the interplay between chromatin, nuclear architecture, carcinogens, and the mutational landscape; the evolutionary forces acting on somatic mutations; and clinical implications of somatic mutations. Somatic mutations have been far less studied in healthy human tissues than in cancer. Early studies focused on blood as it is readily accessible and because of the known effects of immune-driven somatic mutation. Recently, somatic mutations have been characterized in tissues like the skin, brain, esophagus, and colon. These studies confirmed that cells harboring certain mutations expand clonally, and the number of clonal populations - as well as the total number of somatic mutations - increases with age. Additionally, recurrent positively selected mutations in specific genes (e.g., NOTCH1) were observed. However, a more comprehensive understanding of somatic mutations across the human body has been limited by the small number of tissues studied to date.

Most studies on somatic evolution in healthy tissues have sequenced DNA from biopsies to high coverage. However, the transcriptome also carries all the genomic information of a cell's transcribed genome, in addition to RNA-specific mutations or edits. RNA-seq has been used to identify germline DNA variants, and recently, single-cell (sc) RNA-seq was used to call DNA somatic mutations in the pancreas of several people. To systematically identify somatic mutations in the human body and to investigate their distribution and functional impact, we developed a method that leverages the genomic information carried by RNA to identify DNA somatic mutations while avoiding most sources of false positives. We applied it to infer somatic mutations across 7500 tissue samples from 36 non-cancerous tissues, allowing us to explore the landscape of somatic mutations throughout the human body. To our knowledge, this is the largest map to date of somatic mutations in non-cancerous tissues.

It has been proposed that somatic mutations contribute to aging and organ deterioration; consistently, we observed a positive correlation between age and mutation burden in most tissues. Interestingly, several brain regions are among the tissues exhibiting stronger age correlation, and somatic mutations have been shown to have a role in neurodegeneration. We observed largely tissue-specific behaviors and some pervasive observations shared across tissues. These results suggest that different cell types are subjected to different evolutionary paths that could be dependent on environmental or developmental differences. For example, while most samples exhibit tissue-specific mutation profiles, some others like transverse colon and the small intestine have similar profiles. Additionally, we observed that genes whose expression is associated with mutation load in several tissues are enriched in DNA repair, autophagy, immune response, cellular transport, cell adhesion, and viral processes, and while these functions have been implicated in mutagenesis in cancer, our results highlight how expression variation of these genes associates with mutational variation in healthy tissues.

Our findings paint a complex landscape of somatic mutation across the human body, highlighting their tissue-specific distributions and functional associations. The prevalence of cancer mutations and positive selection of cancer driver genes in non-diseased tissues suggests the possibility of a poised pre-cancerous state, which could also contribute to aging. Finally, our method for inferring somatic mutations from RNA-seq data may help accelerate the study of somatic evolution and its role in aging and disease.

Mitochondria are the power plants of the cell, a herd of replicating bacteria-like organelles that contain their own small genomes. They are responsible for packaging the chemical energy store molecules used to power cell processes. Mitochondria constantly undergo fusion and fission, and otherwise promiscuously pass around their component parts. The population in each cell is gardened by the quality control mechanism of mitophagy that works to remove damaged mitochondria. There is good evidence to suggest that, with aging, changes in gene expression cause a growing imbalance between fission and fusion, leading to large mitochondria that are resistant to mitophagy even when dysfunctional. This occurs in all cells, in comparison to another mechanism by which a comparatively few cells suffer mitochondrial DNA damage that causes them to become very dysfunctional and churn out oxidative molecules that disrupt tissue function throughout the body. Loss of energy production has a major impact in all tissues, but particularly in the energy-hungry tissues of muscle and brain.

Mitochondria are highly dynamic and constantly undergo morphological changes between fission (division) and fusion in response to various metabolic and environmental cues. A fusion process assists to homogenize the contents of damaged mitochondria resulting in mitochondrial elongation. Fission, on the other hand, leads to mitochondrial fragmentation and promotes clearance of damaged mitochondria through a form of selective autophagy - mitophagy. Excessive or untimely fission or fusion may be detrimental to mitochondrial quality and mitochondrial homeostasis.

Defective segments of mitochondria are segregated from the rest of the mitochondrial network through fission for elimination by mitophagy. Fragmented mitochondria and decreased baseline of mitophagy have been noted in aging hearts. Several proteins involved in mitochondrial turnover such as PINK1 and PGC-1α tend to decrease in old animals. These data indicated a decline in the function and regulation of mitophagy during aging. Recent studies suggested that aging-related mitochondrial DNA mutations may disrupt the receptor- (NIX and FUNDC1) mediated mitophagy in the differentiation process in adult cardiac progenitor cells (CPCs), which resulted in sustained fission and less functional fragmented mitochondria. Therefore, some activators of mitophagy have been used in aging models and showed some beneficial effects. For instance, urolithin A has been widely reported to extend lifespan in C. elegans and improve physical exercise capacity in rodents through upregulating mitophagy.

However, why and how mitophagy declines during aging have not been well defined. Several hypotheses were speculated thus far. For example, it was reported S-nitrosoglutathione reductase (GSNOR/ADH5), a protein denitrosylase that regulates S-nitrosylation, was downregulated with aging in mice and humans. Accumulation of S-nitrosylation severely impaired mitophagy, rather than autophagy, leading to hyperactivated mitochondrial fission.

In essence, mitophagy is considered a self-defense and garbage removal process that maintains mitochondrial homeostasis and cellular health, in the face of pathological stimuli. Dozens of species have depicted a unique protective role of mitophagy in aging and cardiovascular diseases, an effect consistent with suppressed mitophagy in multiple pathways. The baseline of mitophagy in different cardiac diseases may help understand the complex effects of mitophagy. The presence of a switch from AMPKα2 to AMPKα1 in failing hearts has been well documented, leading to a decrease of AMPKα2-mediated mitophagy and development of heart failure. In another independent study, upregulated CK2α following acute cardiac ischemia-reperfusion injury was found to suppress FUNDC1-mediated mitophagy, leading to infarct area expansion and cardiac dysfunction. Furthermore, ischemia activated FUNDC1-mediated mitophagy while reperfusion suppressed mitophagy possibly through activating Ripk3. Not surprisingly, interventions that restored mitophagy to normal levels, but not above normal levels, in these conditions should help to maintain mitochondrial homeostasis and cellular function.

Link: https://doi.org/10.1155/2019/9825061

The ubiquitin-proteasome system acts to degrade damaged and unwanted proteins, breaking them down to constituent parts that can be recycled. Ubiquitin is used to tag proteins designated for recycling, and these are drawn into the proteasome structure to be dismantled. There is some evidence for the activity of the proteasome to decline with age, but it isn't as clear-cut as the evidence for autophagy to falter. To the degree that proteasomal activity does decline, this may be a matter of reduced expression of important component parts of the proteasome, given that increasing expression of some component proteins can improve proteasomal function, or something more complex, such as impairment of the ability of proteasomes to move around the cell. These are proximate causes, and, as is often the case, it is very unclear as to how they relate to the underlying damage that causes aging.

Ubiquitin has long been known to be associated with pathologies of the brain, including that of Alzheimer's disease (AD). Our understanding of the link between ubiquitin-mediated proteolysis and neurodegenerative diseases such as AD, however, has only begun to improve with the elucidation of the mechanistic details of protein degradation. Although proteolysis by the ubiquitin-proteasome pathway (UPP) was originally assumed to operate only on abnormal proteins, research over many years has shown physiological roles for the UPP in various cells, including neurons. Several cellular functions are altered with aging. It is reasonable to hypothesize that ubiquitin-proteasome-mediated proteolysis is also impaired with aging. Investigations, however, have not yielded consistent results.

It is generally accepted that two main types of pathological phenomena occur in the AD brain. One is the accumulation of amyloid β (Aβ), the clumps of which lead to the development of plaques. The second is the accumulation of phosphorylated microtubule-associated protein tau, which ultimately forms tangles. The UPP is linked to both of these pathways of AD pathogenesis. In AD, ubiquitinated proteins accumulate, and it is believed that the proteolytic system in neurons is overwhelmed by aggregating proteins. Based on this logic, investigations were made of the proteasome in both postmortem human AD brains and in the brains of AD model mice. Studies found that proteasome activation by rolipram - a phosphodiesterase 4 (PDE4) inhibitor - decreased tau levels and improved cognition.

Improving the function of UPP components should, in principle, ameliorate some of the symptoms of AD. Because synaptic dysfunction and cognitive impairment are seen early in AD and the UPP has a role in synaptic plasticity and memory, it might be possible to manipulate the UPP to rescue some deficits. Based on the research thus far, there is no clear-cut relationship between aging and impairment of the proteasome function. When individual molecules are studied, however, a clearer picture emerges. In investigating the connections between the UPP and AD, many studies have focused on transgenic mouse models of AD based on the familial form of the human disease. These models were mainly based on the "Aβ hypothesis" of AD. Because the link of the UPP to AD is not just through Aβ, it would be worth investigating how the UPP relates to other factors contributing to AD such as insulin resistance and inflammation in the brain.

Link: https://doi.org/10.3389/fnagi.2019.00324

Lingering populations of senescent cells grow with age, and cause considerable harm via their inflammatory secretions. They are a tool to promote regeneration and resistance to cancer in the short term, but like many short term systems, they become damaging when left switched on for the long term. As I noted just yesterday, even looking at only the past year of studies of senolytic therapies to selectively destroy senescent cells, there is strong evidence in animal models for their ability to prevent or reverse a score of common age-related conditions, a broad range from Alzheimer's disease and other forms of neurodegeneration to fibrosis of the heart and kidney. This is just a starting point. Senolytics have yet to be tested in earnest for many more conditions that could plausibly be reversed by the targeted removal of senescent cells; there is only so much funding, and only so many scientists.

As the study of senescent cells in the context of aging expands, with the continued influx of new funding driven by a growing interest in this part of the field, we should expect to see ever more examples such as the one I'll note today. This is yet another age-related condition with poor treatment options in which animal models are shown for the first time to benefit from the application of senolytics.

In this case the condition is glaucoma, loss of vision caused by degeneration of retinal ganglion cells and the optic nerve. In most cases - but not all - this is caused by increased pressure in the eye, driven by hypertension and degeneration of fluid channels responsible for draining the eye. The precise nature of the relationship between risk factors such as pressure and mechanisms of neural degeneration in the eye has been far from clear, unfortunately. In this context, it is a ray of hope that the research here demonstrates cellular senescence as an important mediating mechanism, showing that removal of these cells prevents half of the retinal ganglion cell death that is produced in a model of raised pressure in the eye.

Early removal of senescent cells protects retinal ganglion cells loss in experimental ocular hypertension

Glaucoma is comprised of progressive optic neuropathies characterized by degeneration of retinal ganglion cells (RGC) and resulting changes in the optic nerve. It is a complex disease where multiple genetic and environmental factors interact. Two of the leading risk factors, increased intraocular pressure (IOP) and age, are related to the extent and rate of RGC loss. Although lowering IOP is the only approved and effective treatment for slowing worsening of vision, many treated glaucoma patients continue to experience loss of vision and some eventually become blind. Several findings suggest that age-related physiological tissue changes contribute significantly to neurodegenerative defects that cause result in the loss of vision.

Mammalian aging is a complex process where distinct molecular processes contribute to age-related tissue dysfunction. It is notable that specific molecular processes underlying RGC damage in aging eyes are poorly understood. While no single defect defines aging, several lines of evidence suggest that activation of senescence is a vital contributor. In a mouse model of glaucoma/ischemic stress, we reported the effects of p16Ink4a on RGC death. Upon increased IOP, the expression of p16Ink4a was elevated, and this led to enhanced senescence in RGCs and their death. Such changes most likely cause further RGC death and directly cause loss of vision. Of particular note, a recent bioinformatic meta-analysis of a published set of genes associated with primary open-angle glaucoma (POAG) pointed at senescence and inflammation as key factors in RGC degeneration in glaucoma.

Glaucoma remains relatively asymptomatic until it is severe, and the number of affected individuals is much higher than the number diagnosed. Numerous clinical studies have shown that lowering IOP slows the disease progression. However, RGC and optic nerve damage are not halted despite lowered IOP, and deterioration of vision progresses in most treated patients. This suggests the possibility that an independent damaging agent or process persists even after the original insult (elevated IOP) has been ameliorated.

We hypothesized that early removal of senescent RGCs that secrete senescent associated secretory proteins (SASP) could protect remaining RGCs from senescence and death induced by IOP elevation. To test this hypothesis, we used an established transgenic p16-3MR mouse model in which the systemic administration of the small molecule ganciclovir (GCV) selectively kills p16INK4a-expressing cells. We show that the early removal of p16Ink4+ cells has a strong protective effect on RGC survival and visual function. We confirm the efficiency of the method by showing the reduced level of p16INK4a expression and lower number of senescent β-galactosidase-positive cells after GCV treatment. Finally, we show that treatment of p16-3MR mice with a known senolytic drug (dasatinib) has a similar protective effect on RGCs as compared to GCV treatment in p16-3MR mice.

The connection between raised blood pressure and dementia is well established. Controlling hypertension via the usual combination of lifestyle choice and medications slows cognitive decline, and any number of epidemiological studies show that dementia patients are more likely to have a history of hypertension. The data noted in this review is interesting for making the point that the pressure damage to the brain and its vasculature that results from high blood pressure occurs over the course of late life, and thus reducing blood pressure has little to no effect on patients already exhibiting dementia. This is one of many areas in aging in which prevention is key, and it is well worth considering that hypertension contributes to overall mortality, not just to incidence of dementia.

Mid-life hypertension is reported to be a factor inducing dementia. Mid-life is typically defined as 45-64 years old. In this manuscript, mid-life hypertension means hypertension in individuals approximately 50 years old, and late-life hypertension means hypertension in those approximately more than 70 years old. The Atherosclerosis Risk in Communities (ARIC) cohort showed that high blood pressure in mid-life (around 48-67 years old) induces poorer cognitive function or dementia 20 years later. Moreover, the Honolulu Heart Program or Honolulu Asia Aging Study demonstrated that subjects less than 50 year old, even those with prehypertension, had an increased risk for dementia only in the untreated group.

Interestingly, subjects receiving antihypertensive medication showed no increased risk for dementia, even in those with systolic blood pressure of more than 140 mmHg, indicating that early intervention in hypertension is one approach to prevent late-life dementia. So, what is the target level of blood pressure in mid-life to prevent dementia? It was reported that systolic blood pressure elevation at age 50 years is associated with increased risk of dementia. Moreover, a systolic blood pressure level of 130 mmHg or lower has been shown to significantly prevent dementia at age 50. However, blood pressure elevation at 60 or 70 years old is not a significant risk, even in those with severe high blood pressure.

On the other hand, intervention for high blood pressure in the very elderly did not significantly reduce the incidence of dementia in the Hypertension In the Very Elderly Trial-COGnitive function assessment (HYVET-COG) trial. Moreover, the HYVET cohort study demonstrated that orthostatic hypotension indicates an increased risk of dementia and cognitive decline. Thus, intensive blood pressure treatment to prevent dementia is not recommended in "very elderly people" because blood pressure lowering fails to maintain cerebral blood flow because of dysfunction of cerebral autoregulation. Therefore, the younger the age at which blood pressure is managed at an appropriate level the better in order to prevent cognitive decline.

Link: https://doi.org/10.1186/s40885-019-0135-7

Evidence from the scientific community shows intermittent fasting to be beneficial in numerous species, including our own. The materials here discuss what I would call time restricted feeding rather than intermittent fasting. Restricting the hours that one eats during the day, but still otherwise eating ad libitum every day, can arguably be thought of as a mild form of intermittent fasting that doesn't rise to the level of, say, alternate day fasting or a quarterly five day implementation of the fasting mimicking diet. Nonetheless, there are benefits. It remains to be robustly determined in humans as to whether the benefits resulting from these milder forms of intermittent fasting are largely derived from a reduction in overall calories consumed or from undergoing periods of low calorie intake. Both have been shown to produce benefits in mice and rats, independently of one another.

Intermittent fasting diets fall generally into two categories: daily time-restricted feeding, which narrows eating times to 6-8 hours per day, and so-called 5:2 intermittent fasting, in which people limit themselves to one moderate-sized meal two days each week. An array of animal and some human studies have shown that alternating between times of fasting and eating supports cellular health, probably by triggering an age-old adaptation to periods of food scarcity called metabolic switching. Such a switch occurs when cells use up their stores of rapidly accessible, sugar-based fuel, and begin converting fat into energy in a slower metabolic process.

Studies have shown that this switch improves blood sugar regulation, increases resistance to stress, and suppresses inflammation for various periods of time. Because most Americans eat three meals plus snacks each day, they do not experience the switch, or the suggested benefits. Studies in both animals and people found intermittent fasting also decreased blood pressure, blood lipid levels, and resting heart rates. Evidence is also mounting that intermittent fasting can modify risk factors associated with obesity and diabetes. Two studies of 100 overweight women showed that those on the 5:2 intermittent fasting diet lost the same amount of weight as women who restricted calories, but did better on measures of insulin sensitivity and reduced belly fat than those in the calorie-reduction group.

More recently, preliminary studies suggest that intermittent fasting could benefit brain health too. A clinical trial found that 220 healthy, nonobese adults who maintained a calorie restricted diet for two years showed signs of improved memory in a battery of cognitive tests. While far more research needs to be done to prove any effects of intermittent fasting on learning and memory, if that proof is found, the fasting - or a pharmaceutical equivalent that mimics it - may offer interventions that can stave off neurodegeneration and dementia.

Link: https://www.hopkinsmedicine.org/news/newsroom/news-releases/intermittent-fasting-live-fast-live-longer