Fight Aging!

An epigenetic clock is a weighted algorithmic combination of the methylation status of various specific CpG sites on the genome, where the number produced matches well with chronological or biological age. It is constructed by applying machine learning techniques to epigenetic data, a catalogue of DNA methylation patterns across the full structure of the genome, taken from blood samples of mice or people at various ages. The early epigenetic clocks use hundreds of CpG sites, and therefore one might reasonably hypothesize that they reflect the entire breadth of the processes of aging. That turns out not to be true, but it was reasonable.

As work on the production of epigenetic clocks progressed, as well as the establishment of other clocks based on transcriptomic, proteomic, and other data, many groups have found highly optimized clocks that use very few CpG sites, less than a dozen. Further, it is possible to identify sites, when using such small numbers, that work the same way in mice, humans, and other mammalian species. This is desirable in one sense, in that such clocks are less costly to implement, particularly at scale. On the other hand, it is not reasonable to think that such clocks will reflect more than a tiny fraction of the processes of aging.

If all one cares about is to measure biological age absent intervention, then it really doesn't matter whether a clock measures only one or only a few of the underlying processes or dysfunctions of age. Absent intervention, all of the processes of aging proceed in parallel, so measuring just one or just a few is good enough. However, it is the case that every new approach to rejuvenation therapy will address only the one target mechanism, a limited portion of the contributions to degenerative aging. It is entirely plausible that an epigenetic clock will underestimate or overestimate the utility of a potential rejuvenation therapy, and the plausibility of that outcome increases as the number of CpG sites decreases. The most important future use for epigenetic and other clocks is to steer research and development towards larger effect sizes, more effective approaches to human rejuvenation. But we are not there yet.

Epigenetic Clocks for Mice Based on Age-Associated Regions That are Conserved Between Mouse Strains and Human

Precise measurement of aging is a prerequisite to identify parameters that may attenuate the aging process. It is fascinating that the DNA methylation (DNAm) patterns change in a highly reproducible and seemingly organized manner during aging of the organism. This epigenetic modification at the cytosine residues of CG dinucleotides (CpGs) impacts on chromatin organization, transcription factor binding, and gene expression. It is therefore anticipated that age-associated DNAm might be of immediate functional relevance for the aging process, albeit this remains to be proven. Today, epigenetic clocks are considered to be the most accurate biomarker for age predictions and there is sound evidence that they also capture aspects of biological aging that are independent from chronological age.

In this study, we used the recently released Infinium Mouse Methylation BeadChip to compare such epigenetic modifications in C57BL/6 (B6) and DBA/2J (DBA) mice. We observed marked differences in age-associated DNA methylation in these commonly used inbred mouse strains, indicating that epigenetic clocks for one strain cannot be simply applied to other strains without further verification. Interestingly, the CpGs with highest age-correlation were still overlapping in B6 and DBA mice and included the genes Hsf4, Prima1, Aspa, and Wnt3a. Furthermore, Hsf4, Aspa, and Wnt3a revealed highly significant age-associated DNA methylation in the homologous regions in human. Subsequently, we used pyrosequencing of the four relevant regions to establish a targeted epigenetic clock that provided very high correlation with chronological age in independent cohorts of B6 and DBA.

Larger signatures that comprise hundreds of CpGs may be more robust than targeted assays that only consider one or few CpGs, since they reflect a broader epigenetic pattern. BeadChip technology makes large signatures easily applicable since all relevant CpGs are addressed in each sample. However, adaptation and integration of different microarray datasets remains a major hurdle and age-predictors may become outdated if a BeadChip release is discontinued. It may therefore be advantageous to rather focus on individual CpGs by targeted methods, such as pyrosequencing, digital droplet PCR, or barcoded amplicon sequencing. These methods give very precise and reproducible results on single CpG level and facilitate fast and more cost-effective analysis. Notably, all 21 CpGs covered by our pyrosequencing assay provided very high correlation with age in all training and validation cohorts. Our four CpG epigenetic age prediction model thus now outperforms our previously published three CpG signatures. Other methods for age prediction in mice have reported lower correlations with a higher number of CpG sites (9-582).

Plenty of evidence points to improvement in the cellular maintenance processes of autophagy (primarily macroautophagy and chaperone-mediated autophagy) as the primary mechanism by which the response to mild stress improves health and extends life. Autophagy recycles broken molecules and damaged structures in the cells. More recycling implies better function, a lesser burden of damage and dysfunction at any given time. This underlies the extension of life span resulting from calorie restriction, for example. Researchers are interested in the development of drugs that mimic these stress responses by artificially upregulating autophagy. mTOR inhibitors achieve this goal, as do other calorie restriction mimetic drugs, but the effects in humans are so far modest, producing effects that, on the whole, compare poorly to the outcome of structured exercise programs, or the practice of calorie restriction itself.

Autophagy refers to a process in which the intracellular components such as abnormal proteins, damaged organelles, foreign pathogens, and other cellular components are degraded via lysosome. This catabolic process is evolutionarily conserved from yeast to mammalian cells. In mammalian cells, autophagy has been traditionally classified into the following three main types, macroautophagy, microautophagy, and chaperone-mediated autophagy (CMA). Among them, macroautophagy is featured by the formation of a unique double-membrane organelle, the autophagosome. In contrast, both microautophagy and CMA bypass autophagosome formation and the cargos are directly delivered to a lysosome.

At present, the majority of the autophagy research is on macroautophagy, or referred as autophagy hereafter in this review. On the other hand, depending on the nature of the cargos, autophagy can be categorized into general/nonselective and selective autophagy. For nonselective autophagy, the cellular cargos are engulfed into the autophagosomes randomly, a process usually induced by general stress conditions such as nutrient starvation. In contrast, selective autophagy refers to selective degradation of specific cargos, and so far, there are many types of selective autophagy being studied, such as mitophagy (selective degradation of mitochondria), endoplasmic reticulum (ER)-phagy (selective degradation of ER), aggrephagy (selective degradation of protein aggregates), and xenophagy (selective degradation of invaded pathogens), just to name a few.

It has been well studied that autophagy have important functions in various biological processes, such as cell survival and cell death, inflammation and immunity, development and differentiation, metabolic homeostasis, and so on. As such, autophagy is known to be closely implicated in the pathogenesis of human diseases. In this review, we will mainly focus on nonselective macroautophagy to provide a systematic discussion on the latest development on the molecular mechanisms, the implication of autophagy in important human diseases including cancer, neurodegeneration, metabolic diseases, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, cardiovascular diseases, and aging. Moreover, we will also discuss the therapeutic potential of targeting autophagy in human diseases. Finally, we will highlight the challenges the autophagy research field is facing and the directions of future study.

Link: https://doi.org/10.1002/mco2.150

Alzheimer's disease develops over twenty years or more, a slow growth of amyloid-β aggregates in the brain that sets the stage for a feedback loop of inflammation, cellular senescence, and tau aggregation that causes severe pathology and eventual death. As researchers demonstrate here, patients who will very likely go on to develop Alzheimer's disease many years in the future can be identified quite early. The mechanisms that will inexorably lead to the condition, and the lifestyle choices that adjust the pace of progress, are in place as much as two decades prior to diagnosis with the clinical stage of the disease. This produces signatures in the bloodstream that can be seen with simple tests, or at least the tests are simple once those signatures have been identified. It is that identification that has proven challenging, but the research community has made rapid progress on this front in the past few years.

The dementia disorder Alzheimer's disease has a symptom-free course of 15 to 20 years before the first clinical symptoms emerge. Using an immuno-infrared sensor, a research team is able to identify signs of Alzheimer's disease in the blood up to 17 years before the first clinical symptoms appear. The sensor detects the misfolding of the protein biomarker amyloid-beta. As the disease progresses, this misfolding causes characteristic deposits in the brain, so-called plaques.

The researchers analysed blood plasma from participants in the ESTHER study for potential Alzheimer's biomarkers. The blood samples had been taken between 2000 and 2002 and then frozen. At that time, the test participants were between 50 and 75 years old and hadn't yet been diagnosed with Alzheimer's disease. For the current study, 68 participants were selected who had been diagnosed with Alzheimer's disease during the 17-year follow-up and compared with 240 control subjects without such a diagnosis. The team aimed to find out whether signs of Alzheimer's disease could already be found in the blood samples at the beginning of the study.

The immuno-infrared sensor was able to identify the 68 test subjects who later developed Alzheimer's disease with a high degree of test accuracy. For comparison, the researchers examined other biomarkers with the complementary, highly sensitive SIMOA technology - specifically the P-tau181 biomarker, which is currently being proposed as a promising biomarker candidate in various studies. "Unlike in the clinical phase, however, this marker is not suitable for the early symptom-free phase of Alzheimer's disease. Surprisingly, we found that the concentration of glial fibre protein (GFAP) can indicate the disease up to 17 years before the clinical phase, even though it does so much less precisely than the immuno-infrared sensor." Still, by combining amyloid-beta misfolding and GFAP concentration, the researchers were able to further increase the accuracy of the test in the symptom-free stage.

Link: https://news.rub.de/english/press-releases/2022-07-21-biology-early-alzheimers-detection-17-years-advance

After decades of work, researchers have finally achieved therapies that can effectively clear amyloid-β aggregates from the brains of patients with Alzheimer's disease. Unfortunately clinical trials have shown no robust benefit to patients as a result. As illustrated by today's open access paper, a sizable contingent in the research community feel that the evidence for amyloid-β aggregation to be the root of the condition remains convincing. Failure means, in their eyes, that the challenge is more difficult than hoped, and the answer should be an increased effort to run longer clinical trials, find more and better anti-amyloid therapies, and in general an increased investment in and focus on clearance of amyloid-β.

Meanwhile, many other groups have their own viewpoints, some of which are gathering a sizable body of evidence in support of different interpretations of the core amyloid cascade hypothesis of Alzheimer's disease. No-one disputes that amyoid-β aggregation is associated with the condition and harmful in animal models, but why it is there, which form of amyloid-β or which of the surrounding biochemistry should be the target, or whether amyloid-β is irrelevant to later stages of the condition, and whether amyloid-β is a side-effect of other, more important pathological mechanisms, such as sustained inflammation of brain tissue or persistent viral infection - these are all ongoing debates that have given rise to significant research programs, clinical trials, and potential therapeutics. Many of these hypotheses and the approaches that arise from them will turn out to be wrong. That list may well include the currently dominant approach to amyloid-β clearance.

If amyloid drives Alzheimer disease, why have anti-amyloid therapies not yet slowed cognitive decline?

Alzheimer's disease (AD) is a major threat to our aging society and will be even more so in the future as life expectancy rises. Scientists from many different disciplines have worked intensively over four decades to try to identify the triggers of the disease and, based on these findings, to develop therapeutic strategies. However, although many clinical trials using approaches based on seemingly well-identified targets have been conducted, none of them seems to have reached its final goal: to substantially slow cognitive decline. This dispiriting news has led some to conclude that decades of intense research have failed because scientists wasted their time focusing on the wrong mechanism. But is this really true? Do we indeed have no idea what triggers AD? Were all clinical trials a failure? In other words, did we simply lose valuable time by working on the wrong targets, and are there mysterious "alternative pathways" that scientists have entirely missed so far?

For decades, scientists have focused their research on a presumably stereotyped neuropathology, namely amyloid plaques and neurofibrillary tangles, both of which are found in all patients with AD. Amyloid plaques are composed of abnormal aggregated forms of the amyloid β-proteins (Aβ) that are generated normally by enzymatic cleavage from the amyloid precursor protein (APP). Amyloid plaques are extracellular, whereas neurofibrillary tangles, composed of aggregated tau proteins, occur within neurons. How are these defining lesions connected, and what triggers the pathology initially? Based on overwhelming genetic evidence, Aβ accumulation and its aggregation into amyloid plaques is capable of initiating the disease and is therefore often placed at the top of a theoretical cascade of events which, via multiple steps, leads to widespread neuronal dysfunction and death. This rather linear view of molecular events has been challenged by the proposed "cellular phase" of AD which, instead of the long-pursued neurocentric view, brings the virtually simultaneous interplay of different types of brain cells, and not just neurons, into focus. As a consequence, alternative pathways, some of which may be independent of Aβ accrual, might also trigger the disease. In this sense, AD may be thought of as a syndrome that has many different causes. But did we really miss the main pathogenic triggers and need to completely reorient AD research?

Aβ dyshomeostasis is an early, invariant, and necessary feature of AD pathogenesis. Then why has only one anti-amyloid agent achieved regulatory approval, and even then, under highly controversial circumstances? The most plausible explanation that emerges from available knowledge is that translating the robust preclinical and biomarker science of Aβ pathobiology into clear-cut clinical benefit has been logistically difficult and fraught with missteps. In our view, anti-amyloid trials have often included inadequate compounds, less than ideal patient selection, initiation of treatment too late in the biological process, and faulty trial execution, including premature trial termination and the expectation that slowing this chronic disease can be accomplished in just 12 to 18 months. The seemingly improved execution of the current Phase III antibody clinical trials (lecanemab, donanemab, and gantenerumab) suggests that we may soon obtain more convincing evidence that sustained amyloid lowering leads to decreased pathological tau, less neurodegeneration, and the blunting of cognitive and functional decline. It would therefore be highly unwise to slow or abandon our efforts to confirm anti-Aβ therapeutic candidates, particularly since alternative, albeit highly attractive, targets (such as tau, ApoE4, and microglial modulation) are well behind Aβ lowering in the quest to lessen the disease course for patients.

If genetic, biochemical, animal modeling, fluid biomarker, and imaging studies all support Aβ as a rational target, and anti-Aβ immunotherapy reduces markers of neurodegeneration and provides some cognitive benefit, what can bring us to full success? It will be quantitative preclinical confirmation that certain antibodies (and other types of therapeutic agents) efficiently lower and neutralize Aβ oligomers as well as amyloid seeds in vivo, followed by the rigorous design and meticulous execution of clinical trials in humans confirmed to have AD pathobiology and treated for at least 18 to 24 months, with validated markers of AD pathology and multiple cognitive and functional end points that confirm each other. Of special importance would be the development of fluid and imaging markers of synaptic dysfunction, since the latter is a particularly important correlate of AD pathobiology.

All biological data changes with age, and enormous sets of such data can be recorded with comparative ease these days. Any sufficiently large set of data can be processed via suitable machine learning approaches in order to produce clocks that correlate with biological age. Some are better than others, some appear to be more sensitive or less sensitive to certain aspects or processes of aging. At the end of the day, these efforts will likely prove useful, but so far they have yet to result in the ability to reliably and rapidly assess a potential rejuvenation therapy for its ability to slow or reverse aging. A clock will always deliver a number, but since the connection between the clock and underlying processes of aging remains unclear, it also remains unclear as to whether that number will in fact usefully reflect changes in biological age produced by a given therapy.

Complexity is a fundamental feature of biological systems. Omics techniques like lipidomics can simultaneously quantify many thousands of molecules, thereby directly capturing the underlying biological complexity. However, this approach transfers the original biological complexity to the resulting datasets, posing challenges in data reduction and analysis. Aging is a prime example of a process that exhibits complex behaviour across multiple scales of biological organisation. The aging process is characterised by slow, cumulative and detrimental changes that are driven by intrinsic biological stochasticity and mediated through non-linear interactions and feedback within and between these levels of organization (ranging from metabolites, macromolecules, organelles and cells to tissue and organs).

Only collectively and over long timeframes do these changes manifest as the exponential increases in morbidity and mortality that define biological aging, making aging a problem more difficult to study than the aetiologies of specific diseases. But aging's time dependence can also be exploited to extract key insights into its underlying biology. Here we explore this idea by using data on changes in lipid composition across the lifespan of an organism to construct and test a LipidClock to predict biological age in the nematode Caenorhabditis elegans. The LipidClock consist of a feature transformation via Principal Component Analysis followed by Elastic Net regression and yields a Mean Absolute Error of 1.45 days for wild type animals and 4.13 days when applied to mutant strains with lifespans that are substantially different from that of wild type. Gompertz aging rates predicted by the LipidClock can be used to simulate survival curves that are in agreement with those from lifespan experiments.

Link: https://doi.org/10.3389/fragi.2022.828239

Is it a challenge to advocate for greater funding for rejuvenation research, a challenge to persuade people that significantly extending healthy human life spans is possible, plausible, and potentially imminent, because we are all relentlessly taught from an early age that death is to be accepted? Our myths, our ever-rewoven heritage of stories modern and ancient, propagandize for aging and death. Our cultures are replete with tales in which longevity is a punishment, and heroes are castigated for even trying to seek a longer life. This is an interesting question: to what degree are we controlled and constrained by the expectations taught to us, directly and indirectly, by the stories that wind their way through life around us?

I suggest that we have been culturally conditioned to think that it is virtuous to accept aging and death. We are taught to believe that although aging and death seem gruesome, they are what is best for us, all things considered. This is what we are supposed to think, and the majority accept it. I call this the Wise View because death acceptance has been the dominant view of philosophers since the beginning. Socrates compared our earthly life to an illness and a prison and described death as a healer and a liberator. The Buddha taught that life is suffering and that the way to escape suffering is to end the cycle of birth, death and rebirth. Stoic philosophers from Zeno to Marcus Aurelius believed that everything that happens in accordance with nature is good, and that therefore we should not only accept death but welcome it as an aspect of a perfect totality.

Many of the stories we tell promote the Wise View. One of the earliest known pieces of literature, the Epic of Gilgamesh, follows Gilgamesh on a quest for eternal life ending with the wisdom that death is the destiny of man. Today we learn about the tedium of immortality from the children's book Tuck Everlasting by Natalie Babbitt, and we are warned about the vice of wanting to resist death in other books and films such as J.K Rowling's Harry Potter, where Voldemort must kill Harry as a step towards his own immortality; C.S. Lewis' The Chronicles of Narnia where the White Witch has gained immortal youth and madness in equal measures; J.R.R. Tolkien's Lord of the Rings trilogy where the ring extends the wearer's life but can also destroy them, as exemplified by the creep Gollum; and Doctor Strange where life extension is the one magical power that is taboo.

We are inundated and saturated with an ideology of death-acceptance. The Wise View resonates with us partly because we think that there is nothing we can do about aging and death, so we do not want to wish for what we cannot have. Youth and immortality are sour grapes to us. Believing that death is, all things considered, not such a bad thing, protects us from experiencing our aging and approaching death as a gruesome tragedy. This need to escape the thought that we are heading towards a personal catastrophe explains why many are so quick to accept arguments against radical life extension, despite their often glaring weaknesses.

Link: https://leaps.org/reverse-aging/

One of the more practical near term approaches to address the age-related decline of mitochondrial function is transplantation of functional mitochondria. As an approach, it bypasses all of the remaining unknowns relating to the biochemistry of mitochondrial aging. Cells will take up whole mitochondria and make use of them, and early studies suggest that providing new mitochondria can improve tissue function when native mitochondria are impaired. It is likely that this improvement will last for only a limited time, as the same processes that degrade the function of mitochondria, such as a lack of effective mitophagy, will still operate on the new arrivals. If that limited time is a few months to a few years, that will nonetheless gives tissues a chance to restore themselves to some degree - and the therapy can always be repeated.

The major focus of the few companies presently working towards this goal of mitochondrial transplantation is the development of practical methods of production of mitochondria. Ultimately, therapies for aging humans that replace mitochondria throughout the body will require enormous numbers of these organelles, and thus the development of a cost-effective means of manufacture at scale. Even producing enough mitochondria for demonstrations in mice proved to be an initial hurdle. It is interesting to see reports along the way in this process of development, such as the materials provided by Mitrix Bio, noted here. Academic papers will be forthcoming, it seems, to describe the details.

Bioreactor-Grown Mitochondria for Potential Anti-Aging

Mitrix Bio announced early results of an 18-month project in which a series of mitochondrial transplants were performed in animal studies of brain, eye, liver, immune system, and skin tissues. In these tests, "young" highly functional mitochondria are grown in prototype bioreactors and transfused into the bloodstream. Cells absorb them to help supplement old, dysfunctional mitochondria and reverse energetic decline. These tests showed apparent age reversal in multiple endpoints in animal disease models in vivo and human cells in vitro. The results indicate potential future therapies for diseases such as Alzheimer's, macular degeneration, cardiovascular disease, frailty, and immunosenescence. Experiments not only point toward specific diseases but suggest anti-aging effects on test animals' strength, cognition, and appearance. A series of peer-reviewed papers will be released in coming months.

For the past decade, researchers have been testing exogenous mitochondrial transplants. But these tests have been confined mainly to rare pediatric diseases and surgery, not the larger world of adult diseases and longevity, due to scarce supplies of donor mitochondria. Just as liver or kidney organ transplants are limited by the availability of donors, mitochondrial "organelle transplants" are limited by scarce supplies of donor mitochondria. The Mitrix Bio project was launched to overcome this limitation for adult diseases. In the Mitrix process, the first step is to grow mitochondria in prototype bioreactors. Next, those mitochondria are given a special coating to protect against immune reactions along with molecular receptors to target specific tissue types. These coated mitochondria are infused into the body, where they travel to desired tissues and take up residence in cells.

"As people age, their tissues experience chronic energy depletion - there's not enough energy for cells to function, DNA becomes damaged, and stem cells lose their stemness. Our goal with mitochondrial transplant is to raise the energetics of the entire system so it's ready for other types of longevity treatments. All things considered, having improved bioenergetics trumps many of the negative impacts of aging. Even if improvement from mitochondrial transplant is indirect, it buys time, and that is what longevity is all about."

Stochastic mutational damage is thought to be problematic where it occurs in stem cells and progenitor cells, and can thus spread widely. A more severe form of such damage is the loss of the entire Y chromosome in men. Researchers here provide evidence, using an engineered mouse lineage, for this to make macrophages more inflammatory, accelerating fibrosis and dysfunction in the heart. This in turn raises mortality, which might explain the observed association between loss of the Y chromosome and increased incidence of age-related disease in humans. Inflammation accelerates all of the common fatal age-related conditions, and dysfunction in immune cells is a real problem in this context.

Why a condition that frequently occurs in aging men, in which an increasing number of hematopoietic cells display a loss of the Y chromosome, is associated with increased risk of mortality and age-related diseases is now a little clearer, thanks to work in mice. This condition - known as mosaic loss of Y chromosome, or mLOY - is a major risk factor for heart failure and cardiac fibrosis in men growing older, according to the study, which includes prospective data from the UK Biobank. The study also revealed that a neutralizing antibody could reverse some cardiac impacts caused by mLOY.

The Y chromosome has been long considered a "genetic wasteland," and beyond biological sex determination, there is little understanding of its functional role. Nevertheless, mLOY in blood cells has been linked to increased risk for mortality, cardiovascular disease, and other age-related disorders. In human somatic cells, mLOY is the most commonly acquired mutation in the male's genome. However, a relationship between mLOY and pathogenesis has not yet been established.

Using CRISPR-Cas9, researchers developed a mouse model of hematopoietic mLOY by reconstituting their bone marrow with cells lacking the Y chromosome. They discovered that these mice displayed increased mortality and were more prone to age-related cardiac fibrosis and decreased cardiac function. According to the findings, bone marrow-derived mLOY macrophages that infiltrate the heart trigger high transforming growth factor β1 (TGF-β1) activity, which leads to fibroblast proliferation and accelerated cardiac tissue fibrosis. Treatment with a TGF-β1 neutralizing antibody was shown to ameliorate these harmful effects. What's more, a prospective study in human patients showed that those with mLOY in blood were also at a greater risk for cardiovascular dysfunction and associated mortality.

Link: https://www.eurekalert.org/news-releases/958410

Fifteen years ago, initial clinical trials were underway for a gene therapy to upregulate PEDF expression in the retina of patients with macular degeneration, the result of years of work on the involvement of PEDF expression in retinal aging. Today, we can see researchers still working with animal models on the fundamental question of whether or not PEDF expression is actually relevant in the aging of the retina. This sort of thing isn't uncommon. Research into the role and relevance of any given protein can span decades, and still go nowhere. This is not a field noted for its speed, or its ability to focus on approaches that work well versus those that are marginal.

The retina is composed of layers of cells that function together to detect and process light signals, which the brain uses to generate vision. The retina's light-sensing photoreceptors sit above the retinal pigment epithelium (RPE), a layer of support cells. The RPE nourishes photoreceptors and recycles pieces of the photoreceptor cells called "outer segments," which get used up and their tips shed each time photoreceptors detect light. If the RPE cannot provide recycled components of older outer segment tips back to photoreceptors, these cells lose their ability to make new segments, and eventually become unable to sense light. And without nutrients supplied by the RPE, photoreceptors die. In people with macular degeneration or certain types of retinal dystrophies, senescence, or death of RPE cells in the retina leads to vision loss.

Previous work has shown that PEDF protects retinal cells, preventing both damage to the cells and abnormal growth of blood vessels in the retina. RPE cells produce and secrete the PEDF protein. The protein then binds to its receptor, PEDF-R, which is also expressed by RPE cells. Binding by PEDF stimulates PEDF-R to break down lipid molecules, key components of the cell membranes that enclose photoreceptor outer segments and other cellular compartments. This breakdown step is a key part of the outer segment recycling process. And while researchers have known that PEDF levels drop in the retina during the aging process, it was not clear whether this loss of PEDF was causing, or merely correlated with, age-related changes in the retina.

To examine the retinal role of PEDF, researchers studied a mouse model that lacks the PEDF gene, finding that the RPE cell nuclei were enlarged, which may indicate changes in how nuclear DNA is packed. The RPE cells also had turned on four genes associated with aging and cellular senescence, and levels of the PEDF receptor were significantly below normal. "One of the most striking things was this reduction in the PEDF receptor on the surface of the RPE cells in the mouse lacking the PEDF protein. It seems there's some sort of feedback-loop involving PEDF that maintains the levels of PEDF-R and lipid metabolism in the RPE."

Link: https://www.nei.nih.gov/about/news-and-events/news/nih-study-finds-loss-youth-protein-may-drive-aging-eye

INDY was one of the earlier longevity-related genes to be robustly identified, a discovery made 20 years ago now. Much of the exploratory work on INDY was carried out in flies, though more than enough time has now passed for mouse data to have also emerged. The authors of today's review paper characterize the benefits resulting from a reduced expression of INDY as a calorie restriction mimetic effect, more or less. That is a fair enough shorthand for any approach that improves cellular maintenance processes in a way that modestly slows the aging process, resisting the accumulation of damage, dysfunctional cells, and chronic inflammation.

Most of the ways known to slow aging in short-lived species are quite similar, viewed from the high level. Given that these species exhibit a sizable plasticity of life span in response to environmental circumstances, achieved via upregulation of stress response mechanisms triggered by heat, cold, toxins, and low nutrient availability, most of what is discovered by any unbiased search are ways to trigger that same upregulation of stress response mechanisms. That has indeed been the case, with inhibition of INDY expression as one such approach. Unfortunately, this category of interventions just isn't as effective at extending life in longer-lived species, as demonstrated by the fact that calorie restriction itself adds only a few years to human life span at most, quite unlike the ~40% life extension observed in mice.

Still, calorie restriction does improve health in humans. It seems likely that out of this large range of ways to improve cellular maintenance, a fair number of drugs, like mTOR inhibitors, will emerge to produce modest gains in human patients. Likely very modest, an acceptable exchange for a low cost drug from the patient's perspective, but a grand waste of time and effort that should have gone elsewhere from the perspective of the billions spent on the drug development process in its later stages.

INDY - From Flies to Worms, Mice, Rats, Non-Human Primates, and Humans

I'm Not Dead Yet (Indy) is a fly homologue of the mammalian SLC13A5 (mSLC13A5) plasma membrane citrate transporter, a key metabolic regulator and energy sensor involved in health, longevity, and disease. Reduction of Indy gene activity in flies, and its homologs in worms, modulates metabolism and extends longevity. The metabolic changes are similar to what is obtained with caloric restriction (dietary restriction). Similar effects on metabolism have been observed in mice and rats.

As a citrate transporter, INDY regulates cytoplasmic citrate levels. Indy flies heterozygous for a P-element insertion have increased spontaneous physical activity, increased fecundity, reduced insulin signaling, increased mitochondrial biogenesis, preserved intestinal stem cell homeostasis, lower lipid levels, and increased stress resistance. Mammalian Indy knockout (mIndy-KO) mice have higher sensitivity to insulin signaling, lower blood pressure and heart rate, preserved memory and are protected from the negative effects of a high-fat diet and some of the negative effects of aging. Reducing mIndy expression in human hepatocarcinoma cells has recently been shown to inhibit cell proliferation. Reduced Indy expression in the fly intestine affects intestinal stem cell proliferation, and has recently been shown to also inhibit germ cell proliferation in males with delayed sperm maturation and decreased spermatocyte numbers.

These results highlight a new connection between energy metabolism and cell proliferation. The overall picture in a variety of species points to a conserved role of INDY for metabolism and health. This is illustrated by an association of high mIndy gene expression with non-alcoholic fatty liver disease in obese humans. mIndy (mSLC13A5) coding region mutations (e.g., loss-of-function) are also associated with adverse effects in humans, such as autosomal recessive early infantile epileptic encephalopathy and Kohlschütter-Tönz syndrome. The recent findings illustrate the importance of mIndy gene for human health and disease. Furthermore, recent work on small-molecule regulators of INDY highlights the promise of INDY-based treatments for ameliorating disease and promoting healthy aging.

While more knowledge is always a good thing in the long run, it is unclear as to what exactly can be done about age-related chronic inflammation in the near term with a better map of the regulatory processes that initiate, sustain, and suppress inflammation. The state of knowledge today strongly suggests that excessive, unwanted inflammation and necessary, important inflammation both run through the same systems of signaling between and within cells. Therapies based on interfering in more critical portions of that signaling can reduce inflammation, and indeed a number of such drugs already exist, but they have the serious side-effect of also interfering in the vital activities of the immune system. It seems likely that the practical way forward is to remove the causes of inflammation rather than suppressing the mechanisms of inflammation. In the case of inflammation provoked by the aging of the gut microbiome, there are comparatively simple approaches that can reset the balance of populations and reduce the presence of inflammatory microbes, such as fecal microbiota transplantation. It only remains to bring them into common medical practice.

Of the distinct niches colonized by our microbiota within or on us, the gastrointestinal tract harbours the most complex microbiota, consisting of bacteria, fungi, viruses, archaea, and protozoa, and acts as a hotspot for host-microbe interactions. The host through evolution and adaptation has developed diverse mechanisms to distinguish between the microbial symbionts and pathogens and respond accordingly by balancing between tolerance and inflammation. The first step of this interaction is mediated by pattern recognition receptors (PRRs), which sense microorganisms through conserved molecular structures. Several families of PRRs have now been well studied, including the Toll-like receptors (TLRs), the nucleotide-binding oligomerization (NOD)-like receptors (NLRs), the C-type lectin receptors, and the RIG-I-like receptors (RLRs).

Once the microbial signatures are recognized by the host, usually a transcriptional response follows, which determines the outcome of this interaction and is critical for maintaining the balance between homeostasis and inflammation. It is at this stage that members of the nuclear factor kappa B (NF-κB), play a crucial balancing act by maintaining tolerance towards the endogenous symbionts, hence establishing homeostasis while activating inflammatory pathways in response to abnormal changes in the microbiome, "dysbiosis", or pathogenic invasion. Most of the cellular PRRs such as TLRs, NLRs and RLRs after sensing microbial signatures follow distinct pathways, which ultimately converge to stimulate NF-κB, suggesting NF-κB's central role in host response to microbes.

The balance in NF-κB response to microbial signatures becomes crucial for host health particularly during ageing and is often linked to ageing associated diseases. Ageing is associated with an overall decline in host organ functions, which changes host requirements and the dynamics between the host and its microbiota, leading to alterations in microbiome composition and diversity. These age-related microbiota transmutations can either be beneficial with the enrichment of health associated microbes and promote healthy ageing or may lead to severe imbalances leading to a potentially detrimental condition, termed dysbiosis. Ageing-associated dysbiosis usually triggers host immune responses, particularly the innate arm of it, since adaptive immunity typically declines with age, a phenomenon termed immunosenescence. This elevated basal level of innate immune responses during ageing leads to sustained inflammation, a condition known as inflammaging, which contributes to increased risk of developing age-related diseases. NF-κB signaling is a central player in this process as it integrates microbial cues via PRRs and in turn orchestrates innate immune responses.

Link: https://doi.org/10.3389/fcell.2022.874940

Aging is characterized by chronic inflammation, disruptive of cell and tissue function, a sizable contribution to the onset and progression of all of the common age-related conditions. The causes of this inflammation are known at the high level, such as the increasing presence of senescent cells and damage-associated molecular patterns, such as DNA debris from dead and dying cells. At the detail level, the real of genomics, transcriptomics, proteomics, and the other omics, much remains to be cataloged. There is the hope that a full map of inflammation in aging would point out more and better regulatory or signal molecules that could be targeted by therapies, but this type of approach has so far proven less effective than hoped, given the side-effects it produces. The goal of blocking only excessive inflammation, without blocking essential inflammation, requires a focus on the causes of inflammation, rather than sabotage of the initiation or progression of inflammation.

The immune system undergoes numerous and profound changes with aging. Hallmarks of immune aging are (a) a state of proinflammatory activation characterized by high circulating levels of proinflammatory cytokines - such as IL-6 and TNF-α - and localized tissue inflammation, and (b) an aberrant response to antigens and pathogens that could either be blunted, such as in flu vaccination, or excessive, such as in response to SARS-CoV-2. Considerable research in both animal models and humans has examined the causes and consequences of inflammaging. Although increased levels of inflammatory mediators (mostly IL-1, IL-6, TNF-α, and its receptors) are detected in all elderly individuals, higher levels of these biomarkers are associated with increased risk for many chronic conditions, including dementia, disability, and physical frailty. Inflammation's causal role in cardiovascular disease was established by the CANTOS trial (Canakinumab Anti-Inflammatory Thrombosis Outcomes Study), which demonstrated that IL-1β inhibition reduced the risk of cardiovascular events versus the placebo, particularly in participants whose IL-6 levels were initially elevated.

Mechanisms identified as hallmarks of aging biology and immune cell dysfunction have all been hypothesized as causes of inflammation. Aging researchers now recognize that measuring a few cytokines in circulation fails to capture the complexity and potential ramifications of inflammaging. Immune cells in tissues, particularly lymphocytes and resident macrophages, show tissue-specific age-related changes likely connected to specific pathological processes. By measuring hundreds or thousands of molecules in a few drops of blood, scientists are attempting to identify (a) signatures of accelerated aging that are both informative of the complexity and diversity of the response and predictive of health outcomes and (b) key molecules and molecular mechanisms that can be targeted for intervention.

Given the extreme complexity of inflammaging, we focus herein on a few topics that have attracted considerable attention and controversy in the field. First, we discuss cellular senescence as a source of local and systemic inflammation. We highlight evidence that mitochondrial dysfunction is a nexus that binds impaired mitophagy with DNA damage and cellular senescence to ultimately foster a chronic inflammatory state. We then summarize efforts to identify circulating signatures of inflammation through "omics." Finally, we review emerging data indicating that inflammation is involved in brain aging and dementia. Our intent is to discuss the causes and consequences of inflammaging and to enrich the research agenda toward the development of new therapeutic strategies.

Link: https://doi.org/10.1172/JCI158448

Much of the recent research into the longevity of large mammals such as elephants has focused on Peto's paradox. If the odds of cancer are based on the number of cells in the body, all of which undergo stochastic and potentially cancerous mutations at some rate, then how is it that large mammals, with many times more cells in their body, do not exhibit a correspondingly larger risk of cancer? The answer being that for larger mammals to evolve at all, their cancer risk must be managed downward by changes in cellular biochemistry that reduce mutation rate or more efficiently destroy potentially cancerous cells. In elephants this appears to be achieved, in large part at least, by the 20-fold duplication of TP53, a cancer suppression gene.

There is a lot more to think about when it comes to the longevity of elephants, however, and today's open access review paper is an interesting read on this topic. For example, the unusual biology of hormones in male elephants, combined with the mating behavior of elephants in general, leads to greater reproductive success later in life, which likely puts selection pressure on greater longevity. Something much like this, or analogous situations such as the Grandmother hypothesis in humans, in which intelligence and culture allows older individuals to materially contribute to the reproductive success of their grandchildren, must exist in order to drive the evolution of increased longevity in a species.

Aging: What We Can Learn From Elephants

Elephants are large-brained, social mammals with a long lifespan. Studies of elephants can provide insight into the aging process, which may be relevant to understanding diseases that affect elderly humans because of their shared characteristics that have arisen through independent evolution. Elephants become sexually mature at 12 to 14 years of age and are known to live into, and past, their 7th decade of life. Because of their relatively long lifespans, elephants may have evolved mechanisms to counter age-associated morbidities, such as cancer and cognitive decline. Elephants rely heavily on their memory, and engage in multiple levels of competitive and collaborative relationships because they live in a fission-fusion system in which groups change membership frequently. Female matrilineal relatives and dependent offspring form tight family units led by an older-aged matriarch, who serves as the primary repository for social and ecological knowledge in the herd. Similar to humans, elephants demonstrate a dependence on social bonds, memory, and cognition to navigate their environment, behaviors that might be associated with specializations of brain anatomy.

Males have a unique combination of behavioral and physiologic traits that reflect the intense pressure to compete for access to estrous females. In general, females are in estrous for only 3-6 days every 3-9 years. Males grow throughout much, or perhaps all, of their lifespan, in terms of stature, as well as body and tusk weight. Males experience musth, unique to elephants, which is characterized by bouts of elevated testosterone and aggression, and heightened sexual activity. Females prefer larger males and those in musth, which may explain why paternity success steadily increases in males from the mid-20s until it peaks around early 50s, after which, it is comparable to a male in his early 40s. This observation suggests male elephants may undergo sexual selection for longevity.

One mechanism allowing elephants to reach longer lifespans may be their multiple copies of the tumor suppressor gene TP53, colloquially known as the "guardian of the genome." Humans have one copy of TP53, whereas savanna, forest, and Asian elephants are estimated to have 19-23, 21-24, and 19-22 TP53 copies, respectively. This is compared to estimates of 19-28, and 22-25 TP53 copies in the extinct woolly mammoth and straight-tusked elephant, respectively. Of the multiple elephant TP53 genes, only one appears to have a comparable gene structure to other mammals, while the other copies appear to be retrogenes, as they lack true introns. Retrogenes can have functional biological roles. Indeed, genetic variation at some elephant TP53 retrogenes is conserved across all three extant elephant species, providing evidence of the functionality of at least some TP53 retrogenes. As reported recently, TP53 is activated in response to cellular stresses in addition to DNA damage. Thus, these multiple copies may have various effects in response to cell stress. Elephants appear to have an enhanced apoptotic response to DNA damage owing to their extensive number of TP53 retrogenes and, as a result, develop cancer at lower rates than expected for their body size and lifespan.

In this recent interview with Aubrey de Grey touches on a number of areas of progress made by the research and development community in recent years, projects that lead towards rejuvenation therapies based on the Strategies for Engineered Negligible Senescence (SENS). In the SENS view, supported by a very sizable literature accumulated over the past century, aging is caused by underlying processes of damage accumulation. What we think of as aging is a diverse collection of downstream consequences of that damage. Periodically repairing the underlying damage, allowing the normal maintenance of the body to continue as it would in youth, remains the most promising approach to aging. Senolytic drugs to clear senescent cells are one example of a rejuvenation therapy based on SENS, and in animal models senolytics produce very impressive results on near all age-related conditions assessed to date.

Ariel VA Feinerman: Can you name the most big breakthrough in each SENS programme since our interview in 2017?

Aubrey de Grey: Well, let's see…

RepleniSENS: probably the initiation of a clinical trial in Japan using iPSC-derived dopaminergic precursors to cure Parkinson's Disease. Other such trials are imminent in the USA.

OncoSENS: definitely the main thing is 6-thiodeoxyguanine, or just THIO for short, which is essential "WILT 2.0". It turns telomerase into a suicide gene, killing cells quickly, rather than waiting for them to divide into telomere-less oblivion.

ApoptoSENS: I'd say it's the successful extension of mouse lifespan with a senolytic. It's a big surprise that just one SENS intervention can have a substantial lifespan effect when initiated late in life.

AmyloSENS: the definitive confirmation that immune therapies can eliminate amyloid in the Alzheimer's brain. Even though there is basically no cognitive benefit, it's a very important thing to know for the future, especially for other amyoloids that are more causal.

LysoSENS: definitely the success of our atherosclerosis team in developing a drug to extract oxidative cholesterol from plaques. That has now become a spinout company, Clarity Therapeutics.

GlycoSENS: the spinning-out of another company, Revel Pharmaceuticals. which is developing cross-link-breakers. That was the result of the pioneering work at Yale that we funded for several years.

MitoSENS: the main thing in our team is a new way to increase the amount of protein that our transferred genes make, but also it's really important that our work over the past few years has gained a lot of respect from mainstream experts who used to think it was never going to work.

Ariel VA Feinerman: Previously you have said that there are two types of epigenetic changes, reversible shift, which is a reaction to the cellular environment, and irreversible noise, which is stochastic. Now researchers claim that epigenetic changes are because of double strand breaks. This type is not shift or noise because this is stochastic and reversible using the Yamanaka factors (OSKM). Can you comment on this?

Aubrey de Grey: The problem is that OKSM doesn't only eliminate noise - it eliminates (very nearly) all epigenetic marks, whether noise or signal. The only reason it can be therapeutic is because doing just a little bit of that wiping of information seems to be OK - the cell can use the residual signal as a guide to rebuild the lost signal, whereas the proportion of the noise that was also removed is really gone. Sounds good! Except ... that in the body (even the young adult) there are a lot of cells that are most of the way to becoming cancerous. These cells are in what we can think of as an epigenetically fragile state: it doesn't take much to tip them over the edge, because their cell-cycle stabilisation defences are already damaged. So, all in all, I am currently quite pessimistic about the future of OKSM-based rejuvenation.

Ariel VA Feinerman: Is any progress with ALT cancer?

Aubrey de Grey: There has been plenty of progress in the past five years, yes, but not by us - indeed, the progress by others that has led to us deprioritising it. But there is still some way to go to find a generic approach to attacking it. I am optimistic, because ALT basically relies on the maintenance of an unstable equilibrium between DNA damage and repair, which should be vulnerable to other stressors.

Ariel VA Feinerman: How does THIO work? How can we protect stem cells from THIO?

Aubrey de Grey: THIO is a brilliant discovery. It works by turning telomerase into a suicide gene. Specifically, telomerase incorporates it into the telomere, but that disrupts the structure that lets the telomere do its job of preventing the cell's DNA repair machinery from joining chromosomes together. So chromosomes do get joined together, and that leads rapidly to cell death. Stem cells, even the most rapidly-dividing ones, have such tiny amounts of telomerase as compared to cancer cells that they are not significantly harmed by the dose and duration needed to kill a telomerase-positive cancer.

Link: https://medium.com/@arielf/inteview-with-aubrey-de-grey-2022-21803a1759de

Researchers here run the numbers to suggest that as much of 40% of the incidence of dementia is the result of lifestyle choices and environmental factors, and thus amenable to prevention. A lot of these line items are known to contribute to the chronic inflammation of aging, and evidence increasingly leans towards an important role for unresolved, lasting inflammation in the progression of neurodegenerative conditions. Much of the focus is on hypertension, the raised blood pressure that is very damaging to fragile tissues such as those of the brain. Hypertension can be controlled to a large degree via changes in diet, weight, and exercise.

How much all-cause dementia could be prevented in the United States? Researchers attribute 41 percent of dementia cases to 12 modifiable lifestyle factors. Obesity, high blood pressure, and lack of exercise accounted for the lion's share. This estimate is on par with a Lancet Commission report linking 40 percent of dementia cases worldwide to the same 12 risk factors: physical inactivity, excess alcohol consumption, obesity, smoking, hypertension, diabetes, depression, traumatic brain injury, hearing loss, few years of education, social isolation, and air pollution. However, the report pegged hearing loss, education, and smoking as the three largest ones.

In the U.S. data, the three most prevalent factors - obesity, hypertension, physical inactivity - also had the largest population attributable fraction (PAF), each accounting for 20 percent of dementia risk. Other common risk factors carried lower risk. Air pollution ranked fifth in prevalence but came in second to last as a risk factor, explaining only 2.2 percent of preventable dementia. Excessive alcohol consumption, defined as drinking more than 14 standard drinks per week, accounted for 0.7 percent. These "unweighted" numbers did not take into account that some risks correlate with each other. For example, physical inactivity increases a person's chances of gaining weight or having high blood pressure, or obesity increases a person's odds of developing diabetes.

Adjusting for such correlations, researchers calculated that each factor directly explained 0.5 to 7.0 percent of the total modifiable risk. Obesity, hypertension, and physical inactivity still came out on top, each accounting for about 7.0 percent. Diabetes was a close fourth, at approximately 4.5 percent.

Link: https://www.alzforum.org/news/research-news/us-40-percent-all-cause-dementia-preventable

Today I'll point out an interesting study in mice that is based on the peripheral amyloid sink view of Alzheimer's disease. Researchers repeatedly replaced the blood in Alzheimer's model mice, that exhibit high levels of amyloid-β in the brain, with blood from normal mice. The result was less amyloid-β in the brain and better cognitive function. While one does always need to begin these discussions by noting that mouse models of Alzheimer's disease are very artificial constructs, in that mice do not naturally develop the condition, and thus the models are all some form of genetic dysfunction that generates a particular pathology that may or may not map well to why Alzheimer's is harmful in humans, this is nonetheless quite interesting.

The peripheral amyloid sink concept is the suggestion that levels of amyloid-β in the circulation and vascular tissues, on the one hand, and in the brain, on the other hand, are in dynamic equilibrium. If amyloid-β is removed from the vasculature and circulation, such as via replacement of blood, then this will cause amyloid-β levels to drop in the brain. One can consider some form of balance being enacted at the blood-brain barrier, in which the barrier is sensitive to levels of amyloid-β on either side, or more simple diffusion processes. But either way, there is some evidence for this to actually work: a phase III trial in humans was successful in improving cognitive function, using replacement of blood.

However, it is entirely possible that this has absolutely nothing to do with redistribution of amyloid-β, and everything to do with the dilution of harmful factors in the old bloodstream and replacement of circulating age-damaged albumin, rife with modifications due to the age-damaged environment. Blood replacement treatments might be expected to reduce the chronic inflammation and tissue dysfunction that results from the presence of damage-associated molecular patterns and other harmful factors present in the bloodstream of an older individual - and thus perhaps reduction of amyloid-β and restoration of cognitive function has more to do with a modest improvement in the brain tissue environment, allowing greater clearance of amyloid-β by immune cells and less cellular dysfunction in general. Proving this one way or another is quite the different challenge from demonstrating that benefits occur, of course.

Whole blood exchange could offer disease-modifying therapy for Alzheimer's disease, study finds

Researchers have shown that the misfolding, aggregation, and buildup of amyloid beta proteins in the brain plays a central role in Alzheimer's disease. Therefore, preventing and removing misfolded protein aggregates is considered a promising treatment for the disease. After multiple blood transfusions, the researchers found that the development of cerebral amyloid plaques in a transgenic mice model of Alzheimer's disease was reduced by 40% to 80%. This reduction also resulted in improved spatial memory performance in aged mice with the amyloid pathology, and lowered the rates of plaque growth over time.

While the exact mechanism by which this blood exchange reduces amyloid pathology and improves memory is currently unknown, there are multiple possibilities. One possible explanation is that lowering amyloid beta proteins in the bloodstream may help facilitate the redistribution of the peptide from the brain to the periphery. Another theory is that blood exchange somehow prevents amyloid beta influx, or inhibits the re-uptake of cleared amyloid beta, among other potential explanations.

Preventive and therapeutic reduction of amyloid deposition and behavioral impairments in a model of Alzheimer's disease by whole blood exchange

Alzheimer's disease (AD) is the major form of dementia in the elderly population. The main neuropathological changes in AD patients are neuronal death, synaptic alterations, brain inflammation, and the presence of cerebral protein aggregates in the form of amyloid plaques and neurofibrillary tangles. Compelling evidence suggests that the misfolding, aggregation, and cerebral deposition of amyloid-beta (Aβ) plays a central role in the disease. Thus, prevention and removal of misfolded protein aggregates is considered a promising strategy to treat AD.

In the present study, we describe that the development of cerebral amyloid plaques in a transgenic mice model of AD (Tg2576) was significantly reduced by 40-80% through exchanging whole blood with normal blood from wild type mice having the same genetic background. Importantly, such reduction resulted in improvement in spatial memory performance in aged Tg2576 mice. The exact mechanism by which blood exchange reduces amyloid pathology and improves memory is presently unknown, but measurements of Aβ in plasma soon after blood exchange suggest that mobilization of Aβ from the brain to blood may be implicated. Our results suggest that a target for AD therapy may exist in the peripheral circulation, which could open a novel disease-modifying intervention for AD.

The vasculature becomes dysfunctional with age, and cerebral small vessel disease is a catch-all category that includes a variety of different malfunctions in the biology of smaller blood vessels that act to reduce blood flow to the brain or damage brain tissue. In recent years, attention has turned to the drainage of cerebrospinal fluid from the brain, with the idea that failure of drainage with age contributes to a buildup of molecular waste and consequent pathology in the brain. The glymphatic system is one of the major paths of drainage, and here researchers provide evidence for its dysfunction to be involved in the cognitive decline observed in patients with cerebral small vessel disease.

Cerebral small vessel disease (CSVD) is common among older people. Cognitive impairment is one of the most important manifestations of CSVD. Vascular cognitive impairment and vascular dementia constitute the second most common cause of cognitive impairment. However, the factors causing cognitive impairment remain unknown. White matter lesions (WMLs) and lacunes, which are classical CSVD markers, are related to cognitive impairment in CSVD and could be used to predict cognitive impairment. However, in the clinic, some CSVD patients with mild WMLs have a severe cognitive impairment, which suggests that there are still some important factors that contribute to cognitive impairment in CSVD aside from traditional imaging markers and other imaging markers might enable predictions of cognitive impairment caused by CSVD.

Commonly, cognitive impairment in patients with CSVD occurs due to cerebral hypoperfusion or because other blood components permeate into the brain through a broken blood-brain barrier (BBB). Both of these situations are harmful to neurons and neuroglia. Recently, the glymphatic system was discovered. With the help of Aquaporin 4, cerebrospinal fluid (CSF) flow in the periarterial space enters the brain and becomes interstitial fluid (ISF). It was then drained orderly through the perivenous space, meningeal or olfactory mucosal lymphatics, cervical lymphatic vessel, and finally returned to the peripheral venous. This CSF-ISF exchange system is called the glymphatic system, and its main role includes metabolic product transportation and metabolic waste elimination.

In patients with Alzheimer's disease (AD) and animal models, dysfunction of the glymphatic system contributes to the deposition of amyloid-β and cognitive impairment. CSVD leads to arteriosclerosis and vascular pulsation, which are the driving forces of the glymphatic system. It is difficult to evaluate the glymphatic system in the human body directly. In 2017, based on diffusion tensor imaging (DTI), researchers proposed the DTI analysis along the perivascular space (ALPS) index to evaluate the glymphatic system function. To further explore the reason underlying cognitive impairment in patients with CSVD and identify other new imaging markers of cognitive impairment in patients with CSVD, we studied the relationship of the ALPS index and cognitive impairment in these patients.

We found that the ALPS index was independently linearly correlated with global cognitive function, executive function, attention function, and memory after adjusting for the aforementioned six risk factors or CSVD markers. Our results suggest that glymphatic system impairment is independently related to cognitive impairment in patients with CSVD.

Link: https://doi.org/10.3389/fnagi.2022.916633

The potential of stem cell therapy still lies ahead. The only outcome reliably achieved to date in human medicine is the reduction of chronic inflammation via transplantation of mesenchymal stem cells. The real goal for this field is, however, the replacement and enhanced performance of specific stem cell populations in order to produce regeneration that does not normally take place, or to restore youthful tissue maintenance in the old. That remains to be achieved in anything more than a preliminary way in even the most well studied stem cell populations, those of muscle, brain, and bone marrow.

In murine models, there have been some therapeutic successes reported when aged systems have an influx of stem cells with restored or robust function. One such study showed that ex-vivo treatment of aged muscle stem cells (MuSCs) with a small-molecule inhibitor and a culturing on a porous hydrogel substrate was able to restore potential to the aged MuSCs, and the improved potential was able to impart restored muscle repair when these cells were transplanted into injured, aged muscle. Another exciting study on aged MuSC rejuvenation recently reported that transplantation of aged MuSCs pulsed with transient expression of iPSC reprogramming factors was able to repair injured muscled from aged mice at a rate similar to young MuSCs. These data were also translated in human studies where aged human MuSCs were transiently reprogrammed and transplanted back to the aged donor and showed increased new tissue formation.

On the flip side of these very positive results of improved muscle repair from reprogrammed MuSCs in the aged environment, hematopoietic stem cell (HSC) transplants into aged mice did not have such promising results. In transplants of young, robust HSCs into aged recipient mice, studies report that the aged niche, where the donor stem cells home to in the bone marrow, have negative effects on the robust stem cells populations, altering the cell-intrinsic potential of the transplanted HSCs. Thus, in aged individuals, there may be complex interactions between intrinsic stem cell alterations and the systemic alterations that both need to be addressed for more effective stem cell therapies.

Harnessing the full potential of stem cells could lead to the mitigation of most aging phenotypes but, like most things worthwhile, we need to be patient to develop the most robust effects with these therapies. It will likely require the cooperation between multiple players-whether combinations of stem cell transplants or coordination between stem cell transplants and other pharmacological interventions. However, we may be just at the beginning of understanding these complex interplays.

Link: https://doi.org/10.1093/gerona/glac003

As noted by the authors of today's open access paper, there is ample evidence to show that double strand breaks in DNA occur during the normal activity of neurons, such as during the synaptic remodeling necessary to learning and memory. Evolution loves reuse, and few possibilities are ignored! This process of utilitarian double strand breaks appears to be used to ensure that nuclear DNA is spatially reconfigured in such a way as to ensure that certain genes are expressed for a time; recall that the pattern of gene expression at any given moment is very much a function of how the mass of nuclear DNA is packaged, which parts of it, and hence which gene sequences, are accessible at any given time to the machinery of transcription.

This is all very interesting, as stochastic DNA damage, such as double strand breaks, is thought to have a role in degenerative aging. But if the process is taking place on a regular basis during the normal function of neurons, that makes it harder to study in the context of aging and neurodegeneration. On the one hand, DNA damage can spread through tissues from stem cells, and this happens in the brain even given the long-lived nature of neurons. On the other hand, recent research has suggested that the process of repairing repeated double strand breaks can produce some of the epigenetic change of aging as a side-effect, due to depletion of molecules needed to maintain a youthful configuration of nuclear DNA. More research is needed to fill out this presently sparse sketch; important details are missing, and the present understanding of DNA damage in the brain is incomplete.

The Role of DNA Damage in Neural Plasticity in Physiology and Neurodegeneration

DNA damage is now widely implicated in aging and the pathophysiology of age-related neurodegenerative disorders, such as amyotrophic lateral sclerosis (ALS), Alzheimer's disease (AD), Huntington's disease (HD), and Parkinson's disease (PD). However, emerging evidence suggests that DNA damage and DNA repair are not only induced by pathological conditions. The same processes involved in neurodegeneration as we age are also involved in fundamental physiological functions of neurons that are related to neural plasticity. Hence, DNA damage and repair are associated with neural plasticity, implying an important role for these processes in neuronal function. Furthermore, in neurodegenerative diseases the selective death of specific groups of neurons is present. This suggests that the unique properties of neurons may contribute to selective neurodegeneration in pathophysiology.

Several studies have shown that neuronal activity generates double strand breaks (DSBs) in cultured neurons. A recent study concluded that DSBs are generated physiologically to resolve topological limitations to gene expression in neurons. Topoisomerase enzymes participate in the overwinding or underwinding of DNA and thus they manage DNA topological constraints. Neuronal activity produces DSBs at specific loci in vitro by topoisomerase IIβ (TopIIβ), in the promoters of early response genes (ERGs, also called immediate early genes, IEGs) that are crucial for experience-driven changes to synapses, learning, and memory. Interestingly, the expression patterns of ERGs in response to neuronal stimulation correlated well with the formation and repair of activity-induced DSBs, implying that generation of DSBs and their subsequent repair are essential steps for proper gene function. Furthermore, DSBs produced during neuronal excitation were repaired within 2 hours of the initial stimulus, suggesting that this process employs rapid DNA repair mechanisms such as non-homologous end joining (NHEJ).

Dysfunction in these processes of DNA damage and repair is also related to a decline in cognitive function and neuronal death in neurodegenerative diseases. However, human post-mortem tissues represent the end-point stage of the disease. Hence studies examining these tissues cannot be used to determine whether DNA damage has a primary or secondary role in pathogenesis. Future studies on the relationship between plasticity and DNA damage may provide a better understanding of the cellular processes that contribute to higher order brain functions.

Distinct groups of neurons are affected in different neurodegenerative diseases, such as motor neurons in ALS or neurons of the entorhinal cortex in AD, and these cells are specialized to perform specific functions. Given that DNA damage and repair are important for the unique functions of neurons, which in turn depend on their activation, it is possible that the interplay between DNA damage and neural plasticity is unique for specific groups of neurons. This could operate through the activation of specific genes by DNA damage, which would differ depending on the type of neurons involved and their associated functions. Therefore, a better understanding of the interplay between DNA damage and neural plasticity is required, as well as dysfunction in these processes in disease. In particular, the inclusion of specific neuronal types may reveal the causes of selective neuronal death in distinct neurodegenerative diseases.

To date, no previous studies have examined therapeutic strategies directed at DNA damage and repair in relation to aberrant neural plasticity. However, this approach has the potential to identify novel treatments for impaired cognitive functions in neurodegenerative diseases associated with excessive DNA damage.

The Longevity Prize initiative is, at least initially, a collaboration between VitaDAO, Foresight Institute, and the Methuselah Foundation. They are trying a different approach to the proven format of research prizes, a step by step progression in which smaller prizes are won in the process of defining concrete goals in medicine and biotechnology that will later receive larger prizes. It is an interesting and novel idea, like much of what orbits VitaDAO. The only way to see how well any novel idea works is to give it a try!

The longevity ecosystem is growing rapidly. But the problem is vast and we're running out of time. The longevity prize encourages novel approaches for turning back our aging clocks. You may be familiar with standard prize models that set a fixed amount to target a specific scientific goal with exact criteria. Those are great! This prize series is different. Its aim is to generate an avalanche of proposals, experiments, and collaborations on undervalued areas. This can include smaller bets growing into larger sums, innovating with novel prize voting mechanisms, or even a series of workshops or hackathons to develop promising ideas. Common to all these prize experiments is their goal to support a growing longevity ecosystem, connecting those who generate proposals for progress with those who want to help execute them, and drive high-trust collaboration toward solving them.

We love to collaborate. The first round of $180k in prizes was fundraised through Gitcoin, supported by community members, whose donations were matched by VitaDAO, Vitalik Buterin, and Stefan George.Thank you for your generous support! If you have an idea for a prize you'd like to sponsor, we'd love to hear from you!

One key problem with the prize model is that academics and biotechs will only perform experiments when they have the money in the bank. That's why our first round of prizes will be given out for hypothesis generation to define the second round of larger prizes. We would like to hear from you: what is the most promising but under-appreciated area of geroscience and longevity biotechnology that we should pursue? Review the literature (and you're welcome to include your own unpublished data), explain why this area is undervalued, generate a hypothesis for making progress, and propose an experiment to further investigate this approach. The more concrete, e.g. including people, resources, and time required for next steps, the better.

Up to $20,000 will be offered in prizes for this round! Finalists will be invited to present their proposal to the judges. Excellent proposals will be moved to the next phase, where they will be eligible for follow-on funding. The prize deadline is the end of 2022.

Link: https://www.longevityprize.com/

Medical imaging allows researchers to assess the burden of amyloid-β and tau deposits in the living brain. As noted here, it is the combination of both amyloid plaques and tau tangles that marks a greatly raised risk of the onset of cognitive decline and dementia, 20-fold higher in fact. This is a very large effect size, suggesting that the interaction of multiple mechanisms is the important driver of neurodegeneration in tauopathies such as Alzheimer's disease.

Do amyloid plaques and tau tangles destine a cognitively intact person to decline? Yes, according to researchers who report that cognitively normal older adults with plaques and tangles declined much faster than those without either pathology - and faster than those with only plaques. Over an average of 3.5 years of follow-up, people with plaques and tangles as measured by PET had a 15 to 20 times higher risk of developing mild cognitive impairment (MCI) or dementia. Other groups analyzing different cohorts appear to be finding the same thing; papers are under review. "This quick progression to MCI is clinically relevant because it tells us that amyloid and tau PET are predictive of imminent cognitive decline. To consider amyloid and tau PET positivity merely as a risk factor, and not manifest disease, may be an underestimation of its malignancy."

Researchers pooled data from 1,325 cognitively intact older adults from seven longitudinal research cohorts and divided them into groups based on their amyloid and tau PET scans: 843 had neither pathology, 328 had only amyloid (A+T-), 55 had amyloid with tau in the medial temporal lobe (A+T+MTL), and 65 had amyloid with tau in the neocortex as well (A+T+Neo). 80 percent of the neocortical-positive participants also had tangles in their MTL, as tau generally spreads from the MTL to the cortex. The researchers tracked scores on the modified preclinical Alzheimer cognitive composite 5 (mPACC5) and Mini-Mental State Exam (MMSE) for an average of 3.5 years after the PET scans. Biomarker-positive participants were an average of seven years older, and had slightly lower baseline MMSE scores, than their biomarker-negative counterparts. While controls held their ground on the mPACC5 and MMSE, A+T- participants slipped a tad and both A+T+ groups declined steeply.

People with plaques and tangles were likelier to develop MCI or dementia. Compared to controls, A+T- volunteers had a 2.5-fold higher risk of developing MCI, while people with A+T+MTL or A+T+Neo had 15 or 19 times higher risk, respectively. Twenty-one people progressed to all-cause dementia; half were A+T+Neo. They were a whopping 40 times likelier to develop dementia in this time frame than controls, while A+T+MTL people had a 5.5-fold higher risk. A+T- volunteers developed dementia at the same rate as controls.

Link: https://www.alzforum.org/news/research-news/destined-decline-plaque-tangle-combo-foretells-impairment

In today's open access paper, researchers discuss the link between the gut microbiome, chronic inflammation in aging, and the onset of age-related hearing loss due to hair cell death and destruction of axons connecting hair cells to the brain. It is definitively the case that changes in the balance of microbial populations in the intestine contributes to rising inflammation in older individuals. But how significant is this effect in comparison to other sources of chronic inflammation, such as excess visceral fat tissue, senescent cells, molecular waste and debris resulting from cell death and dysfunction due to other processes of aging, and so forth? It is very hard to answer that sort of question without fixing just the one contributing cause of inflammation in isolation, without affecting any of the others, and then see what happens. Identifying the mechanism is one thing, assessing its relative importance quite another.

That said, a study to determine whether or not the gut microbiome contributes significantly to age-related hearing loss could be started tomorrow, were there someone willing to put up the funds and manage the regulatory burden that attends even simple tests in humans. Gather a hundred aged volunteers in the early stages of age-related hearing loss, perform fecal microbiota transplants from young donors, and then assess the progression of their condition over the next five years or so. It is well established in animal models that fecal microbiota transplantation resets the gut microbiome to a youthful configuration for an extended period of time, reduces inflammation, improves health, and even extends life expectancy in short-lived species such as killifish. So why not try?

Age-Related Hearing Loss: The Link between Inflammaging, Immunosenescence, and Gut Dysbiosis

Age-related hearing loss (ARHL), or presbyacusis, is a type of sensorineural hearing loss that primarily affects the elderly. However, the age of onset, rate of decline, and severity of hearing loss vary widely. ARHL is the most common sensory disorder, with a high economic impact. The World Health Organization (WHO) estimates that by 2050, 2.5 billion people, predominantly over 60, will be living with some degree of hearing loss . Despite the high prevalence of this sensory disorder, there is a paucity of both preventative and treatment strategies other than prosthetic devices (hearing aids and cochlear implants).

Presbyacusis typically presents as bilateral, progressive, and irreversible. The increasing prevalence of presbyacusis may be attributable to environmental factors, notably noise exposure and the rise in metabolic diseases. This sensory disorder can be characterised by reduced hearing sensitivity and speech understanding in background noise, slowed central processing of acoustic information, and impaired localisation of sound sources. Hearing loss affects high frequencies initially and eventually spreads to lower frequencies involved in speech understanding. Untreated hearing impairment contributes to social isolation, loss of self-esteem, depression, and cognitive decline. Even mild levels of hearing loss increase the long-term risk of cognitive decline and dementia.

ARHL has a complex pathophysiology linked to genetic risk factors that determine the rate and extent of cochlear degeneration. However, the severity of the hearing loss is also influenced by previous otological diseases, chronic illnesses, cumulative noise exposure, use of ototoxic drugs, and lifestyle. Moreover, this condition has been associated with numerous comorbidities, including dementia, frailty, Alzheimer's disease, and type II diabetes. A common trait of these disorders is chronic inflammation in target organs.

Various stimuli can sustain inflammaging, including pathogens, cell debris, nutrients, and gut microbiota. As a result of ageing, the immune system can become defective, leading to the accumulation of unresolved inflammatory processes in the body. Gut microbiota plays a central role in inflammaging because it can release inflammatory mediators and crosstalk with other organ systems. A proinflammatory gut environment associated with ageing could result in a leaky gut and the translocation of bacterial metabolites and inflammatory mediators to distant organs via the systemic circulation. Here, we postulate that inflammaging, as a result of immunosenescence and gut dysbiosis, accelerates age-related cochlear degeneration, contributing to the development of ARHL. Age-dependent gut dysbiosis was included as a hypothetical link that should receive more attention in future studies.

Cancers employ a range of mechanisms to subvert and suppress the activities of immune cells attempting to destroy cancerous cells. One issue that appears inherent to T cells of the adaptive immune system, however, is the exhaustion that sets in following repeated exposure to molecules present on cancerous cells or in the tumor environment that trigger T cell receptors. This is how T cells identify targets. Individual T cells are initially effective at killing cancerous cells after T cell receptor interactions, but then become increasingly less effective over time. Can this be prevented? Potentially yes, but the processes involved are not simple, as researchers here explain.

The T cells found in the human immune system are some of the front-line soldiers in recognizing, attacking, and directing the fight against foreign cells and molecules. They recognize their opponents-from pathogens to cancers-through unique receptors on their surfaces. When a molecule binds to one of these T cell receptors, it activates the T cell, which begins producing a variety of immune molecules. Scientists have long known, however, that this response diminishes over time. When a T cell receptor is activated continuously for weeks or months, the cell gradually produces fewer immune molecules and becomes less effective at destroying a cancer or pathogen.

Researchers long thought that T cell exhaustion might be driven by just a few genes that ended up permanently switched on or off after chronic receptor activation. But in recent years, studies on exhausted T cells began to hint that the cells undergo more major rewiring, with thousands of genes turned on or off. The genes found to be linked to T cell exhaustion helped support this idea; the most critical genes were epigenetic regulators, which remodel the physical structure of DNA to turn on or off hundreds of genes at once. These findings help explain how completely different an exhausted T cell is from other functional T cell states.

The researchers carried out detailed analyses of the epigenetic regulators identified in their screen to understand how they interacted with each other, and homed in on a few particularly important genes. Then, they used CRISPR/Cas9 gene editing to further study the effects of blocking individual genes in T cells that were delivered into living mice. They showed that in mice with tumors, blocking the gene Arid1a led to higher levels of T cells and smaller tumors after just 15 days. Moreover, at a molecular level, the T cells from those mice more closely resembled healthy, persistent immune cells than exhausted, less active T cells.

Link: https://gladstone.org/news/scientists-prevent-exhaustion-cancer-fighting-t-cells

A growing body of evidence implicates the changing behavior of microglia in the aging of the brain and onset of neurodegeneration. Microglia are analogous to macrophages, innate immune cells unique to the central nervous system. They adopt different packages of behaviors, called polarizations, in response to circumstances. With age, microglia tend towards an inflammatory polarization, triggered by systemic inflammatory signaling and molecular debris characteristic of aged tissues. Further, an increasing number of microglia become senescent, producing pro-inflammatory signals that contribute further to the inflammation of brain tissue and dysfunction of other microglia. Yet for all this, microglia are also protective in function, at least until they are overwhelmed by the aged environment and begin contributing to its decline rather than fighting against it.

Neuroinflammation is a hallmark of many neurodegenerative diseases (NDs) and plays a fundamental role in mediating the onset and progression of disease. Microglia, which function as first-line immune guardians of the central nervous system (CNS), are the central drivers of neuroinflammation. Numerous human postmortem studies and in vivo imaging analyses have shown chronically activated microglia in patients with various acute and chronic neuropathological diseases. While microglial activation is a common feature of many NDs, the exact role of microglia in various pathological states is complex and often contradictory. However, there is a consensus that microglia play a biphasic role in pathological conditions, with detrimental and protective phenotypes, and the overall response of microglia and the activation of different phenotypes depends on the nature and duration of the inflammatory insult, as well as the stage of disease development.

This review provides a comprehensive overview of current research on the various microglia phenotypes and inflammatory responses in health, aging, and NDs, with a special emphasis on the heterogeneous phenotypic response of microglia in acute and chronic diseases such as hemorrhagic stroke (HS), Alzheimer's disease (AD), and Parkinson's disease (PD). The primary focus is translational research in preclinical animal models and bulk/single-cell transcriptome studies in human postmortem samples. Additionally, this review covers key microglial receptors and signaling pathways that are potential therapeutic targets to regulate microglial inflammatory responses during aging and in NDs. Additionally, age-, sex-, and species-specific microglial differences will be briefly reviewed.

Link: https://doi.org/10.3390/cells11132091

We are as old as our arteries, as the saying goes. The aging of the vasculature impacts all of the tissues in the body, and there are many distinct mechanisms by which this happens. The loss of capillary density reduces the supply of oxygen and nutrients to energy-hungry tissues such as muscles and the brain. The stiffening of vessels leads to hypertension and pressure damage to delicate tissues throughout the body. The leakage of the blood-brain barrier allows unwanted molecules and cells to provoke chronic inflammation in the brain. The fatty deposits of atherosclerosis narrow and weaken blood vessels, further reducing blood flow and allowing harmful rupture and blockage in vessels large and small.

A broad range of underlying mechanisms of aging contribute to the vascular dysfunction in old people. Effective repair and rejuvenation will not be achieved by just one therapy, or one class of therapies. Chronic inflammation, disruptive of vascular smooth muscle activity, must be addressed, such as via targeted destruction of senescent cells. The cross-linking that stiffens blood vessel walls must be reversed. The localized deposits of cholesterol characteristic of atherosclerosis must be cleared. And so on and so forth. Vascular aging is one of the better examples to clearly demonstrate that the manifestations of aging are the sum of many underlying processes. Incremental gains will be made by each new treatment that targets one of those processes, but all must be dealt with in order to achieve complete rejuvenation.

Aging of Vascular System Is a Complex Process: The Cornerstone Mechanisms

Changes in arterial structure and function accompanying aging lead to an increased risk of cardiovascular diseases (CVD). Thus, understanding the mechanisms by which age affects the vascular system can help to avoid altogether or to reduce the high risk of developing cardiovascular diseases in elderly people. Several new (preliminary) clinical studies have found that the most important vascular changes occur with aging and described 2 key traits: (1) generalized endothelial dysfunction and (2) stiffness of the central artery. As for generalized endothelial dysfunction, vascular aging alters the endothelium function and the cells that cover the lumen of blood vessels. Endothelial dysfunction includes a decrease in vasodilatory and antithrombotic properties, with an elevation in oxidative stress and inflammatory cytokines, which favor atherogenesis and thrombosis and predispose to cardiovascular diseases. Both human and experimental studies have proven a reduction in the bioavailability of nitric oxide (NO), a major mediator of vasorelaxation and antiatherogenic processes that are the foundation of age-related endothelial dysfunction.

With aging, the elasticity of arteries, especially the aorta, decreases. This leads to arterial stiffness, which is, at least in part, the result of gradual fragmentation and loss of elastin fibers and accumulation of stiffer collagen fibers. The risk of hypertension and the range of various disorders are tightly linked to increased arterial stiffness. Vascular calcification is specific for aging and vascular stiffness. The development of calcification is accelerated in patients with hypertension, diabetes mellitus, and other disorders. However, an exact mechanism linking calcification with aging is still unclear.

During the process of aging, a shift towards the pro-inflammatory phenotype with elevated expression of inflammatory cytokines, adhesion molecules, and chemokines from endothelial cells (ECs) has been observed. These pro-inflammatory cytokines include interleukin (IL)-6, IL-1β, cellular adhesion molecules, tumor necrosis factor-alpha (TNF-α), and monocyte chemoattractant protein-1. Prolonged exposure to TNF-α leads to early aging of the endothelium, which can be avoided by suppressing the activation of NF-KB. This fact gives rise to the hypothesis that inflammation leads to premature aging of the endothelium. Thus, human aging is a chronic, systemic and low-grade pro-inflammatory condition, and this phenomenon has been defined as "inflammaging".

All body systems age, lose their performance, and structural disorders accumulate. The cardiovascular system is no exception. And it is cardiovascular diseases that occupy a leading position as a cause of death, especially among the elderly. The aging of the cardiovascular system is well described from a mechanical point of view. Moreover, it is known that at the cellular level, a huge number of mechanisms are involved in this process, from mitochondrial dysfunction to inflammation. It is on these mechanisms, as well as the potential for taking control of the aging of the cardiovascular system, that we focused on in this review.

While the destination is the same, blindness due to a breakdown of retinal structure and function, not all cases of age-related macular degeneration start in the same way. There are notable differences between patients in the early stages of the condition. Researchers here suggest that vascular dysfunction drives one form of macular degeneration, reduced blood flow to the retina leading to the aggregation of molecular waste and consequent cell death. This is one example of many: cardiovascular aging contributes indirectly to a great many of the common age-related conditions.

Age-related macular degeneration (AMD) is the leading cause of visual impairment and blindness in people over 65 years old and is the result of damage to the central area of the retina called the macula, which is responsible for reading and driving vision. One major form of early AMD is called drusen, where small yellow cholesterol deposits form in a layer under the retina. They can deprive the retina of blood and oxygen, leading to vision loss. Drusen formation can be slowed by appropriate vitamin supplementation.

The other major form of early AMD is the presence of subretinal drusenoid deposits (SDD), which is lesser known, and requires high-tech retinal imaging to detect. These deposits are also made of fatty lipids and other materials, but form in a different layer beneath the light sensitive retina cells, where they are also associated with vision loss. Currently, there is no known treatment for SDD.

Researchers analyzed 126 patients with AMD and found that patients with cardiovascular disease or stroke were three times more likely to have SDD than patients without. The researchers suggested that the underlying heart and vascular disease likely compromises blood circulation in the eye, leading to the SDDs beneath the retina and ultimately causing vision loss and blindness. "We believe poor ocular circulation that causes SDDs is a manifestation of underlying vascular disease. This study further demonstrates that AMD is not a single condition or an isolated disease, but is often a signal of systemic malfunction which could benefit from targeted medical evaluation in addition to localized eye care."

Link: https://www.mountsinai.org/about/newsroom/2022/blinding-eye-disease-is-strongly-associated-with-heart-disease-and-stroke

Researchers here provide evidence for one particular oral bacterial species associated with gum disease to provoke changes in microglia population in the brain, leading to chronic inflammation and acceleration of neurodegenerative conditions. The correlation between periodontal disease and neurodegenerative diseases such as Alzheimer's disease is well known, and there are established pathways and mechanisms for oral bacteria to deliver pro-inflammatory compounds into the body. However, some studies suggest that the contribution of gum disease to the incidence of neurodegenerative conditions is modest at best, in comparison to other factors.

Fusobacterium nucleatum (F. nucleatum) is a common type of bacteria that proliferates in periodontal disease. F. nucleatum can also generate severe generalized inflammation, which is a symptom of many chronic diseases including type 2 diabetes and Alzheimer's disease. The latest research, done in mice, shows that F. nucleatum results in an abnormal proliferation of microglial cells, which are immune cells in the brain that normally remove damaged neurons and infections and help maintain the overall health of the central nervous system. This over-supply of microglial cells also created an increased inflammatory response, the researchers found. Chronic inflammation or infection is believed to be a key determinant in the cognitive decline that occurs as Alzheimer's disease progresses.

Possible links between periodontal disease and Alzheimer's have been posited by scientists in the past. While the new research does not show that F. nucleatum-related periodontal disease leads directly to Alzheimer's disease, the new study suggests that periodontal disease caused by F. nucleatum and left untreated or poorly treated could exacerbate symptoms of Alzheimer's disease. Conversely, treating periodontal disease effectively in those who have early-stage Alzheimer's could potentially slow Alzheimer's progression.

Link: https://now.tufts.edu/2022/07/11/studying-link-between-gum-disease-and-alzheimers-disease

A growing body of evidence points to the role of senescent supporting cells in the brain as a meaningful cause of neurodegenerative conditions. In this context, a number of research groups have focused on microglia, the innate immune cells of the brain. Microglia become increasingly overactive and inflammatory with age, stimulated by features of the aged tissue environment that resemble the molecular signals of pathogens or cancerous cells. A significant number of microglia become senescent, and do so at a time when the immune system as a whole becomes less competent in its task of clearing senescent cells in a timely manner. Senescent cells secrete a pro-inflammatory mix of signals that is harmful to surrounding tissue.

Inflammation in the brain is coming to be seen as a central pillar of neurodegenerative conditions, and the research community is in the process of testing a broad range of approaches to suppression of inflammation. Most, however, involve interference in specific inflammatory signals that block both excessive and necessary inflammation, and thus reduce the efficacy of the immune response. Targeted removal of senescent cells via senolytic treatments is (more or less) the only present approach that can only eliminate the excessive and harmful inflammatory signaling. Given the animal evidence for senolytic therapies to greatly improve pathology in animal models, and the availability of cheap small molecule senolytics that cross the blood-brain barrier, far more human trials should be underway than is presently the case.

Photoinduced elimination of senescent microglia cells in vivo by chiral gold nanoparticles

Parkinson's disease (PD) is an age-related brain disease that is associated with motivation and cognitive disorders and the assembly of alpha-synuclein (α-syn); there is no effective therapeutic treatment for this condition. Along with tissue dysfunction, the typical senescence-associated secretory phenotype is significantly characterized by the generation of interleukin-6 (IL-6) and interleukin-1β (IL-1β). Indeed, the accumulation of senescent cells is associated with a range of age-related diseases as well as neurodegenerative diseases. However, it is still unclear how senescence in the brain contributes to PD and what role it might play in therapeutic strategies of PD.

It had been reported that senescent cells could give rise to local and systemic inflammation and contribute to neurodegeneration in neurodegeneration diseases like PD. In addition, direct exposure to amyloid-β (Aβ) was shown to cause senescence in oligodendrocyte precursor cells (OPCs), and the clearance of OPCs by senolytic therapy alleviated Aβ-associated inflammation and restored cognitive deficits in Alzheimer's disease mice, thus illustrating the potential for senescence clearance to be used in clinical practice. Moreover, senescent cells play a role in the initiation and progression of tau-mediated disease, and targeting of senescent cells may provide a therapeutic avenue for the treatment of such pathologies. Therefore, eliminating senescent cells may hold therapeutic promise for alleviating the symptoms of PD.

In this study, chiral gold nanoparticles (NPs) with different helical directions were synthesized to selectively induce the apoptosis of senescent cells under light illumination. By modifying anti-B2MG and anti-DCR2 antibodies, senescent microglia cells could be cleared by chiral NPs without damaging the activities of normal cells under illumination. Mechanistic studies revealed that the clearance of senescent cells was mediated by the activation of the Fas signaling pathway. The in vivo injection of chiral NPs successfully confirmed that the elimination of senescent microglia cells in the brain could further alleviate the symptoms of PD mice in which the alpha-synuclein (α-syn) in cerebrospinal fluid decreased from 83.83 ± 4.76 ng/mL to 8.66 ± 1.79 ng/mL and the pathological symptoms of the PD mice were greatly improved after two months of treatment.

Cerebral small vessel disease is the name given to the manifestation and consequences of a broad grab-bag of pathologies that affect the capillaries and other small blood vessels of the brain. That includes loss of elasticity, loss of capillary density, amyloid accumulation, leakage of the blood-brain barrier, and other similar problems leading to greater damage of tissues around blood vessels and a reduced blood supply to critical areas of the brain. Researchers here mount the argument that this is largely a consequence of the chronic inflammation of aging, a hypothesis that will be assessed in the years ahead by the widespread deployment of senolytic therapies, capable of removing senescent cells and their pro-inflammatory signaling from the body and brain.

Cerebral small vessel disease (CSVD) is one of the most important causes of vascular dementia. Immunosenescence and inflammatory response, with the involvement of the cerebrovascular system, constitute the basis of this disease. Immunosenescence identifies a condition of deterioration of the immune organs and consequent dysregulation of the immune response caused by cellular senescence, which exposes older adults to a greater vulnerability. A low-grade chronic inflammation status also accompanies it without overt infections, an "inflammaging" condition. The correlation between immunosenescence and inflammaging is fundamental in understanding the pathogenesis of age-related CSVD (ArCSVD).

The production of inflammatory mediators caused by inflammaging promotes cellular senescence and the decrease of the adaptive immune response. Vice versa, the depletion of the adaptive immune mechanisms favours the stimulation of the innate immune system and the production of inflammatory mediators leading to inflammaging. Furthermore, endothelial dysfunction, chronic inflammation promoted by senescent innate immune cells, oxidative stress and impairment of microglia functions constitute, therefore, the framework within which small vessel disease develops: it is a concatenation of molecular events that promotes the decline of the central nervous system and cognitive functions slowly and progressively.

Because the causative molecular mechanisms have not yet been fully elucidated, the road of scientific research is stretched in this direction, seeking to discover other aberrant processes and ensure therapeutic tools able to enhance the life expectancy of people affected by ArCSVD. Although the concept of CSVD is broader, this manuscript focuses on describing the neurobiological basis and immune system alterations behind cerebral aging. Furthermore, the purpose of our work is to detect patients with CSVD at an early stage, through the evaluation of precocious MRI changes and serum markers of inflammation, to treat untimely risk factors that influence the burden and the worsening of the cerebral disease.

Link: https://doi.org/10.3390/ijms23137136

It is becoming increasingly clear that chronic inflammation is important in the major neurodegenerative conditions, such as Alzheimer's disease. Animal studies suggest that a sizable portion of that inflammation is caused by the activities of activated and senescent microglia, innate immune cells of the brain. Both the use of CSF1R inhibitors (such as pexidartinib) to clear all microglia and the use of senolytics (such as the dasatinib and quercetin combination) to selectively destroy senescent microglia have shown benefits in animal models of neurodegeneration and brain injury. Interestingly, dasatinib is both a senolytic and a CSF1R inhibitor. Since these drugs are readily available and already used in human medicine, it would be quite feasible to run clinical trials, given the funding and the will to do so.

Alzheimer's disease (AD) is a common, progressive, and devastating neurodegenerative disorder that mainly affects the elderly. Microglial dysregulation, amyloid-beta (Aβ) plaques, and intracellular neurofibrillary tangles play crucial roles in the pathogenesis of AD. In the brain, microglia play roles as immune cells to provide protection against virus injuries and diseases. They have significant contributions in the development of the brain, cognition, homeostasis of the brain, and plasticity. Multiple studies have confirmed that uncontrolled microglial function can result in impaired microglial mitophagy, induced Aβ accumulation and tau pathology, and a chronic neuroinflammatory environment.

In the brain, most of the genes that are associated with AD risk are highly expressed by microglia. Although it was initially regarded that microglia reaction is incidental and induced by dystrophic neurites and Aβ plaques, nonetheless, it has been reported by genome-wide association studies that most of the risk loci for AD are located in genes that are occasionally uniquely and highly expressed in microglia. This finding further suggests that microglia play significant roles in early AD stages and they be targeted for the development of novel therapeutics.

In this review, we have summarized the molecular pathogenesis of AD, microglial activities in the adult brain, the role of microglia in the aging brain, and the role of microglia in AD. We have also particularly focused on the significance of targeting microglia for the treatment of AD.

Link: https://doi.org/10.3390/molecules27134124

The brain generates half a liter of cerebrospinal fluid every day, which circulates through the brain and is then drained from the brain via pathways that, for the most part, have only recently been studied in any great depth. Yet cerebrospinal fluid drainage is most likely critical to maintaining the health of the brain via removal of metabolic waste. All of the drainage channels discovered to date atrophy in some way with aging, and there is evidence for several to be particularly degraded in Alzheimer's disease.

Today's open access paper revises what is known of one potential drainage path, showing that it is likely more relevant than previously thought in this context. Like other recent work on the glymphatic system, it illustrates that the brain remains one of the least well explored structures in the body, and that we cannot take present consensus for granted when it comes to many of the fine details of anatomy and function.

To what degree is neurodegeneration a matter of failed clearance of waste from the brain? The most practical way to find out is to restore cerebrospinal fluid drainage in old people, an accomplishment that still lies a fair way in the future, given the present state of research. Leucadia Therapeutics will soon enough trial an approach to restore drainage through the cribriform plate, but this only drains a small portion of the brain, the olfactory bulb where Alzheimer's disease begins. Other approaches targeting the broader drainage of the brain will be needed in order to treat more advanced stages of neurodegenerative disease.

Periarteriolar spaces modulate cerebrospinal fluid transport into brain and demonstrate altered morphology in aging and Alzheimer's disease

Cerebrospinal fluid (CSF) imparts neurorestorative functions, serving unique roles in development, immunity, and brain maintenance. It exchanges with brain interstitial fluid (ISF) by traversing a brain-wide network of perivascular spaces (PVS). Notably, CSF-ISF exchange has been demonstrated to facilitate the clearance of metabolic brain waste, such as β-amyloid. PVS are often regarded as Virchow-Robin spaces (VRS), yet the anatomy and boundaries of these spaces have never been clearly depicted. Indeed, original descriptions disputed VRS structure, although subsequent literature generally summarizes them as homogeneous perivascular reflections comprised of simple pial membranes. Some have suggested that CSF crosses pial membranes to enter PVS by percolating through pial pores that localize to adventitia of leptomeningeal vessels. However, others argue against the existence of PVS and the localization of associated pial pores.

Whereas these theories form the bases for current PVS models, anatomic evidence remains limited and little work has been published since the time of early PVS descriptions. Surprisingly few investigations have comprehensively and systematically evaluated the morphology of pia mater or the fluid pathways next to cerebral vessels, and discrepant reporting has resulted in an abundance of nomenclatures and partial anatomic descriptions. Given inconsistent interpretations, this study was undertaken with the aim of elucidating pial and PVS structure and tracer movement patterns at cerebral cortical surfaces in mice.

We show that pia is perforated and permissive to PVS fluid flow. Furthermore, we demonstrate that pia is comprised of vascular and cerebral layers that coalesce in variable patterns along leptomeningeal arteries, often merging around penetrating arterioles. Heterogeneous pial architectures form variable sieve-like structures that differentially influence cerebrospinal fluid (CSF) transport along PVS. Additionally, pial layers atrophy with age. Old mice also exhibit areas of pial denudation that are not observed in young animals, but pia is unexpectedly hypertrophied in a mouse model of Alzheimer's disease. Moreover, pial thickness correlates with improved CSF flow and reduced β-amyloid deposits in PVS of old mice.

In conclusion, we show that PVS morphology in mice is variable and that the structure and function of pia suggests a previously unrecognized role in regulating CSF transport and amyloid clearance in aging and disease.

We humans are longer-lived than our near primate cousins, and this is a comparatively recent development in evolutionary time. It is thought that this longevity arises from our greater intelligence and culture. When grandparents can contribute to the reproductive success of grandchildren, there is a selection pressure favoring mechanisms that allow for individual survival to older ages than would otherwise be the case. Chimpanzees do not have sufficient intelligence and culture for grandparents to greatly influence the success of their grandchildren, natural selection does not operate as strongly on the shape of later life, and thus chimpanzees are not as long-lived as humans.

According to long-standing canon in evolutionary biology, natural selection is cruelly selfish, favoring traits that help promote reproductive success. However, by the age fertility ceases, the story goes that selection becomes blind to what happens to our bodies. After the age of menopause, our cells are more vulnerable to mutations. In the vast majority of animals, this usually means that death follows shortly after fertility ends. Which puts humans (and some species of whale) in a unique club: animals that continue to live long after their reproductive lives end. How is it that we can live decades in selection's shadow? In most animals, including chimpanzees - our closest primate brethren - this link between fertility and longevity is very pronounced, where survival drops in sync with the ability to reproduce. Meanwhile in humans, women can live for decades after their ability to have children ends.

One of the leading ideas for human longevity is called the Grandmother Hypothesis - the idea that, through their efforts, maternal grandmothers can increase their fitness by helping improve the survival of their grandchildren, thereby enabling their daughters to have more children. Such fitness effects help ensure that the grandmother's DNA is passed down. In a new paper, researchers take the kernel of that idea - intergenerational transfers, or resource sharing between old and young - and show that it has played a fundamental role in the force of selection at different ages. Food sharing in non-industrial societies is perhaps the most obvious example.

"In our model, the large surplus that adults produce helps improve the survival and fertility of close kin, and of other group members who reliably share their food, too. Viewed through the lens of food production and its effects, it turns out that the indirect fitness value of adults is also highest among reproductive-aged adults. But using demographic and economic data from multiple hunter-gatherers and horticulturalists, we find that the surplus provided by older adults also generates positive selection for their survival. Once you take into account that elders are also actively involved in helping others forage, then it adds even more fitness value to their activity and to them being alive."

In contrast, chimpanzees - who represent our best guess as to what humans' last common ancestor may have been like - are able to forage for themselves by age 5. However, their foraging activities require less skill, and they produce minimal surplus. Even so, the authors show that if a chimpanzee-like ancestor would share their food more widely, they could still generate enough indirect fitness contributions to increase the force of selection in later adulthood. "What this suggests is that human longevity is really a story about cooperation. Chimpanzee grandmothers are rarely observed doing anything for their grandkids."

Link: https://www.news.ucsb.edu/2022/020677/importance-elders

Researchers here produce evidence to suggest that senescent cells are involved in the pathology of ischemic stroke to a significant degree. Clearing these cells in hours and days following a stroke may act to reduce the damage resulting from a temporary loss of blood flow to areas of the brain. This is a proposition that can be readily tested in animal models of induced stroke, using senolytic therapies that cross the blood-brain barrier, such as the dasatinib and quercetin combination, so we may hear more on this topic in the near future.

Aging is a major risk factor for cerebral infarction. Since cellular senescence is intrinsic to aging, we postulated that stroke-induced cellular senescence might contribute to neural dysfunction. Adult male Wistar rats underwent 60-minute middle cerebral artery occlusion and were grouped according to 3 reperfusion times: 24 hours, 3, and 7 days. The major biomarkers of senescence: 1) accumulation of the lysosomal pigment, lipofuscin; 2) expression of the cell cycle arrest markers p21, p53, and p16INK4a; and 3) expression of the senescence-associated secretory phenotype cytokines interleukin-6 (IL-6), tumor necrosis factor α (TNF-α), and interleukin-1β (IL-1β) were investigated in brain samples.

Lipofuscin accumulation was scarce at the initial stage of brain damage (24 hours), but progressively increased until it reached massive distribution at 7 days post-ischemia. Lipofuscin granules (aggresomes) were mainly confined to the infarcted areas, that is parietal cortex and adjacent caudate-putamen, which were equally affected. The expression of p21, p53, and p16INK4a, and that of IL-6, TNF-α, and IL-1β, was significantly higher in the ischemic hemisphere than in the non-ischemic hemisphere. These data indicate that brain cell senescence develops during acute ischemic infarction and suggest that the acute treatment of ischemic stroke might be enhanced using senolytic drugs.

Link: https://doi.org/10.1093/jnen/nlac048

Correlations have been found between infectious disease and incidence of neurodegenerative conditions. The dominant hypothesis is that microglia, innate immune cells of the brain, are made more inflammatory by infection, and the resulting chronic inflammation in brain tissue produces dysfunction that contributes to neurodegeneration. The role of microglia in the onset and progression of neurodegenerative conditions is studied more generally as well, as these cells react to signs of damage in aging tissue in much the same way as they react to infection. Further, microglia also enter a state of cellular senescence in increasing numbers with age, becoming highly pro-inflammatory.

A sizable fraction of senescent microglia can be removed by senolytic treatments that pass the blood-brain barrier, such as the dasatinib and quercetin combination, and this has shown benefits in animal models of neurodegeneration. Equally, microglia can be cleared completely from the brain by blocking CSF1R. A new population of microglia is produced and replaces the old within a few weeks, lacking the damage and dysfunction of their predecessors. This too has been shown to produce benefits in animal models of neurodegeneration.

Microglial Priming in Infections and Its Risk to Neurodegenerative Diseases

Infections of different etiologies, neurotropic or not, have been associated with acute and long-term neurological consequences. These consequences involve cognitive decline and behavioral disorders such as depression and anxiety. The main cause of these sequelae is an inflammatory condition in the central nervous system (CNS) characterized by an increase in pro-inflammatory mediators secreted by glial cells, such as microglia and astrocytes.

Microglia, which has long been described as a resident immune cell in the CNS, is currently considered an essential and versatile cell, having well-defined roles in maintaining neuronal networks, supporting synaptic plasticity, repairing injuries, and participating in the inflammatory process. Microglial cells express pattern recognition receptors (PRRs) that recognize molecules known as pathogen-associated molecular pattern (PAMP) molecules and damage-associated molecular patterns (DAMPs). During infection, irrespective of whether the pathogen can invade the CNS, the microglia will respond quickly by altering its state. Once confronted with stimuli, microglia induce and modulate a broad spectrum of molecular and cellular responses in an attempt to eradicate the pathogen.

In recent years, several studies have shown the involvement of the microglial inflammatory response caused by infections in the development of neurodegenerative diseases. This has been associated with a transitory microglial state subsequent to an inflammatory response, known as microglial priming, in which these cells are more responsive to stimuli. Thus, systemic inflammation and infections induce a transitory state in microglia that may lead to changes in their state and function, making priming them for subsequent immune challenges.

Thus, repeated infectious processes can act as a second hit and trigger a response in the primed microglia. However, it is important to emphasize that the aging process itself can be considered a second hit. It was shown that early postnatal infection of rats with LPS combined with the aging process resulted in less successful cognitive aging in these animals. Aging is a risk factor for the development of many neurodegenerative diseases because the natural aging process includes functional and structural changes within the brain. Among these changes is immune system dysfunction, which generates a low-grade chronic pro-inflammatory condition called inflammaging. Considering that microglia are long-lived cells and are repeatedly exposed to infections during a lifetime, microglial priming may not be beneficial, as it may contribute indirectly to neurodegenerative disorders.

A negligibly senescent species exhibits little evidence of age-related degeneration or increased mortality risk over much of its life span. The term is becoming a little overused, attached to species that are merely resilient rather than exceptional, but it nonetheless appears that some higher animals, such as naked mole-rats, age little until very late life. Further, there is very good evidence for some lower animals, such as hydra, to be functionally immortal. Are all of the species thought to exhibit minimal degenerative aging in fact doing so, however? Researchers here argue that much of the evidence for negligible senescence gathered from wild populations suffers from methodological flaws, and that these species are not in fact negligibly senescent.

Negligible or negative senescence occurs when mortality risk is stable or decreases with age, and has been observed in some wild animals. Age-independent mortality in animals may lead to an abnormally long maximum individual lifespans and be incompatible with evolutionary theories of senescence. The reason why there is no evidence of senescence in these animals has not been fully understood. Recovery rates are usually very low for wild animals with high dispersal ability and/or small body size (e.g., bats, rodents, and most birds). The only information concerning senescence for most of these species is the reported lifespan when individuals are last seen or caught.

We deduced the probability density function of the reported lifespan based on the assumption that the real lifespan corresponding to Weibull or Gompertz distribution. We show that the magnitude of the increase in mortality risk is largely underestimated based on the reported lifespans with low recovery probability. The risk of mortality can aberrantly appear to have a negative correlation with age when it actually increases with increasing lifespan. We demonstrated that the underestimated aging rate for wild animals with low recovery probability can be generalizable to any aging models.

Our work provides an explanation for the appearance of negligible senescence in many wild animals. Humans attempt to obtain insights from other creatures to better understand our own biology and its gain insight into how to enhance and extended human health. Our advice is to take a second glance before admiring the negligible senescence in other animals. This ability to escape from senescence is possibly only as beautiful illusion in animals.

Link: https://doi.org/10.1002/ece3.8970

Researchers here report that an epidemiological study population that practices long term intermittent fasting suffered a lesser severity and lower mortality rate in the early stages of the COVID-19 pandemic. The SARS-CoV-2 virus produces mortality via runaway inflammatory signaling, and people with a greater burden of chronic inflammation, such as through age or obesity, are less resilient. Intermittent fasting lowers inflammatory signaling, but it also produces a range of other benefits that improve resistance to infection. Further, it may be the case that the ability to fast on a schedule for decades selects for people who are more conscientious and health-minded, and who better cope with infectious disease of all sorts as a result - but the biochemistry is certainly interesting.

Fasting modifies energy utilisation by consuming glucose and glycogen, inducing gluconeogenesis, and subsequently activating ketogenesis. In the switch to ketosis during fasting, circulating levels of fatty acids, including linoleic acid, increase. Intriguingly, linoleic acid tightly binds to the spike protein of SARS-CoV-2, the cause of COVID-19. The attachment of linoleic acid to the spike reduces the affinity of SARS-CoV-2 for ACE2. An acute rise in linoleic acid while a person is fasting, thus, provides a direct mechanism for fasting to acutely reduce the severity of COVID-19.

In terms of chronic protection from severe outcomes of infection, the multifaceted protein galectin-3 was increased, independent of weight change, by low-frequency intermittent fasting in the 6-month Weekly One-Day Water-only Fasting Interventional (WONDERFUL) Trial. Galectin-3 modulates inflammation with proinflammatory actions during acute infection and anti-inflammatory functions when infection resolves. It minimises risk from chronic metabolic disorders (eg, diabetes), and is elevated in patients with diabetes and heart failure (HF), perhaps as a protective mechanism to reduce risk. Importantly, galectin-3 directly binds to a wide variety of pathogens, activates the innate immune system, impacts respiratory infections, increases expression of human genes encoding proteins with antiviral capacities and inhibits viral replication. Given the wide array of pathogens affected by galectin-3, it may also limit SARS-CoV-2 infection. The chronic increase of galectin-3 by intermittent fasting may, thus, provide a mechanistic link in which long-term participation in fasting could reduce COVID-19 severity.

Previously, routine periodic fasting was associated with lower risk of coronary artery disease (CAD), lower risk of type 2 diabetes, and - in patients with a more than 42-year history of fasting - improved longitudinal outcomes including greater survival and lower risk of incident HF. These associations may result from various mechanisms not related to weight loss. Such risk reductions by fasting of diagnoses that exacerbate the severity of COVID-19 (eg, diabetes, CAD and HF) may indirectly reduce COVID-19 severity, providing a possible third biological mechanism for fasting-induced protection from severe COVID-19 outcomes.

Link: https://doi.org/10.1136/bmjnph-2022-000462

There are many ways in which biological data can be processed via machine learning techniques to produce clocks that assess the burden of aging. Today's open access paper draws a distinction between aging clocks, which provide information on biological age, and mortality timers, which provide information on risk of death. Aging affects everything in the body, and all aspects of physiology and cellular biochemistry undergo at least some change. So epigenetic marks on the genome, levels of transcription of various genes, circulating proteins in the bloodstream, the pattern of microbial populations in the gut microbiome, specific chemical modifications to proteins, and much more can be assessed in bulk and then mined for associations with age and mortality risk. Even physical measures such as grip strength, ability to stand from sitting, walking speed, and so forth, can be algorithmically combined to form clocks.

With so much data to use in the production of clocks, it is inevitable that the quality and applicability of individual clocks will vary widely on a case by case basis. It is at present always unclear as to how the specific metrics that form the clock are caused by specific underlying processes of aging. That isn't an obstacle to the use of the clock in studies of natural aging, but it is a roadblock to the use of a clock as a way to assess the success of a potential age-slowing or age-reversing interventions. Interventions that address mechanisms of aging only impact a limited set of those mechanisms, or just one mechanism. A clock may be overly weighted towards that mechanism, or it may be insensitive to that mechanism, and in either case the results will be misleading. A great deal of work has yet to be accomplished to allow clocks to reach their true potential, as ways to steer medical development towards the most effective approaches to rejuvenation.

Aging clocks & mortality timers, methylation, glycomic, telomeric and more. A window to measuring biological age

Aging clocks can be devised from any biological system that changes during age. Measuring the amount of variation in those biological systems may allow scientists to peer into how far an organism has drifted from youthful function or how close they are to mortality. Aging clocks specifically aim to inform subjects of their biological age, but many of these clocks deliver no information on how long a subject may have left. However, in cases where the data can deliver information on impending death (unless some type of intervention is taken), then those clocks are also mortality timers that can better serve a subject's decision making or the advice from a healthcare practitioner. Three categories exist, aging clocks that deliver biological age, aging clocks and mortality timers that deliver biological age and information to predict death, and mortality timers that only offer information that can be used to predict the onset of disease or death.

Even though aging clocks have become popular, the term mortality timer should also be used (where applicable) across the industry to deliver sobering information that may assist in changing poor decision making related to a subject's lifestyle. Many aging clocks and mortality timers exist, such as blood biomarkers (proteomics), epigenetic mechanisms, extracellular vesicles, immune system factors, telomere length, glycomic levels, grip strength, blood vessel health, and many more biological systems could be used to determine a subject's age. However, the accuracy to predict age, overall health, or impending demise may be lacking. From analyzing various aging clocks to mortality timers, it becomes evident that even though some aging clocks may deliver vast amounts of biological data, no single clock can deliver all biological data across all tissues from the generic samples collected with commercial kits.

All clocks appear to have limitations on the data they can deliver, albeit the data are extremely extensive from some aging clocks such as epigenetic, blood tests, and glycomic clocks. The findings of this article are (in no order of effectiveness) that epigenetic, glycomic, and blood/serum biomarkers are the three most powerful clocks that can be used, as not only can a biological age prediction be made, along with disease potential to disease penetrance, but they can also function as rough mortality timers. An impending mortality diagnosis is a sobering prediction to any subject, so clocks that can also deliver rough time of death also function as extreme motivation for subjects to change their lifestyle habits as a matter of urgency. Aging clocks will continue to evolve as new biomarkers are found; however, any biological machinery that wanes with age can be used to elucidate data regarding biological age.

The chronic inflammation of aging is harmful, disruptive of tissue structure and function, altering cell behavior for the worse. The immune system reacts to many of the varied signs of molecular damage that become prevalent in old tissues, such as DNA debris from dying cells, and the result is unresolved inflammatory signaling. Neurodegenerative conditions in particular appear to be driven by inflammation, but given that the brain is separated from the body by the blood-brain barrier, and the immune systems of brain and body are also distinct and separate, how is it that inflammation in the body generates neuroinflammation in the brain? Researchers here discuss what is known of the mechanisms involved.

Inflammation in the brain has drawn widespread attention due to its implication in several diseases at multiple stages of life. For instance, some studies have suggested a relationship between neuroinflammation and several types of dementia. Several insults can cause neuroinflammation, such as viral infection in the central nervous system, peripheral inflammation such as chronic joint pain and gut inflammation, and autoimmune issues. In patients with specific types of cancer, such as small cell lung cancer, the immune system cross-reacts with distinct antigens to cause damage to neural tissue and trigger neuroinflammation.

Taken together, persistent systemic inflammation increases the likelihood of neuroinflammation. Meanwhile, factors such as lifestyle also contribute to neuroinflammation. Unhealthy eating habits have been shown to influence the balance of intestinal microbiota, change the blood-brain barrier (BBB) permeability, and cause neuroinflammation. Moreover, mental stress has been shown to increase the levels of several cytokines, such as tumor necrosis factor-alpha (TNF-α) and interleukin-1 (IL-1) to trigger neuroinflammation. Among the known causes of neuroinflammation, the influence of systemic inflammation on neuroinflammation has scarcely been explored. Recent evidence suggests that chronic peripheral inflammation causes systemic inflammation which may enhance the synthesis of pro-inflammatory cytokines and other inflammation-promoting mediators, activating neuroinflammation in the diseased brain.

Some studies have pointed out the relationship between systemic inflammation and microglial activation via multiple neurotoxic factors, including TNF-α, IL-1, and ROS. Microglia activation is the principal driver of inflammation in the brain. It has been suggested that chronic inflammation breaks down the BBB, degrading the separation of central and peripheral circulation system, leaving the central nervous system (CNS) vulnerable. The close bidirectional relationship of the gut-brain axis, which includes neural, hormonal, and immune communication also plays a vital role in neuroinflammation caused by systemic inflammation. Thus, the persistence of peripheral inflammation causes systemic inflammation and the enhancement of pro-inflammatory factors and disruption of the brain tissue protection, all lead to neuroinflammation.

Link: https://doi.org/10.3389/fnagi.2022.903455

The editorial here is focused on Alzheimer's disease specifically, but the sentiments expressed apply equally to all age-related diseases. We are entering a new era, in which the research and development community stops trying to treat the symptoms of age-related disease and increasingly focuses on causes of age-related diseases. These conditions are in no way separate from the underlying mechanisms of aging: every age related disease is a manifestation of aging, and a consequence of underlying processes of aging that can be targeted, slowed, reversed. While advocates for aging research have been saying this for decades, the broader research community is now increasingly adopting this view. The future is bright!

Alzheimer's disease (AD) is characterized by senile plaques comprising β-amyloid (Aβ) proteins and neurofibrillary tangles formed by hyperphosphorylated tau aggregates. Massive efforts and resources have been poured into interventions aimed at removing or decreasing the production of Aβ. Until recently, amyloid and tau have been the focus of most drugs in development for AD. Beyond the accumulation of plaques and tangles, numerous processes go awry with aging that contribute to, or exacerbate, the pathology and progression of AD, including inflammation, impaired proteostasis, vascular dysfunction, mitochondrial/metabolic dysfunction, epigenetic dysregulation, and synaptic dysfunction. Thus, a combination of drugs to address many of these defects may be necessary to effectively treat AD. In recent years, an increasing number of drugs targeting these biological processes have emerged in the drug development pipeline for AD.

Currently, there are 143 agents in clinical trials for AD, of which 119 agents are disease-modifying agents. Of the disease-modifying agents, there are now more agents in AD clinical trials that are targeting inflammation (23; 19.3%) than amyloid (20; 16.8%) or tau (13; 10.9%). Inflammation is a major hallmark of aging, and chronic systemic inflammation is associated with brain volume shrinkage and impaired cognitive functions. While broad-spectrum anti-inflammatory drugs have failed to improve cognitive outcomes in AD patients, recent efforts have targeted specific aspects of inflammation that are harmful to the brain while sparing normal immune function. For example, senescent cells are thought to fuel age-related pathologies by evading cell death while continuing to release proinflammatory cytokines and chemokines to damage the surrounding tissue. Senolytic drugs can selectively induce apoptosis of these senescent cells, and there are currently 3 phase II clinical trials underway to test a senolytic combination of dasatinib (tyrosine kinase inhibitor) and quercetin (flavonoid) in mild cognitive impairment or early-stage AD.

Between the breadth of new drug targets under investigation that address the biology of aging, the rapid development and validation of new biomarkers, and the improved design and rigor of clinical trials, we are in a new era of Alzheimer's research and drug development. Given the multifaceted nature of AD pathogenesis and progression, and the many biological processes that become impaired with aging, it is unlikely that drugs addressing a single target will have enough efficacy in treating AD in a clinically meaningful manner. However, if incremental benefits are observed with some agents, combination trials should be considered. Combination therapies are the standard of care for many diseases of aging, including cancer and cardiovascular diseases, and will likely be necessary to successfully treat AD.

Link: https://doi.org/10.14283/jpad.2022.64

It is well known that cancer survivors who underwent chemotherapy or radiotherapy exhibit a shorter life expectancy, greater chance of unrelated cancer incidence, and greater risk of age-related disease. The most reasonable hypothesis at present is that these undesirable outcomes are the result of an increased burden of senescent cells. Historically, cancer treatments have been in large part designed to force cancerous cells into senescence, those that are not killed outright by the therapy. Since these cancer therapies are toxic to cells, they also tend to cause off-target cell death and senescence. It is possible that similar issues can arise from the more aggressive cancer immunotherapies, but the mechanisms by which the burden of cellular senescence is increased would be very different and more indirect.

Today's open access paper presents a broad discussion of the ways in which cancer therapies may provoke accelerated aging. It is centered on an increased burden of cellular senescence, but also touches on other hallmarks of aging. Cancer patients should hope that cellular senescence is the primary mechanism by which accelerated aging manifests following treatment, as senolytic treatments capable of selectively destroying lingering senescent cells are under development. Clinical trials to assess whether first generation senolytics (such as the dasatinib and quercetin combination) prevent the increased risk of age-related conditions in cancer survivors would take years to run though to a robust conclusion. It may be possible to get a good idea as to the efficacy of senolytics more rapidly, however, by looking at whether or not they can meaningfully reduce some of the side-effects of chemotherapy or radiotherapy in the first few months after treatment.

The Achilles' heel of cancer survivors: fundamentals of accelerated cellular senescence

Cancer survivors are at a significantly higher risk of age-related diseases than non-cancer controls, comparable to incident rates in the elderly population. Cellular senescence is a biologic aging hallmark and plays a causative role in numerous age-related diseases, many of which affect cancer survivors. Furthermore, many cancer therapies induce senescence, suggesting that therapy induced senescence (TIS) may be responsible for cancer survivors' various side effects.

A seminal study showed that treating fibroblasts with the chemotherapeutic doxorubicin induces senescence, as indicated by higher SA-β-gal, p16INK4, p21CIP1, and DNA damage response expression. Notably, doxorubicin induces senescence systemically and not only in tumor cells. In addition, doxorubicin significantly impairs hematopoietic stem cell function by reducing the number of colony-forming units, an effect rescued by ganciclovir-mediated (GCV-mediated) clearance of senescent cells (SCs). Furthermore, cardiomyopathy, a well-known side effect of doxorubicin, was almost entirely prevented by GCV treatment. Treating mouse breast cancer models with doxorubicin arrests tumor growth, with later cancer relapse, but combining doxorubicin with GCV significantly improves the survival of mice, reduces the incidence of metastasis, and reduces the number of metastatic foci in mice that developed metastasis. Lastly, the nocturnal running time of mice was significantly impaired after doxorubicin treatment, and GCV treatment almost entirely rescued this effect.

Eliminating SCs alleviates many acute effects (elevated inflammatory markers and cardiotoxicity) and chronic effects (fatigue, cancer relapse, metastasis) of doxorubicin, suggesting TIS-dependent pathogenesis of cancer therapy-related adverse effects in survivors, at least those treated with doxorubicin.

Focusing on cellular senescence over other mechanisms assumes that senescence drives accelerated aging processes in cancer survivors while conferring a relatively limited role to other biologic aging hallmarks. This, however, has not been proven; but since transformative preclinical advancements in alleviating age-related health conditions have been achieved by elimination of SCs, we feel it appropriate to focus on cellular senescence and advocate that considering cellular senescence as the driver of early aging in survivors could have great benefits in advancing the implementation of potential cutting-edge interventions to mitigate premature aging.

Undoubtedly, there is a concerted effort from the scientific community to address the phenotypes, mechanisms, biomarkers, and interventions of early aging in cancer survivors. Knowledge about cellular senescence has exponentially increased in recent years on the basis of preclinical studies, but only the outcomes of well-designed, robust clinical studies can prove whether senotherapies will be beneficial in decreasing morbidity, increasing longevity, and improving quality of life in survivors. Thus, the scientific community must go through the rigorous process of translating bench work into clinical trials with a well-defined outcome. Only after completion of randomized trials, if senolytics and other anti-aging drugs show excellent short- and long-term safety and efficacy, should these drugs be used in the clinic.

Tau protein is involved in the pathology of Alzheimer's disease. It is one of the few proteins in the body capable of becoming altered in ways that form harmful aggregates that disrupt cell function and lead to cell death. Given a much better understanding of the biochemistry by which tau protein becomes modified in ways that make it toxic, it might be possible to interfere in that modification process with small molecule drugs. This approach has worked for transthyretin amyloidosis, leading to drugs that significantly reduce the harmful aggregation of transthyretin by interfering in one specific step in the modification of transthyretin molecules. The research here is an example of much the same sort of work, a project that might lead to analogous treatments targeting tau aggregation in the aging brain.

A new study has shown how a protein called tau, a critical factor in the development of Alzheimer's disease, turns from normal to a disease state - and demonstrates how this discovery could deliver a therapeutic target. The findings provide hope for preventing the tau transformation process from happening, thereby keeping tau in a healthy state and avoiding toxic effects on brain cells. In the course of Alzheimer's disease development, tau accumulates in deposits inside brain cells. During this process, tau gets heavily modified, with various deposits made up of tau carrying multiple small changes at many different positions within the tau molecule. While such changes to tau have been known to neuropathologists for decades, it remained unclear how tau arrives at this multi-modified stage. The new study has solved part of this mystery and provides a new mechanism to explain how tau gets progressively modified.

The study set out to answer whether one change at one specific spot in tau would make it easier for another spot to be modified. The team focussed on the relationship between tau and protein kinases, which are enzymes that introduce changes in tau. Usually, protein kinases target specific spots, called phosphorylation sites, in tau and other proteins, and introduce changes only at these specific spots. Researchers suspected that some of these enzymes are able to target several spots in tau and would do so even more efficiently if tau were already modified at one spot to begin with. While the study did discover that one change in tau does makes it easier for another change to be introduced, it was also able to identify "master sites" in tau, being specific spots that govern subsequent modifications at most of the other sites.

The next step for the team was to see whether master sites could be targeted to reduce the toxic properties of tau in Alzheimer's, in a bid to improve memory function. The current study employed mice that have both amyloid and tau and developed Alzheimer's-like symptoms, including memory deficits. The researchers found that mice did not develop memory deficits when they had a version of tau that lacked one of the identified master sites, compared with mice that had the usual version of tau. The team will now investigate how its findings can be translated into a treatment.

Link: https://www.eurekalert.org/news-releases/957875

Cellular senescence and mitochondrial dysfunction are entwined phenomena in aging. On the one hand senescent cells exhibit a form of mitochondrial dysfunction, while on the other hand the decline of mitochondrial function with age contributes to a rising burden of cellular senescence in tissues. The interesting part of this paper is the discussion of mitochondrial function as a target to reduce the burden of senescence cells, either by preventing cells from becoming senescent, reducing the harmful signals secreted by senescent cells, or forcing these errant cells to self-destruct.

We would like to speculate that the dysfunctional nature of senescent cell mitochondria could be an advantage for interventions that aim to induce senescent cell apoptosis. Anti-senescence interventions, including both senolytic approaches (which aim to specifically ablate senescent cells) and senostatic/senomorphic approaches (designed to block the senescence-associated secretory phenotype (SASP) and thus the proliferation of senescence via bystander signaling), have been extraordinarily successful in relieving a very wide range of broadly age-associated degenerative conditions in experimental mice, and clinical trials for many of these are ongoing.

The low mitochondrial membrane potential (MMP) of senescent cells might be advantageous. Like many cancer cells, senescent cells have less capacity to maintain MMP compared with normal cells and are thus exposed to prolonged mitochondrial permeability transition pore (mPTP) opening, suggesting MMP as a selective functional target for senescent cells. We expect that low doses of mitochondrial uncouplers, such as FCCP or CCCP, will lead to a persistent depolarization of the mitochondrial membrane in senescent cells, resulting in constant mPTP opening and cell death. However, the same doses of uncoupler should be well tolerated by non-senescent cells with their more robust OXPHOS machinery and thus better ability to maintain MMP.

Accordingly, combination of a senolytic drug with an uncoupler should enhance senolytic sensitivity and specificity, enabling therapeutic efficacy to be reached at substantially lower doses of senolytic drugs, thus broadening the therapeutic window and reducing the risk of side effects for senolytic interventions.

Link: https://doi.org/10.1172/JCI158447

The extracellular matrix is constructed and maintained by cells, and provides structural and other support to the cell populations of a tissue. The extracellular matrix changes with age, and is of great importance to tissue function, but the details of extracellular matrix aging do not receive anywhere near the attention given to the biochemistry of cells. The arrangement of molecules of the extracellular matrix determines the structural properties of tissue, and changes such as cross-linking alter that in harmful ways, such as by reducing the elasticity of skin and blood vessel walls. It is more than just structure, however. Countless molecules in the extracellular matrix are recognized by cells and their presence or absence changes cell behavior, just like other forms of cell signaling.

In today's open access paper, researchers note one example of an extracellular matrix molecule, CYR61, that both declines with advancing age and appears necessary to support the function of mesenchymal stem cells in bone marrow. Stem cells reside in a niche in tissue, and the structure of that niche, and behavior of the supporting cells making up the niche, has great influence on stem cell function. Stem cell populations produce a supply of daughter somatic cells that support a tissue, but this supply is diminished with age. Given that this loss has detrimental effects on tissue function, and is likely a sizable contribution to degenerative aging as a whole, there is a keen interest in the research community in better understanding the mechanisms of stem cell aging.

Matrix-bound Cyr61/CCN1 is required to retain the properties of the bone marrow mesenchymal stem cell niche but is depleted with aging

Previously, we showed that extracellular matrices (ECMs), produced ex vivo by various types of stromal cells, direct bone marrow mesenchymal stem cells (BM-MSCs) in a tissue-specific manner and recapitulate physiologic changes characteristic of the aging microenvironment. In particular, BM-MSCs obtained from elderly donors and cultured on ECM produced by young BM stromal cells showed improved quantity, quality, and osteogenic differentiation. In the present study, we searched for matrix components that are required for a functional BM-MSC niche by comparing ECMs produced by BM stromal cells from "young" (≤25 years old) versus "elderly" (≥60 years old) donors.

With increasing donor age, ECM fibrillar organization and mechanical integrity deteriorated, along with the ability to promote BM-MSC proliferation and responsiveness to growth factors. Proteomic analyses revealed that the matricellular protein, Cyr61/CCN1, was present in young BM-ECM, but undetectable in elderly BM-ECM. To assess the role of Cyr61 in the BM-MSC niche, we used genetic methods to down-regulate the incorporation of Cyr61 during production of young ECM and up-regulate its incorporation in elderly ECM. The results showed that Cyr61-depleted young ECM lost the ability to promote BM-MSC proliferation and growth factor responsiveness. However, up-regulating the incorporation of Cyr61 during synthesis of elderly ECM restored its ability to support BM-MSC responsiveness to osteogenic factors such as BMP-2 and IGF-1.

We next examined aging bone and compared bone mineral density and Cyr61 content of L4-L5 vertebral bodies in "young" (9-11 m/o) and "elderly" (21-33 m/o) mice. Our analyses showed that low bone mineral density was associated with decreased amounts of Cyr61 in osseous tissue of elderly versus young mice. Our results strongly demonstrate a novel role for ECM-bound Cyr61 in the BM-MSC niche, where it is responsible for retention of BM-MSC proliferation and growth factor responsiveness, while depletion of Cyr61 from the BM niche contributes to an aging-related dysregulation of BM-MSCs. Our results also suggest new potential therapeutic targets for treating age-related bone loss by restoring specific ECM components to the stem cell niche.

Epigenetic clocks produce a value that correlates well with chronological age, and is thought to reflect biological age, in that people with higher epigenetic ages appear to have a worse risk of age-related disease. What underlying processes produce the characteristic epigenetic changes measured by the clocks, however? Without knowing this, it is hard to take clock data seriously as an assessment of the potential for any given novel intervention to slow or reverse aging. Perhaps the clock places too much weight on one specific mechanism of aging, or is insensitive to another, which would distort the outcome for potential therapies that targeted those mechanisms. Thus as researchers add clock data to their studies, it remains important to also collect other measures of health to corroborate or dispute the observed changes in epigenetic age.

In this work, we refer to the measurement made by an aging clock as biological age (BA) given that the disparity between BA and chronological age (CA) significantly correlates with age-related health outcomes such as mortality and disease burden. Whether or not the metric provided by an aging clock truly represents BA is, however, debatable. Ultimately, these clocks make a calculation based on a set of inputs, which are typically molecular in nature and predictably vary with age in a population. In the case of epigenetic models, the methylation status (i.e., methylated or demethylated) of CpGs is utilized. If an intervention decreases the number outputted by an epigenetic clock, this means that the status of specific DNA methylation sites resembles that of a younger individual. While such a change may indicate that an individual has become biologically younger, it is feasible that a more youthful epigenetic signature can be induced irrespective of BA. One way to explore these two possibilities would be to determine if inputs used by aging clocks represent downstream biomarkers or instead causally contribute to age-related dysfunction.

Future trials using aging clocks should also take care to make traditional clinical measurements. Tests that assess functional performance in older adults - such as grip strength, gait speed, the 6-min walk test, and the timed up-and-go test - are especially valuable. In addition to estimating BA, it would be helpful to measure classical clinical biomarkers that are known to associate with lifespan and healthspan. Ultimately, the utility of BA being reduced without a concomitant functional improvement and/or a decreased risk of mortality is questionable. Conversely, a reduction in BA that is tethered to a clear enhancement in health and/or longer life is of interest. Long-term, longitudinal trials in older populations would be exceptionally valuable and offer insight into how a change in BA alters mortality-risk on an individual level. As more trials are published, we will gain a more thorough understanding of how clinically significant altering an aging clock is.

Link: https://doi.org/10.1111/acel.13664

Researchers here provide evidence for ovarian fibrosis to be an important mechanism in limiting the age at which female mammals can remain fertile. Interestingly, existing antifibrotic drugs can produce some reversal of this fibrosis, enough to restore ovulation in mice. Fibrosis is a malfunction of tissue maintenance; cells produce too much collagen, creating scar-like deposits that disrupt tissue structure and function. The range of present drug treatments can produce only a little benefit for most fibrotic conditions, and thus the positive results here are quite intriguing.

The female ovary contains a finite number of oocytes, and their release at ovulation becomes sporadic and disordered with aging and with obesity, leading to loss of fertility. Understanding the molecular defects underpinning this pathology is essential as age of childbearing and obesity rates increase globally. We identify that fibrosis within the ovarian stromal compartment is an underlying mechanism responsible for impaired oocyte release, which is initiated by mitochondrial dysfunction leading to diminished bioenergetics, oxidative damage, inflammation, and collagen deposition.

Furthermore, antifibrosis drugs (pirfenidone and BGP-15) eliminate fibrotic collagen and restore ovulation in reproductively old and obese mice, in association with dampened M2 macrophage polarization and up-regulated MMP13 protease. This is the first evidence that ovarian fibrosis is reversible and indicates that drugs targeting mitochondrial metabolism may be a viable therapeutic strategy for women with metabolic disorders or advancing age to maintain ovarian function and extend fertility.

Link: https://doi.org/10.1126/sciadv.abn4564

Detrimental changes in the gut microbiome might prove to be one of the easier issues to fix in the aging human body. When we talk about an aged gut microbiome, we mean that the balance of microbial populations has shifted. There are more harmful microbes that either produce damaging metabolites or otherwise engage with tissue and the immune system to provoke chronic inflammation. At the same time there are fewer beneficial microbes working to produce metabolites that are necessary for tissue function, such as the butyrate that promotes neurogenesis. Rejuvenation in the context of the gut microbiome means only rebalancing these populations, nothing more complicated than that is needed.

How to go about achieving the goal of putting a youthful microbiome into an old body? The approach with the most robust evidence in animal studies is fecal microbiota transplantation, which is to say literally taking the microbiome from a young individual and placing it into an old individual. This restores a youthful microbiome for a lasting period of time, reduces inflammation, improves other measures of health, and in short-lived species acts to extend life span. Fecal microbiota transplantation is already practiced in human medicine, but only as a treatment for C. difficle infection, in which a pathogenic microbial species has overtaken the gut, but can be out-competed by transplanted species. It would not be a great leap to adapt this to the treatment of aging.

The authors of today's open access paper are much in favor of stool banking as a way to establish material for transplantation, sampling a young individual's microbiome and storing it for later. This seems to me to have the same issues as stem cell banking, in that over a time span of decades it is highly unlikely that technology will remain static. Producing a youthful microbiome for transplant, either by screening out unwanted species from young donors, or by manufacturing to order, should be an everyday occurrence not so very long from now. Screening donors could be implemented now, given a sufficiently motivated industry.

Rejuvenating the human gut microbiome

Industrial advances have been associated with large-scale changes in the human gut microbiome and a higher incidence of complex human diseases. Rewilding the human gut microbiome by transplanting the whole gut microbial community from donors in nonindustrial societies may result in a dramatic mismatch between our industrial environment/lifestyles and the ancestral microbiome.

Emerging studies suggest that stool banking and autologous fecal microbiota transplantation (FMT), using the recipients' own stool samples collected at a younger age when they are disease-free, may be a better - or at least an alternative - solution. This leads to the idea of rejuvenating the human gut microbiome. The conceptual similarity between stool banking for autologous FMT and cord blood banking for an autologous transplant implies the potential for rejuvenating the human gut microbiome.

Here we propose rejuvenating the human gut microbiome by stool banking and autologous fecal microbiota transplantation, that is, collecting the hosts' stool samples at a younger age when they are at optimal health, and cryopreserving the samples in a stool bank for the hosts' own future use. In this article we discuss the motivation, applications, feasibility, and challenges of this solution. Basic research in cataloging, characterizing, and even engineering individual microbes (or well-defined consortia of them) and their functions (or metabolic fuels/products) is still a very promising solution to restoring a healthy gut microbiota. However, considering the daunting complexity of the human gut microbiota, both bottom-up mechanistic approaches and top-down systems approaches (based on FMT) will be needed.

Researchers here review the evidence for accumulating numbers of senescent cells to drive the dysfunction of chronic obstructive pulmonary disease (COPD). It is now well known that senescent cells secrete a potent mix of signals that provoke inflammation and remodeling of tissue structure. This is necessary in the short term as a response to injury, potentially cancerous cells, and similar issues that require the attention of the immune system, regeneration, and potentially the destruction of errant cells. When sustained for the long term, however, it is highly disruptive to tissue structure and function, producing outcomes such as fibrosis and a chronic, unresolved inflammation that harmfully alters cell behavior.

Researchers coined the term "COPD-associated secretory phenotype" (CASP) to refer to the inflammatory mediators that are increased in COPD and provided a comparison of CASP and senescence-associated secretory phenotype (SASP) factors. In summary, there is a large degree of overlap, supporting the notion that they are strongly linked and reinforces the theory that senescence, along with SASP, is a major contributor to the inflammation that defines COPD.

Typically, cells undergoing senescence chemoattract immune cells, resulting in clearance of these senescent cells by immune cells such as NK cells and macrophages. However, senescent cells in diseased tissues can also impede innate and adaptive immune responses. Senescent cells accumulate in tissues during aging and could influence several pathological features observed in COPD, such as inflammation-associated tissue damage and remodeling. It is difficult to determine whether inflammation observed in COPD is primarily due to senescence, as many other contributing factors within the disease may contribute. However, the presence of enhanced senescent cell frequency in the lungs does contribute to a modified immune response that may influence several aspects of COPD pathogenesis.

There is increasing interest in the resolution of abundant senescence as a potential therapeutic approach in COPD. Senolytic agents, compounds that facilitate the elimination of senescent cells, have received considerable attention lately as a potential treatment for COPD. However, the investigation of these agents is limited by the lack of universal markers of senescence. A better understanding of pathways that induce and reinforce senescence in COPD may allow us to discover possible biomarkers that could serve as targets for these senolytic therapies.

Overall, there is mounting evidence to suggest that senescence could contribute to cells being resistant to apoptosis, exhibiting elevated inflammation, and reduced dead cell clearance, resulting in extensive tissue remodeling observed in COPD. Targeting senescent cells using senolytics to selectively remove senescent cells or modulate SASP using small molecules or antibodies represents a novel approach to countering COPD progression. Several treatments that may target cellular senescence are in development.

Link: https://doi.org/10.3390/medicina58060817

The accumulation of senescent cells is a contributing cause of degenerative aging. Researchers are very interested in better understanding the processes by which cells are pushed into the senescent state, as this knowledge might lead to better approaches to prevention of senescence. It remains an open question as to the degree to which prevention of senescence via any specific mechanism is beneficial versus harmful. Will it primarily allow cells on the edge of senescence due to transient circumstances, or circumstances that otherwise have little effect on cell viability, to recover and be productive in tissues? Will it allow damaged and potentially cancerous cells to continue their activities unimpeded? These questions remain to be answered on a case by case basis.

When a healthy human cell divides to form two identical cells, a small piece of DNA is shaved off each chromosome's tip, so that telomeres become gradually shorter with each division. However, it remains unclear whether over a person's lifetime, a cell may divide so often that its telomeres erode completely, prompting transition to a senescent state. Researchers have known for decades that telomere shortening triggers senescence in lab-grown cells, but they could only hypothesize that DNA damage at telomeres could make cells senescent.

Until now, testing this hypothesis had not been possible because the tools used to damage DNA were non-specific, causing lesions across the whole chromosome. A new tool uses a special protein that binds exclusively to telomeres. This protein acts like a catcher's mitt, grabbing hold of light-sensitive dye "baseballs" that researchers tossed into the cell. When activated with light, the dye produces DNA-damaging reactive oxygen molecules. Because the dye-catching protein binds only to telomeres, the tool creates DNA lesions specifically at chromosome tips.

Using human cells grown in a dish, the researchers found that damage at telomeres sent the cells into a senescent state after just four days - much faster than the weeks or months of repeated cell divisions that it takes to induce senescence by telomere shortening in the lab. "We found a new mechanism for inducing senescent cells that is completely dependent on telomeres. These findings also solve the puzzle of why dysfunctional telomeres are not always shorter than functional ones. Now that we understand this mechanism, we can start to test interventions to prevent senescence. For example, maybe there are ways to target antioxidants to the telomeres to protect them from oxidative damage."

Link: https://www.upmc.com/media/news/063022-zombie-cells

Just a few of the thousands of proteins in the human body can become altered and misfold in ways that encourage other molecules of that protein to do the same, forming aggregates that precipitate into toxic, solid deposits in cells and tissue. Neurodegenerative conditions in particular are characterized by these proteins, such as amyloid-β, TDP-43, tau, and α-synuclein, the last of which is the subject of today's open access paper. Parkinson's disease is the most studied of synucleinopathies, in which an excessive buildup of α-synuclein correlates with pathology and loss of function in the brain.

The common neurodegenerative conditions are associated with chronic, unresolved inflammation in brain tissue, and there is good reason to believe that this inflammation, disruptive of cell and tissue function, is an important part of the onset and progression of neurodegeneration. To what degree are the protein aggregates found in every aged brain, and in excessive amounts in patients with neurodegenerative conditions, involved in creating that inflammation? Are their contributions sizable in comparison to, say, the presence of persistent pathogens such as herpesviruses, or the growing burden of senescent supporting cells in the brain?

The Role of Alpha-Synuclein Autoantibodies in the Induction of Brain Inflammation and Neurodegeneration in Aged Humans

Aging is a major risk factor for developing neuroinflammation. As it progresses, neuroinflammation can cause neuron death in the brain, particularly in the hippocampus. This brain region is crucial for learning and memory function. Hence, aged humans who experience loss of neurons in this region exhibit frequent tendency of memory loss. Aging and its association for the development of numerous brain diseases are continuously increasing in prevalence. Increased plasma, cerebrospinal fluid (CSF), and brain level of alpha-synuclein (α-syn) and their association to microglial cells activation, pro-inflammatory cytokines production, neurodegeneration, and cognitive deficits have been observed in aged humans. However, the exact mechanism by which such α-syn abnormalities trigger neuroinflammation in aged humans are poorly defined.

Studies have shown that irregular accumulations and distributions of α-syn and/or the development of α-syn-reactive immunoglobulin G (IgG) autoantibodies are linked to the brain production of pro-inflammatory cytokines, i.e., interleukin-1 beta (IL1β), IL-6, and tumor necrosis factor alpha (TNF-α), which lead to neuron death and memory deficits in several age-related neurodegenerative diseases, i.e., Alzheimer's disease (AD), Parkinson's disease (PD), multiple system atrophy (MSA), rapid eye movement sleep behavior disorder (RBD), frontotemporal lobar dementia (PLD), and dementia with Lewy bodies (LBD). Therefore, this current study explored the involvement of α-syn, α-syn-reactive IgG autoantibodies, and Fc gamma receptors (FcγRs) function in aging human nervous system.

Based on the elevated brain expression of α-syn-reactive IgG auto antibodies and the higher expression of activating FcγR in aged humans, this report suggests that the α-syn-reactive IgG auto antibodies and their immunological reaction to α-syn are the basis of the formation of alpha-synuclein-specific IgG immune complexes (α-syn-IgG-ICs) in aged human brains. Furthermore, the strong interaction between such α-syn-IgG-ICs and activation of FcγR fuels the downstream signaling that causes microglial cells and/or neurons activation, pro-inflammatory cytokines production, and the death of neurons in aged humans.

Based on animal data, the growing burden of senescent cells with age appears to provide a significant contribution to age-related degeneration. Cells become senescent in response to tissue injury, significant cellular damage, signaling from other senescent cells, or reaching the Hayflick limit on replication. In youth, senescent cells are efficiently cleared, either destroying themselves via programmed cell death, or being destroyed by the immune system. In later life, clearance slows, and as a result there are ever more lingering senescent cells delivering signals that disrupt tissue structure and function and provoking chronic inflammation. Removing these cells via senolytic therapies has been shown to produce rapid reversal of many age-related pathologies in mice, and thus the research community is actively engaged in finding more ways to selectively provoke programmed cell death in senescent cells, to add to those already discovered.

Super-enhancers regulate genes with important functions in processes that are cell type-specific or define cell identity. Mouse embryonic fibroblasts establish 40 senescence-associated super-enhancers regardless of how they become senescent, with 50 activated genes located in the vicinity of these enhancers. Here we show, through gene knockdown and analysis of three core biological properties of senescent cells that a relatively large number of senescence-associated super-enhancer-regulated genes promote survival of senescent mouse embryonic fibroblasts.

Of these, Mdm2, Rnase4, and Ang act by suppressing p53-mediated apoptosis through various mechanisms that are also engaged in response to DNA damage. MDM2 and RNASE4 transcription is also elevated in human senescent fibroblasts to restrain p53 and promote survival. These findings further support the idea that senescent cells actively combat apoptosis on multiple fronts and therefore have numerous therapeutically exploitable vulnerabilities for elimination of detrimental senescent cells implicated in aging and aging-related diseases. These insights provide molecular entry points for the development of targeted therapeutics that eliminate senescent cells at sites of pathology.

Link: https://doi.org/10.1038/s41467-022-31239-x

Alex Zhavoronkov, who these days is as much interested in accelerating progress in cryonics as in translational research for the treatment of aging, here reports on his time at the recent Systems Aging Gordon Research Conference, one of a growing number of new conference series serving academic efforts make headway in the matter of treating aging as a medical condition. As a general rule, more successful conference series tend to indicate a larger and more successful field: more researchers, more funding, more attention from the world at large. The proliferation of conferences focused on aging is a good sign.

With Vadim Gladyshev serving as chairman and Steve Horvath as vice-chairman, the conference set the stage for the field, paving the way for the development of interventions to delay and reverse aging. Both are world-renowned researchers, and spoke and led the discussions at the conference. The conference was attended by a number of prominent researchers from renowned institutions; such as Cynthia Kenyon of Calico Labs, who discussed about interventions that slow aging, Morten Scheibye-Knudsen of the University of Copenhagen, who talked about modulating DNA repair for healthy aging, and Emma Teeling of the University College Dublin, who spoke about the genetic basis of exceptional longevity of bats.

Day one was about "Delaying Age," and was led by Steve Horvath as the discussion leader. On this day, Cynthia Kenyon, Richard Miller of the University of Michigan and Inigo Martincorena of the Sanger Institute presented. Richard and Inigo presented on drugs and mutations that slow aging in mice, and somatic mutations and clonal expansions in aging, respectively. Day two was all about "Epigenetic Reprogramming and Rejuvenation." It was led by Joe Betts-LaCroix of Retro Biosciences. Manuel Serrano of IRB Barcelona started the day with a talk on understanding and manipulating in vivo reprogramming and its effects on aging. He was followed by Vittorio Sebastiano of Stanford University, who spoke about transient reprogramming for multifaceted reversal of aging. Jacob Kimmel of NewLimit Research followed Vittorio with a talk on reprogramming strategies to restore youthful gene expression. Then came Morgan Levine of Yale University, who discussed DNA methylation landscapes in aging and reprogramming.

The first discussion topic for day three was "Epigenetic Biomarkers," with Kristen Fortney of Bioage leading the discussions. First to the podium was Nick Schaum of Astera Institute, whose discussion topic was "rejuvenome: toward a functional and multiomics understanding of aging and rejuvenation". He was followed by Riccardo Marioni of University of Edinburgh and Ake Lu of San Diego Institute of Science, who discussed about epigenetic clocks and universal DNA methylating age, respectively. "Artificial Intelligence and Machine Learning" was the first subject matter for day four, which was moderated by Marc Kirschner of Harvard. Sergiy Libert of Calico started the day with a talk on construction and analysis of the physiology clock for human aging. I took to the podium next and discussed applications of deep aging clocks in clinical practice and drug discovery. I was followed by Kristen Fortney of Bioage and Albert-laszlo Barabasi of Northeastern University, who discussed data-informed drug discovery for aging and the dark matter of nutrition, respectively.

Over the course of the five-day event, presentations covered many topics, like delaying aging, aging clocks, longevity intervention, and so much more. Many organizations like MIT, Stanford, and Yale were represented. It was truly a great opportunity to network with peers. With this successful conference on aging, the GRC has now plans the second Systems Aging meeting in 2024.

Link: https://www.forbes.com/sites/alexzhavoronkov/2022/06/29/a-week-at-the-most-secretive-conference-on-aging/

The important point made by the authors of today's open access paper is that, in the matter of epigenetic clocks, the focus of the research community should shift from the production of ever more refined clocks that better correlate with chronological age, biological age, or specific manifestations of aging, to attempts to understand how exactly the mechanisms and dysfunctions of aging determine change in these clocks. This is now well understood in most parts of the research community, but it still has to be said, and often.

The real promise of epigenetic clocks, and clocks built on transcriptomic, proteomic, and other similar data, is to make the assessment of potential rejuvenation therapies a rapid and cost-effective process. Simply run the clock before and after the treatment, a very favorable alternative to the lengthy studies that are the only present alternative. Without an understanding of which biological processes the clock reflects, however, that data can't be trusted until that specific clock is calibrated against the specific therapeutic approach with slow, expensive lifespan studies. Perhaps the clock undervalues some mechanisms of aging and overvalues others. At present no-one knows whether or not this is the case for any given clock. This state of affairs is a roadblock for the goal of speeding up the process of research and development.

Epigenetic aging: Biological age prediction and informing a mechanistic theory of aging

Nearly a decade ago, researchers showed that a large number of CpG sites in the human genome increase or decrease in methylation fraction over time, such that one can select among these CpG sites to measure the rate at which an individual ages. These so-called "epigenetic clocks" train regularized linear regression models to predict the chronological age of an individual from the methylation values of CpG sites distributed across the genome. During training, the CpG sites for which the methylation fractions are most predictive of chronological age are identified and selected for use in the linear regression equation. The number of CpG sites selected has depended greatly on the particular approach used but is typically between two and a few hundred.

In the time since these epigenetic clocks were introduced, substantial development effort has been invested into improving their predictive accuracy and extending their range of applications. The first randomized clinical trial using an epigenetic clock as the main validator of intervention efficacy was recently conducted. The prediction of epigenetic age has also been made more accessible and efficient; epigenetic clock software packages are readily available, with some requiring methylation values at only a few CpG sites for accurate age predictions. The sophistication of epigenetic clocks today is greater than it was a decade ago because the tools have broader reach, and we fully expect this trend to continue.

While optimization of existing concepts and methods is important, it is also vital that the field keeps moving. Beyond the construction of increasingly accurate chronological clocks, there are many unanswered questions related to the specific mechanisms by which the epigenome influences aging and, reciprocally, by which aging influences the epigenome. Prediction of age was an important first step, but - in our view - the focus must shift from chasing increasingly accurate age computations to understanding the links between the epigenome and the mechanisms and physiological changes of aging.

You might recall that an approach to reversing presbyopia by breaking a type of cross-link in the lens of the eye is in the fairly late stages of development. Cross-links stiffen the lens, making it hard to focus properly because the muscles of the eye are no longer able to produce enough force to obtain the desired result. The founders of a new company, Lento Bio, plan to do much the same thing for a different set of cross-link targets in the lens, those based on advanced glycation end-products, with the hope of improving upon the promising results already obtained via this strategy.

Lento Bio, Inc., a preclinical pharmaceutical company focused on developing small molecule therapeutics to target molecular damage driving age-related disease, announced its launch today. The company will initially focus on developing pharmaceutical eyedrops to treat a common vision disorder, presbyopia, or age-related farsightedness. Lento Bio will be supported and incubated by Ichor Life Sciences, a pre-clinical contract research organization, at Clarkson University's Peyton Hall Biotechnology Incubator.

Presbyopia is caused by stiffening of the eye lens, which stems from molecular crosslinks including advanced glycation end products (AGE) that cause tissue rigidity. The small molecule drugs being developed by Lento Bio will target underlying molecular damage accumulation with the goal of reversing the process of tissue-stiffening in the ocular lens. Upon successful completion of its first project, Lento Bio plans to apply its anti-glycation products more widely to include systemic diseases of aging.

"Lento Bio is starting from a solid foundation of established research into molecular aging damage and will focus development efforts towards the most accessible and relevant disease indications. Through bringing the problem to the science we aim to accelerate the creation of clinical assets and validate our disease hypothesis. We look forward towards collaborating with the scientific teams at Ichor and Clarkson University to pursue research and development of small molecule drugs."

Link: https://ichorlifesciences.com/2022/06/lento-bio/

The gut microbiome changes with age, in part because the immune system falters in its task of removing harmful microbes. Microbial populations responsible for producing beneficial metabolites decline in number, while populations that provoke chronic inflammation and other harms grow in number. Researchers are only just beginning to catalog the long list of harmful outcomes produced by an aged gut microbiome. The open access paper here is an example of this research, using mice to demonstrate a connection between the gut microbiome and hippocampal function in the brain, essential to memory.

Aging is known to be associated with hippocampus-dependent memory decline, but the underlying causes of this age-related memory impairment remain yet highly debated. Here we showed that fecal microbiota transplantation (FMT) from aged, but not young, animal donors in young mice is sufficient to trigger profound hippocampal alterations including astrogliosis, decreased adult neurogenesis, decreased novelty-induced neuronal activation and impairment in hippocampus-dependent memory. Furthermore, similar alterations were reported when mice were subjected to an FMT from aged human donors.

To decipher the mechanisms involved in mediating these microbiota-induced effects on brain function, we mapped the vagus nerve (VN)-related neuronal activity patterns and report that aged-mice FM transplanted animals showed a reduction in neuronal activity in the ascending VN output brain structure, whether under basal condition or after VN stimulation. Targeted pharmacogenetic manipulation of VN-ascending neurons demonstrated that the decrease in vagal activity is detrimental to hippocampal functions. In contrast, increasing vagal ascending activity alleviated the adverse effects of aged mice FMT on hippocampal functions, and had a detrimental effect on memory in aged mice. Thus, pharmacogenetic VN stimulation is a potential therapeutic strategy to lessen microbiota-dependent age-associated impairments in hippocampal functions.

Link: https://doi.org/10.1172/jci.insight.147700

A growing body of academic work is focused on the activity of transposable elements in degenerative aging, and some of these projects may produce approaches to therapy based on suppressing this activity. Transposable elements are DNA sequences capable of copying themselves within the genome, thought to be the result of ancient viral infections, but which contribute to evolution by providing a ready path to mutational change. Transposable elements are suppressed in youth, but with age the regulation of gene expression becomes more ragged, and transposable elements exhibit ever greater activity. This is supposed by many researchers to contribute to degenerative aging in much the same way as other stochastic mutational damage, though proving this is ever a challenge, and also via provoking chronic innate immune responses to what might look like viral activity.

There are several categories of transposable element, one of which, the retroviruses, is the topic of today's open access paper. The researchers assess the evidence for one particular pathway to be responsible for ensuring that retrovirus activation in older individuals produces an inflammatory response. As more researchers engage with the question of the role of transposable elements in aging, we'll see more research directed at potential target mechanisms that might be used to suppress transposable element activity in later life. Suppressing transposable element activity is the right way forward to determine just how much damage is being caused by this age-related failure to control the replication of transposable elements, to determine just how much of an influence this process has on degenerative aging. In matters relating to aging, fixing a given mechanism is really the only way to assess the degree to which that specific mechanism is hurting us all.

Endogenous Retroviruses (ERVs): Does RLR (RIG-I-Like Receptors)-MAVS Pathway Directly Control Senescence and Aging as a Consequence of ERV De-Repression?

Transposable elements (TE) make up about 46% of the human genome. They consist in repetitive sequences which are capable to or potentially capable to actively or passively insert copies of themselves elsewhere in the genome. TE are classified in Class I TEs, if they are RNA retrotransposons that require reverse transcriptase activity for transposition, and Class II TEs, or DNA transposons, that require transposase enzyme for their mobilization. LINE (long interspersed nuclear elements) and SINE (short interspersed nuclear elements) are the most studied and abundant class I TEs. The third family of Class I TEs consists of long terminal repeat (LTR) retroelements, known as HERVs (human endogenous retroviruses). HERV are residues of viral infections from the past that have remained in the human genome and occupy about 8% of it.

Bi-directional transcription of hERVs is a common feature of autoimmunity, neurodegeneration, and cancer. Higher rates of cancer incidence, neurodegeneration, and autoimmunity but a lower prevalence of autoimmune diseases characterize elderly people. Although the re-expression of hERVs is commonly observed in different cellular models of senescence as a result of the loss of their epigenetic transcriptional silencing, the hERVs modulation during aging is more complex, with a peak of activation in the sixties and a decline in the nineties. What is clearly accepted, instead, is the impact of the re-activation of dormant hERV on the maintenance of stemness and tissue self-renewing properties.

An innate cellular immunity system, based on the RLR-MAVS circuit, controls the degradation of double-stranded DNAs arising from the transcription of hERV elements, similarly to what happens for the accumulation of cytoplasmic DNA leading to the activation of cGAS/STING pathway. While agonists and inhibitors of the cGAS-STING pathway are considered promising immunomodulatory molecules, the effect of the RLR-MAVS pathway on innate immunity is still largely based on correlations and not on causality. Here we review the most recent evidence regarding the activation of MDA5-RIG1-MAVS pathway as a result of hERV de-repression during aging, immunosenescence, cancer, and autoimmunity. We will also deal with the epigenetic mechanisms controlling hERV repression and with the strategies that can be adopted to modulate hERV expression in a therapeutic perspective. Finally, we will discuss if the RLR-MAVS signalling pathway actively modulates physiological and pathological conditions or if it is passively activated by them.

A great deal of time and effort was required to achieve the first pig to human heart transplant, including the production of genetically engineered pigs that lack the cell features that provoke rejection, and which minimize the presence of porcine viruses. Nonetheless, the first transplanted heart failed after some weeks for reasons that are yet to be determined, undergoing widespread cell death. This suggests that the remainder of the path towards viable xenotransplantation will be longer than hoped. As a strategy, xenotransplantation competes with work on the production of organs built from patient cells, an approach that will likely take at least as long to be realized.

The pig that served as the heart donor came from a population that has been extensively genetically engineered to limit the possibility of rejection by the human immune system. The line was also free of a specific virus that inserts itself into the pig genome (porcine endogenous retrovirus C, or PERV-C) and was raised in conditions that should limit pathogen exposure. The animal was also screened for viruses prior to the transplant, and the patient was screened for pig pathogens afterward.

While patient weight loss was a concern, at five weeks after the transplant, there were no indications of rejection, and the heart was still functioning. Things started to go bad about seven weeks post-transplant when the patient's blood pressure began to drop. Fluid started building on his lungs, and he had to be intubated. Imaging showed that his heart was still clearing out most of the volume of the ventricles with each beat, but the total volume had shrunk as the walls of the ventricle thickened. Eventually, external oxygenation had to be restarted.

Pig DNA began to show up in the bloodstream, indicating tissue damage; some anti-pig-cell antibodies were also detected, suggesting a degree of rejection. But a biopsy failed to find any signs of it in the heart tissue; instead, there were signs that capillaries in the heart were leaking, creating swelling and allowing blood cells into the heart tissue. A week later, a second biopsy indicated that about 40 percent of the heart muscle cells in the transplant were dead or dying, even though there were still no indications of rejection in the tissue. That level of damage brought an end to things and life support was withdrawn.

Link: https://arstechnica.com/science/2022/06/pig-heart-transplant-failed-as-its-heart-muscle-cells-died/

One should always be somewhat dubious when researchers claim the primacy of any single mechanism in age-related dysfunction. It is one thing to demonstrate that a mechanism exists and is damaging, and quite another to show that it provides a significant contribution to aging in animal models or humans. Aging is enormously complex, and it has traditionally proven very challenging to repair or ameliorate just one mechanism in isolation, in order to see what happens. Bear this in mind while reading this otherwise interesting paper on the function of ALCAT1 in age-related mitochondrial dysfunction.

Cardiolipin (CL) is a mitochondrial signature phospholipid that plays a pivotal role in mitochondrial dynamics, membrane structure, oxidative phosphorylation, mitochondrial DNA bioenergetics, and mitophagy. The depletion or abnormal acyl composition of CL causes mitochondrial dysfunction, which is implicated in the pathogenesis of aging and age-related disorders. However, the molecular mechanisms by which mitochondrial dysfunction causes age-related diseases remain poorly understood.

Recent development in the field has identified acyl-CoA:lysocardiolipin acyltransferase 1 (ALCAT1), an acyltransferase upregulated by oxidative stress, as a key enzyme that promotes mitochondrial dysfunction in age-related diseases. ALCAT1 catalyzes CL remodeling with very-long-chain polyunsaturated fatty acids, such as docosahexaenoic acid (DHA). Enrichment of DHA renders CL highly sensitive to oxidative damage by reactive oxygen species (ROS). Oxidized CL becomes a new source of ROS in the form of lipid peroxides, leading to a vicious cycle of oxidative stress, CL depletion, and mitochondrial dysfunction. Consequently, ablation or the pharmacological inhibition of ALCAT1 have been shown to mitigate obesity, type 2 diabetes, heart failure, cardiomyopathy, fatty liver diseases, neurodegenerative diseases, and cancer.

The findings suggest that age-related disorders are one disease (aging) manifested by different mitochondrion-sensitive tissues, and therefore should be treated as one disease. This review will discuss a unified hypothesis on CL remodeling by ALCAT1 as the common denominator of mitochondrial dysfunction, linking mitochondrial dysfunction to the development of age-related diseases.

Link: https://doi.org/10.3390/cells11121906

The immune system becomes ever more inflammatory with advancing age, a state known as inflammaging, even as it loses competence in destroying pathogens and unwanted cells. This sustained, unresolved inflammation is harmful, the cause of numerous harmful changes in cell function and failures of tissue maintenance. It accelerates the onset and progression of all of the common age-related conditions. This is caused in part by the pro-inflammatory signaling of senescent cells, present in increasing numbers in the aged body. Another important contribution, and a focus in today's open access paper, is the activation of innate immune cells by signs of cell dysfunction and damage such as DNA debris. These are known as damage associated molecular patterns (DAMPs), and their presence is characteristic of aging, provoking the innate immune system into overactivation.

What can be done to minimize inflammaging? Blocking specific inflammatory signals can reduce inflammation, as established therapies for autoimmune conditions demonstrate, but at the cost of further reducing the effectiveness of the immune system. This type of strategy blocks both necessary and excessive inflammation. Compare this with removal of senescent cells via senolytic therapies, an approach that does only remove the excessive inflammatory signaling. Is it possible to remove DAMPs, and thereby prevent activation of the innate immune system? Not at present. The only practical way to reduce DAMPs is to modestly slow aging as a whole, achieved via life-long strategies such as calorie restriction. We can hope that progress will be made towards better approaches in the years ahead, but this sort of strategy is not a focus in today's research community.

Inflammaging is driven by upregulation of innate immune receptors and systemic interferon signaling and is ameliorated by dietary restriction

A prominent aging-associated condition is a chronic inflammation referred to as "inflammaging," a pro-inflammatory phenotype that accompanies aging in mammals. Inflammaging is a highly significant risk factor for most, if not all, aging-related diseases including obesity and type 2 diabetes, cardiovascular diseases, Alzheimer's disease, and cancer, as well as vulnerability to infectious disease and vaccine failure.

Dietary restriction (DR) decreases the calorie intake without inducing malnutrition. Lifetime DR is a non-pharmacological intervention that can extend the lifespan in a wide range of organisms. It has been shown that long-term DR (LTDR) also reduces some aspects of inflammation, leading to the hypothesis that a life-long energy accumulation can be the origin of chronic inflammation. A very recent study carried out in rats has shown that late-life DR attenuated aging-related changes in cell type composition and gene expression, and reversed the aging-associated increase of senescence markers and alterations of the immune system. However, it is still largely unknown which signaling pathways and networks regulate the induction of inflammaging across tissues and whether DR could have an impact on rescuing such systemic induction of inflammaging.

In this study we employ a transcriptome-wide and multi-tissue approach to analyze the influence of both LTDR and short-term DR (STDR) at old age on the aging phenotype. We were able to characterize a common transcriptional gene network driving inflammaging in most of the analyzed tissues. This network is characterized by chromatin opening and upregulation in the transcription of innate immune system receptors and by activation of interferon signaling through interferon regulatory factors, inflammatory cytokines, and Stat1-mediated transcription. We also found that both DR interventions ameliorate this inflammaging phenotype, albeit with some differences mainly at tissue-specific level. Further chromatin accessibility analysis showed that DR can also rescue the aging-associated epigenetic alteration on the inflammaging-related genes, but not the genome-wide impairment of chromatin that accompanies old cells.

In this study, we showed that aging changed the transcriptome of different tissues and that DR was able to partially rescue the age transcriptome. DR intervention in late life has been recently shown to not provide as beneficial effects as long-life DR in lifespan and healthspan extension. For this reason, we compare old mice with mice treated with both a lifetime DR (LTDR) and a short-term DR at late life (STDR). We found that responses to the aging, LTDR, and STDR both in magnitude and functional aspects were tissue specific. LTDR has been previously shown to strongly prevent a pro-inflammatory phenotype in aged white adipose tissue pre-adipocytes, whereas a late-onset DR failed in preventing it. Our data show that LTDR was more effective in rescuing inflammaging in liver and kidney, while STDR mitigated aging-associated activation of inflammatory pathways more effectively in blood; in other tissues both LTDR and STDR prevented the pro-inflammatory phenotype to a similar extent.

The dominant cancer therapies of chemotherapy and radiotherapy have not yet been replaced by immunotherapies for more than a handful of cancer types. These classes of therapy produce a significantly increased burden of senescent cells in patients; one of the goals of cancer therapy is to drive cancerous cells into senescence, those that cannot be killed. These additional senescent cells in turn accelerate the progression of degenerative aging. The advent of senolytic therapies to clear senescent cells from aged tissues will make a sizable difference to these patients. More effort should be undertaken today to enable patient access to the existing, low-cost first generation senolytics, such as the dasatinib and quercetin combination.

A new study found that adult survivors of cancer had a 42% greater risk of cardiovascular diseases (CVD) than people without cancer. The authors found that survivors of cancer had a particularly higher risk of developing heart failure (52% higher risk), followed by stroke (22% higher risk). There were no significant differences in the risk of coronary heart disease between those with and without cancer.

The analysis used data from the Atherosclerosis Risk in Communities Study, a prospective community-based population study, initiated in 1987, of CVD and its risk factors. The study had 12,414 participants, with a mean age of 54 who were followed through 2020. Although the study was not designed to pinpoint the causes of increased CVD risk among survivors of cancer, the main hypothesis involves a combination of cancer and noncancer related factors such as inflammation, oxidative stress, cardiac toxicity from specific cancer treatments, and traditional risk factors like hypertension, diabetes, and obesity. While the excess risk of CVD in this group was not fully explained by traditional cardiovascular risk factors such as obesity, high blood pressure and cholesterol levels, and diabetes, it is still very important to address these risk factors that are common in survivors of cancer.

Cardiac toxicity from cancer therapies, or negative cardiac effects of cancer therapies, may be particularly important in increasing the risk of CVD in some survivors of cancer. For example, survivors of breast and blood cancers had significantly higher risk of CVD, and these cancers are typically managed with a combination of chemotherapy and chest radiation that can damage the heart. Conversely, survivors of prostate cancer did not have an increased risk of CVD. These patients can be managed with active surveillance or local therapies without the risk of cardiac toxicity.

Link: https://www.eurekalert.org/news-releases/957222

This review paper provides an overview of what is known and theorized of the influence of the gut microbiome on the aging of the vasculature. Cardiovascular disease is the largest cause of human mortality, and there is considerable interest in better understanding how to slow its onset, given the lack of progress towards meaningful reversal of conditions such as atherosclerosis. The relative abundance of populations in the gut microbiome change with age in ways that (a) diminish the production of beneficial metabolites, and (b) provoke chronic inflammation. It is most likely primarily this latter point that drives issues in the vasculature, given the strong evidence for chronic inflammation to drive the progression of cardiovascular disease. That said, as noted here, direct correlations between the microbiome and some of the preferred measures of vascular aging have yet to be established, or are not in evidence.

The gut microbiota is a critical regulator of human physiology, deleterious changes to its composition and function (dysbiosis) have been linked to the development and progression of cardiovascular diseases. Vascular ageing (VA) is a process of progressive stiffening of the arterial tree associated with arterial wall remodeling, which can precede hypertension and organ damage, and is associated with cardiovascular risk. Arterial stiffness has become the preferred marker of VA.

In our systematic review, we found an association between gut microbiota composition and arterial stiffness, with two patterns, in most animal and human studies: a direct correlation between arterial stiffness and abundances of bacteria associated with altered gut permeability and inflammation; an inverse relationship between arterial stiffness, microbiota diversity, and abundances of bacteria associated with most fit microbiota composition.

Interventional studies were able to show a stable link between microbiota modification and arterial stiffness only in animals. None of the human interventional trials was able to demonstrate this relationship, and very few adjusted the analyses for determinants of arterial stiffness. We observed a lack of large randomized interventional trials in humans that test the role of gut microbiota modifications on arterial stiffness, and take into account blood pressure and hemodynamic alterations.

Link: https://doi.org/10.3390/jcm11123557

Senescent cells serve many purposes in the body, such as aiding in wound healing and suppression of cancer, but they become harmful when present in significant numbers for an extended period of time. This occurs with age, as the immune system becomes less effective at its task of clearing those senescent cells that fail to undergo programmed cell death. As senescent cells are created constantly, when somatic cells hit the Hayflick limit on replication, and to a lesser degree in response to molecular damage, a slowing of clearance leads to an accumulation of these errant cells. Senescent cells secrete a mix of signals, the senescence-associated secretory phenotype (SASP), that, when present over the long term, provokes harmful inflammation, restructuring of the extracellular matrix, and detrimental changes in cell behavior.

Atherosclerosis is an inflammatory condition, in which fatty deposits form in artery walls due to the dysfunction of the macrophage cells responsible for removing that damage. More inflammatory signaling makes matters worse, by both changing the behavior of macrophages, and calling in more macrophages to swell the mass of the atherosclerotic plaque. That is enough on its own to consider targeting senescent cells for destruction, to remove their inflammatory signaling as a way to slow the growth of plaque. Today's open access paper adds a few other concerns, such as the way in which senescent cells may be disruptive of the protective fibrosis that helps stabilize soft plaques.

There is good reason to think that senolytic therapies to selectively destroy senescent cells may be beneficial in the context of atherosclerosis, or indeed in any age-related condition with a strong connection to chronic inflammation, but not all senolytics may effectively target the relevant senescent populations, or localize sufficiently to the arteries, as noted in the paper here. The question of whether senescent cells provide a major contribution or a minor contribution to the progression of atherosclerosis remains open, though the early attempts to produce benefits in animal models have not been promising. If that state of affairs continue, then attention must return to other pathological mechanisms.

Senescence in Vascular Smooth Muscle Cells and Atherosclerosis

Vascular smooth muscle cells (VSMCs) are the primary cell type involved in the atherosclerosis process; senescent VSMCs are observed in both aged vessels and atherosclerotic plaques. Cellular senescence is not a static cellular state, but a dynamic process during which cells undergo quiescence (initial transient senescence), early senescence (stable growth arrest), complete senescence (chromatin changes associated with senescence and SASP), and late/deep senescence (phenotypic diversification). Similar to other cell types, senescent VSMCs have impaired proliferative potential coupled with increased propensity for expression of cellular senescence markers and cell death.

VSMCs aging is characterized by a shift from a contractile phenotype to a synthetic phenotype, impaired response to contractile or diastolic mediators secreted by endothelial cells, and changes in ion channel expression and abundance in the cell membrane. In atherosclerosis, senescent VSMCs may be present only in the intima rather than the mesenchyme, and VSMCs senescence is associated primarily with plaque size rather than plaque formation. Advanced atherosclerotic plaques are covered by fibrous caps containing VSMCs and extracellular matrix (ECM) molecules. Given that VSMCs can secrete and deposit ECM proteins, they are generally considered to be protective against atherosclerotic plaque instability. However, senescent VSMCs promote plaque vulnerability by secreting matrix-degrading proteases. Compared with normal VSMCs, collagen secretion from senescent VSMCs is reduced which further impairs plaque stability. Thus, senescent VSMCs not only accumulate in the atherosclerotic setting, but their properties exacerbate the development of atherosclerosis and increase the risk of atherosclerosis-related complications.

It is unclear whether senolytic drugs prevent atherosclerosis through multiple mechanisms or whether they do so only by clearing senescent cells. Not all anti-aging drugs are effective against atherosclerosis; long-term oral administration of dasatinib + quercetin (D + Q) significantly reduced aortic medial senescent cell markers in chronic hypercholesterolemic mice and naturally aging mice, as well as improving vasomotor function, but the mice still developed atherosclerosis. Further, the size of atherosclerotic plaques did not decrease following these treatments.

Researchers here note a sizable reduction in Alzheimer's disease risk in that part of the aged population that receives influenza vaccines. There is the usual question as to whether vaccination is a proxy for conscientiousness in health matters throughout later life, but here the focus is on biological mechanisms that might explain the effect. The most plausible to my eyes is the phenomenon of trained immunity, in which vaccination for a specific pathogen can provoke a general improvement in all functions of the innate immune system. This improvement includes reduced inflammation, and the chronic inflammation of aging is clearly important in the onset and progression of neurodegenerative conditions.

This retrospective cohort study revealed that in adults aged 65 or old without dementia, mild cognitive impairment, or encephalopathy, patients who received at least one influenza vaccine were 40% less likely than their non-vaccinated peers to develop incident Alzheimer's disease (AD) during the 4-year follow-up period. The mechanisms underlying the apparent protective effects of influenza vaccination on AD risk merit further investigation. These mechanisms - and those underlying the effects of adulthood vaccinations on all-cause dementia risk in general - can be grouped into at least three broad, non-exclusive categories: 1) influenza-specific mechanisms, including mitigation of damage secondary to influenza infection and/or epitopic similarity between influenza proteins and AD pathology; 2) non-influenza-specific training of the innate immune system; and 3) non-influenza-specific changes in adaptive immunity via lymphocyte-mediated cross-reactivity.

The apparent effect of influenza vaccination on AD risk may be secondary to influenza-specific immunity conferred by the vaccine. Central nervous system (CNS) injury during influenza infection can occur from direct viral invasion of nervous tissues or as collateral damage from the systemic immune response to peripheral infection. An association between flu infection and AD risk is supported by mouse studies demonstrating that peripheral infection of wild-type mice with non-neurotropic influenza strains induces excessive microglial activation and subsequent alteration of neuronal morphology, particularly in the hippocampus, that persists after infection resolution.

Long-term, non-influenza-specific alteration of the innate immune system presents another class of mechanisms potentially underlying influenza vaccination's apparent effect on AD risk. Several vaccines, including the influenza vaccine, are associated with non-specific protective effects via long-term reprogramming of innate immune cells, a process termed "trained immunity". Several studies have shown that the innate-related changes in peripheral cytokines associated with vaccination can directly affect microglial activity, including the efficiency of microglia in clearing amyloid-β aggregates. Another mechanism related to innate immunity that potentially underlies the association between flu vaccination and AD is alteration of the sustained low-grade systemic elevation of proinflammatory cytokines referred to as "inflammaging" that is commonly observed among older adults.

Link: https://doi.org/10.3233/JAD-220361

Researchers here report on an investigation of mechanisms by which aged human skin is improved in function when transplanted onto young immunocompromised mice. They identified VEGF-A as a factor involved in this improvement, and showed that delivering VEGF-A to human skin models can reduce signatures of aging. This is interesting, as a number of skin conditions exhibit high levels of VEGF-A, and are treated by therapies that are shown to inhibit VEGF-A in addition to other effects. Thus more work is needed here in order to understand whether or not VEGF-A based treatments are a viable path to improving aged skin function.

Human skin is ideally suited as a preclinical aging research model but is rarely used by mainstream aging research for this purpose. Yet, aging of the human body becomes nowhere sooner and more immediately visible than in skin changes and hair graying. While massive industry efforts therefore cater to the ancient human desire to halt or reverse the phenotype of aging skin, success at this frontier has remained moderate at best, and many product claims of in vivo rejuvenation of human skin are typically insufficiently substantiated. Nevertheless, the molecular mechanisms that underlie extrinsic and intrinsic skin aging in vivo are becoming increasingly understood, albeit mostly in nonhuman animal models of uncertain clinical relevance.

Previously, we had shown that grafting aged human skin to immunocompromised young mice reverts several aging-associated parameters in the epidermis of the human xenotransplants. Yet, it is unknown whether the observed skin rejuvenation effects extend beyond the epidermis, and the molecular mechanisms that underlie this striking epidermal rejuvenation phenomenon have remained elusive. Examining this accessible, experimentally pliable, and clinically relevant model for human organ rejuvenation in vivo, the present study hoped to identify druggable targets for human organ rejuvenation.

Transplanting aged human skin onto young immunocompromised mice morphologically rejuvenates the xenotransplants. This is accompanied by angiogenesis, epidermal repigmentation, and substantial improvements in key aging-associated biomarkers, including ß-galactosidase, p16ink4a, SIRT1, PGC1α, collagen 17A, and MMP1. Angiogenesis- and hypoxia-related pathways, namely, vascular endothelial growth factor A (VEGF-A) and HIF1A, are most up-regulated in rejuvenated human skin. This rejuvenation cascade, which can be prevented by VEGF-A-neutralizing antibodies, appears to be initiated by murine VEGF-A, which then up-regulates VEGF-A expression/secretion within aged human skin.

While intradermally injected VEGF-loaded nanoparticles suffice to induce a molecular rejuvenation signature in aged human skin transplanted onto old mice, VEGF-A treatment improves key aging parameters also in isolated, organ-cultured aged human skin, i.e., in the absence of functional skin vasculature, neural, or murine host inputs. This identifies VEGF-A as the first pharmacologically pliable master pathway for human organ rejuvenation in vivo and demonstrates the potential of our humanized mouse model for clinically relevant aging research.

Link: https://doi.org/10.1126/sciadv.abm6756