Fight Aging!

In today's study, researchers report on a comparison between mice undergoing life-long exercise (a wheel in their cage) versus more sedentary mice (no wheel). The authors note that the age-related onset of sarcopenia is much reduced in the exercising mice, which we could perhaps take as more of an indication of the harms of a lack of exercise than of the benefits of exercise per se. This is perhaps the least interesting part of the data and discussion, however. One of the points being made by the researchers is that the effects of life-long exercise are underestimated by the research community, because this intervention is not well studied in either mice or humans, at least in comparison to shorter periods of exercise commencing in old age.

The other point being made is that while it is known that exercise helps to blunt the loss of capillary density with age, the markers that the researchers assessed for cellular biochemistry related to angiogenesis, the creation of blood vessels, are not telling a story that matches up with the observed outcome. Thus the present understanding of the way in which exercise interacts with maintenance of capillary networks over the long term is probably incomplete, and there are other pathways to discover and investigate.

Capillary density is important in the operation of energy-hungry tissues such as muscle and the brain, being the road by which nutrients reach cells. Fewer capillaries means a lesser supply of nutrients and a consequent stress on cells and loss of tissue function. This issue of capillary densitry is probably a useful point of intervention, given safe strategies to adjust the operation of angiogenesis, such as VEGF gene therapy or CXCL12 upregulation via small molecule drugs.

Effects of lifelong spontaneous exercise on skeletal muscle and angiogenesis in super-aged mice

The effect of endurance exercise on sarcopenia is underestimated compared to that of resistance exercise. The reason for this is that the studies so far have mainly focused on therapeutic approaches after the onset of sarcopenia. In addition, large-scale epidemiological studies are difficult to control for variables that directly or indirectly affect endurance exercise. In the case of clinical studies, it is difficult to obtain various physiological phenotypes in the muscles following endurance exercise through research because long-term endurance exercise intervention over a lifetime is virtually impossible.

Our previous study indirectly demonstrated that the risk of premature death can be lowered by maintaining energy homeostasis in super-aged mice subjected to lifelong spontaneous exercise (LSE). Therefore, it was expected that the onset of sarcopenia caused by aging would be delayed or the risk of sarcopenia occurring during aging would be lowered if LSE that mimics endurance exercise is performed. We aimed to investigate the quantity and quality of skeletal muscle in 25-month-old super-aged mice (99-week-old, corresponding to a human age of at least 70 years), which corresponds to the late life of naturally aging mice used as a rodent model for sarcopenia. In particular, one of the key points of this study was to explain capillary density (expression of angiogenesis-related genes and angiogenic capacity), which is known to be closely related to endurance exercise, by integrating the results of our previous study.

Our findings show that LSE could maintain skeletal muscle mass, quality, and fitness levels in super-aged mice. In addition, ex vivo experiments showed that the angiogenic capacity was maintained at a high level. However, these results were not consistent with the related changes in the expression of genes and/or proteins involved in protein synthesis or angiogenesis. Based on the results of previous studies, it seems certain that the expression at the molecular level does not represent the phenotypes of skeletal muscle and angiogenesis. This is because aging and long-term exercise are variables that can affect both protein synthesis and the expression patterns of angiogenesis-related genes and proteins. Therefore, in aging and exercise-related research, various physical fitness and angiogenesis variables and phenotypes should be analyzed.

Data for the ability of metformin to slow aging has researchers looking at other antidiabetic drugs these days, even given that the evidence for metformin to have a meaningful impact on aging in non-diabetic animals is not great, very mixed, and even the human data for a modest addition of a few years in type 2 diabetes patients is most likely not as good as the impact of exercise and control of weight. Still, repurposing drugs to produce modest effects in a different condition has long been a going concern; regulators make it so hard to develop new drugs that it makes economic sense to repurpose existing drugs, even when the likely gains for patients are marginal. The research noted here is par for the course in this respect, finding a gender-specific modest effect on mouse life span for an antidiabetic. Generally, effect sizes in mice for near all metabolism-altering approaches that slow aging are much larger than in humans, so the result here is not all that exciting.

Canagliflozin (Cana), a clinically important anti-diabetes drug, leads to a 14% increase in median lifespan and a 9% increase in the 90th percentile age when given to genetically heterogeneous male mice from 7 months of age, but does not increase lifespan in female mice. A histopathological study was conducted on 22-month-old mice to see if Cana retarded diverse forms of age-dependent pathology. This agent was found to diminish incidence or severity, in male mice only, of cardiomyopathy, glomerulonephropathy, arteriosclerosis, hepatic microvesicular cytoplasmic vacuolation (lipidosis), and adrenal cortical neoplasms. Protection against atrophy of the exocrine pancreas was seen in both males and females.

Thus, the extension of lifespan in Cana-treated male mice, which is likely to reflect host- or tumor-mediated delay in lethal neoplasms, is accompanied by parallel retardation of lesions, in multiple tissues, that seldom if ever lead to death in these mice. Canagliflozin thus can be considered a drug that acts to slow the aging process and should be evaluated for potential protective effects against many other late-life conditions.

Link: https://doi.org/10.1007/s11357-022-00641-0

The aging of the vasculature, set aside from any other part of the body, arguably kills the largest fraction of humanity at the present time. It isn't just the dysfunctions of macrophages that lead to atherosclerotic plaque, and the narrowing of blood vessels and stroke and heart attack. It isn't just the declining density of capillary networks, reducing blood supply to energy-hungry tissues. It isn't just blood-brain barrier leakage and the consequent inflammation of the brain, or the stiffening of arteries that causes hypertension and remodeling of the heart. The vasculature is so vital that a great many mechanisms compete in their ability to cause harm with advancing age and the growing burden of cell and tissue damage.

Aging represents the main risk factor for cardiovascular disease (CVD) which carries the highest burden for the older population and is the leading cause of death worldwide. Vascular aging is a gradually developing process characterized by alterations in the properties of the vascular wall that start very early in life. In fact, it has been documented that the architecture of the vascular system is programmed in utero and most of the elastin, the major structural component underlying arterial wall elasticity, is synthesized and deposited during that period.

The phenotype of vascular aging in adults will be identified by certain vascular alterations which result in vascular dysfunction and development of a wide range of age-related vascular pathologies. These alterations are divided into structural changes which include the progressive thickening of the vascular wall along with vascular smooth muscle cell (VSMC) migration and proliferation, namely vascular remodeling, and the functional changes which include endothelial dysfunction, loss of arterial elasticity and reduced arterial compliance, all of which result in increased arterial stiffness.

The pathogenesis behind these changes in vascular aging involves multiple complex cellular and molecular mechanisms such as mitochondrial dysfunction and oxidative stress, inflammation, loss of proteostasis, genomic instability, cellular senescence, increased apoptosis and necroptosis, epigenetic alterations, and extracellular matrix (ECM) remodeling. As many age-related cardiovascular and cerebrovascular diseases are due to alterations in vascular function or are exacerbated by vascular functional and structural changes, it is important to thoroughly elucidate those fundamental pathophysiological mechanisms underlying the vascular aging process, in an attempt to develop novel treatments to reduce age-associated mortality. In this review, we describe the fundamental cellular and molecular mechanisms of aging: oxidative stress, chronic low-grade inflammation, cell matrix injury, epigenetic alterations, telomere length, cellular senescence and autophagy, considering in vitro and in vivo preclinical research and clinical studies.

Link: https://doi.org/10.3390/ijms23158672

One has to be somewhat careful when declaring that an intervention produces accelerated aging. Interventions that reduce health and life span in ways that mimic aspects of aging tend to be narrow in effect, causing elevated levels of a specific form of molecular damage, often one of those thought to be involved in natural aging. DNA repair deficiencies cause what looks a lot like accelerated aging, but should really be thought of as an excess of only one type of age-related damage, nuclear DNA damage. It might be possible to learn things from this type of malfunction, but given that it is very unlike natural aging, it is more likely that a close inspection of the cellular biochemistry and tissue dysfunction involved would be misleading. One can make similar, more difficult arguments regarding whether or not excess visceral fat tissue produces accelerated aging by increasing the burden of cellular senescence, or whether this should be viewed in much the same way as DNA repair deficiencies.

In today's open access paper, researchers note that engineering a greater activity of retrotransposons, in effect producing DNA damage as the transposable elements replicate themselves to break the parts of the genome they copy into, accelerates aspects of aging in flies. This is a closer analogy to DNA repair deficiencies than the question of obesity, again a way to amplify natural processes of DNA damage with consequences that can mimic natural aging in some ways. Retrotransposons are tightly controlled in youth, but epigenetic aging allows them ever greater freedom to replicate in later life. There is a fair amount of evidence to implicate this process in age-related disease and loss of function, but as is the case for so much of aging it is hard to pin down exactly how much harm is caused by this one process, versus all of the other processes of aging. Speeding it up in isolation of other mechanisms is one way to make an estimate, but it is nowhere near as compelling as the much harder demonstration, yet to be achieved, of slowing it down.

Artificially stimulating retrotransposon activity increases mortality and accelerates a subset of aging phenotypes in Drosophila

Transposable elements (TE) are mobile sequences of DNA that can become transcriptionally active as an animal ages. Whether TE activity is simply a byproduct of heterochromatin breakdown or can contribute towards the aging process is not known. Here we place the TE gypsy under the control of the UAS GAL4 system to model TE activation during aging. We find that increased TE activity shortens the lifespan of male D. melanogaster. The effect is only apparent in middle aged animals. The increase in mortality is not seen in young animals. An intact reverse transcriptase is necessary for the decrease in lifespan implicating a DNA mediated process in the effect.

The decline in lifespan in the active gypsy flies is accompanied by the acceleration of a subset of aging phenotypes. TE activity increases sensitivity to oxidative stress and promotes a decline in circadian rhythmicity. The overexpression of the Forkhead-box O family (FOXO) stress response transcription factor can partially rescue the detrimental effects of increased TE activity on lifespan. Our results provide evidence that active TEs can behave as effectors in the aging process and suggest a potential novel role for dFOXO in its promotion of longevity in D. melanogaster.

The accumulation of senescent cells in aged tissues is an important contributing cause of aging, but it is only one cause of many. Nonetheless, removing even just a third of lingering senescent cells in some tissues produces a degree of rejuvenation in old mice that is large enough to be very interesting. Much of this effect appears mediated by a reduction in inflammatory signaling and thus in the chronic inflammation that disrupts tissue function in later life. We can hope that clinical trials and the ongoing development of first and second generation senolytic therapies to clear senescent cells will demonstrate similar benefits to health in humans.

Chronic inflammation, one of the major hallmarks of aging, is thought to be partly caused by senescent cells that may accumulate in older individuals. As we age, a small number of cells in tissues throughout our body become senescent. These cells undergo irreversible cell cycle arrest - in other words, they can no longer divide. The unique cells may have some evolutionary benefit. Rapid cell division, for example, can lead to cancer, and senescence may be an evolutionary adaptation that reduces the risk of certain cells becoming cancerous. However, senescent cells also produce inflammatory cytokines that accelerate the process of aging.

Researchers hypothesize that through targeting senescent cells, they could potentially reign in chronic inflammation in aging individuals. To study senescence in mice, the researchers will mark various cells with fluorescent markers to track how the cells age over time and to see if they become senescent. Next, they will use unbiased transcriptional sequencing and spatial sequencing approaches - techniques used to help researchers generate a map of the cell they are sequencing - to try and discover new markers that are unique to senescent cells.

The team hopes their work will lead to the development of approaches to target senescent cells in a way that reduces the inflammation they produce. Some researchers, for example, are studying ways to eliminate senescent cells using drugs known as senolytics. However, the use of these drugs is controversial because current senolytic drugs aren't specific to just getting rid of senescent cells and may harm other cells as well. The workcould potentially help scientists identify senescent cells causing chronic inflammation and develop newer, more precision drugs targeting these cells.

Link: https://medicine.yale.edu/news-article/how-studying-cellular-senescence-can-help-researchers-learn-to-delay-aging/

Mice in which the POLG genek critical to repair of mitochondrial DNA, is disabled via genetic engineering exhibit accelerated aging. Researchers here show that these mice also show an accelerated rate of nuclear DNA damage and shorter telomere length. Telomeres shorten with each cell division in somatic cells, eventually reaching the Hayflick limit and senescence or programmed cell death, while stem cells produce daughter cells with long telomeres to replace losses. Average telomere length is thus, loosely, a measure of stem cell function, though since it is normally measured in immune cells from a blood sample, it also reflects immune system stress. The raised rate of nuclear DNA strand breaks may be the more interesting correlation here, given recent work suggesting that this repeated cycles of damage and repair of this sort results in epigenetic changes characteristic of aging.

Mitochondrial dysfunction plays an important role in the aging process. However, the mechanism by which this dysfunction causes aging is not fully understood. The accumulation of mutations in the mitochondrial genome (or "mtDNA") has been proposed as a contributor. One compelling piece of evidence in support of this hypothesis comes from the PolgD257A/D257A mutator mouse (Polgmut/mut). These mice express an error-prone mitochondrial DNA polymerase that results in the accumulation of mtDNA mutations, accelerated aging, and premature death. In this paper, we have used the Polgmut/mut model to investigate whether the age-related biological effects observed in these mice are triggered by oxidative damage to the DNA that compromises the integrity of the genome.

Our results show that mutator mouse has significantly higher levels of 8-oxoguanine (8-oxoGua) that are correlated with increased nuclear DNA (nDNA) strand breakage and oxidative nDNA damage, shorter average telomere length, and reduced mtDNA integrity. Based on these results, we propose a model whereby the increased level of reactive oxygen species (ROS) associated with the accumulation of mtDNA mutations in Polgmut/mut mice results in higher levels of 8-oxoGua, which in turn lead to compromised DNA integrity and accelerated aging via increased DNA fragmentation and telomere shortening. These results suggest that mitochondria play a central role in aging and may guide future research to develop potential therapeutics for mitigating aging process.

Link: https://doi.org/10.1111/acel.13669

Fecal microbiota transplantation from young individuals to old individuals reduces inflammation, improves health, and extends life span in killifish, a short lived species. It at least reduces inflammation and improves health in mice. Despite being used to treat C. Difficile infections, in which the gut microbiome is overtaken by that unwelcome species of bacteria, there is next to no data in humans on the very interesting question of whether the gut microbiome, and the many declines in health that are associated with age-related shifts in the microbiome, can be improved by transplanting a sample of youthful gut microbes.

The study reported in today's open access paper doesn't help in providing an answer, I think. It is good to see that old people with C. Difficile infections resistant to other treatments can be helped by fecal microbiota transplantation. It is good to see that the patients experience improved cognitive function. But one can't separate the unpleasant effects of C. Difficile from the unpleasant effects of gut microbiome aging in this small study in that respect, and the choice of antibiotics for a control group, who were actually worse off after the treatment, just muddies the water, given the effects of antibiotics on the broader gut microbiome. The outcomes do not allow us to say all that much about how healthy older humans will benefit from the transplantation of a young gut microbiome, other than it appears safe to undertake.

In particular, we might look at chronic inflammation as one of the more relevant outcomes of gut microbiome aging. Inflammatory populations expand in number, perhaps because they are no longer adequately restrained by the immune system as it ages into immunosenescence. Chronic inflammation is strongly implicated in the progression of neurodegeneration and cognitive decline. Runaway C. Difficile infection is a highly inflammatory condition, however. Thus getting rid of the C. Difficile population obscures the question of whether and how the transplant is also improving the gut microbiome more generally in these older patients.

Fecal microbiota transplantation can improve cognition in patients with cognitive decline and Clostridioides difficile infection

After fecal microbiota transplantation (FMT) to treat Clostridioides difficile infection (CDI), cognitive improvement is noticeable, suggesting an essential association between the gut microbiome and neural function. Although the gut microbiome has been associated with cognitive function, it remains to be elucidated whether fecal microbiota transplantation can improve cognition in patients with cognitive decline.

The study included 10 patients (age range, 63-90 years; female, 80%) with dementia and severe CDI who were receiving FMT. Also, 10 patients (age range, 62-91; female, 80%) with dementia and severe CDI who were not receiving FMT. They were evaluated using cognitive function tests (Mini-Mental State Examination [MMSE] and Clinical Dementia Rating scale Sum of Boxes [CDR-SB]) at 1 month before and after FMT or antibiotics treatment (control group). The patients' fecal samples were analyzed to compare the composition of their gut microbiota before and 3 weeks after FMT or antibiotics treatment.

Ten patients receiving FMT showed significantly improvements in clinical symptoms and cognitive functions compared to control group. The MMSE and CDR-SB of FMT group were improved compare to antibiotics treatment (MMSE: median 16.00 vs 10.0; CDR-SB: median 5.50 vs 8.0). FMT led to changes in the recipient's gut microbiota composition, with enrichment of Proteobacteria and Bacteroidetes. Alanine, aspartate, and glutamate metabolism pathways were also significantly different after FMT.

This study revealed important interactions between the gut microbiome and cognitive function. Moreover, it suggested that FMT may effectively delay cognitive decline in patients with dementia.

These days, articles in the popular, non-scientific media on the topic of treating aging as a medical condition tend towards being something other than terrible. This is a considerable improvement over the state of affairs a decade ago, and night and day in comparison to the press attitudes towards aging research in the early years of this century. There is always room for improvement, and journalists are near always ill-informed about near everything they commit to paper, but nonetheless the tone is heading in the right direction: that the treatment of aging is a project, it is underway, there are many competing approaches and opinions, and, given the importance of the resulting therapies to all of our lives, this part of the scientific endeavor should not be ignored.

For all the advances in medical technology humans have developed, there is one thing it hasn't been able to do: stop us from getting old. We've managed to extend the human lifetime dramatically in the last couple of centuries, greatly diminishing infant and child mortality and pushing back on disease with antibiotics and vaccines. But the general trajectory of life endures: once we get into the last quarter of our lives, our health gradually declines. That may soon change, as researchers focus on treating the diseases and conditions that plague us as we get older. It's not impossible that we might soon see medicines that greatly improve and maintain our health and independence as we head into our golden years.

"Until now, we've been treating medicine in this very unsystematic way. In a sense, we've been picking off the endpoints of aging, things like cancer and heart disease, without actually addressing the fundamental underlying causes that are resulting in those diseases. So what we could do by understanding these hallmarks of aging, is potentially come up with treatments to intervene in them directly. And that means preventative treatments, treatments can go in earlier and stop people getting ill in the first place."

There are already treatments for cellular senescence, drugs that target these redundant cells and remove them, along with the toxic cocktail of molecules that accompany them and contribute to heart disease and cancer. Using these treatments on mice essentially made the mice biologically younger. "It's not as though they were hobbling along in a sort of geriatric state, which has somehow been extended by this anti-aging treatment. What they found is that the mice were healthier too. So they got less cancer, they got less heart disease, they got fewer cataracts, they were less frail."

That's an important concept to get across. Most people, when they think of increasing human lifetimes from, say, 80 to 120 years, assume that this means we'll just be very old for a longer time, which doesn't hold a lot of appeal. But if we could live to 120 and be healthy and active until we're, say, 118, then that's a much more attractive proposition.

Link: https://www.cbc.ca/radio/spark/with-advances-in-medicine-could-80-become-the-new-40-1.6427495

Researchers here propose a better way of measuring the burden of cellular senescence in aged tissues, one that works well across different tissues and species. It is complicated, involving expression of many genes, but the existing simple metrics, such as measurement of senescence-associated beta-galactosidase levels, are increasingly thought inadequate to the task. Senescent cells likely vary in character and metabolism between tissues in ways that have become meaningful now that researchers are past the period of early validation of therapies targeting senescent cells. Now it is important to obtain a much better idea as to the effectiveness of various potential treatments in mice or humans than is presently the case.

Cellular senescence is now recognized as a fundamental mechanism of aging in animals and humans. Senescent cells can develop a senescence-associated secretory phenotype (SASP), consisting of pro-inflammatory cytokines, chemokines, extracellular matrix-degrading proteins, and other factors that have deleterious paracrine and systemic effects. Further, because senescent cells accumulate in multiple tissues in temporal and spatial synchrony with age-associated functional decline in both animals and humans, they have been hypothesized to drive the deterioration linked to numerous chronic diseases. Importantly, the SASP as a feature of cellular senescence represents not just a locally or systemically detrimental set of factors that, in the aging organism, cause physical, metabolic, and cognitive decline, but is also a therapeutic target of interest. Thus, given the broad availability of next-generation sequencing, there is considerable interest in monitoring responses to senolytic treatments. However, this has been challenging, especially at the single cell level. In part, this is due to an imprecise definition of the heterogeneous population of senescent cells and their associated SASP which complicates appropriate monitoring of senescent cell clearance.

Due to variations in the composition of a "senescence gene set" in the current literature, in the present study we sought to identify commonly regulated genes in various age-related datasets in a transcriptome-wide approach that included whole-transcriptome as well as single cell RNA-sequencing (scRNA-seq). Based on an extensive review of the literature, we defined a panel of 125 genes as our senescence gene set ("SenMayo"), which we then validated in our own as well as publicly available datasets of tissues from aged humans and mice, including changes in this gene set following the clearance of senescent cells. Recognizing the difficulty of identifying senescent cells within scRNA-seq analyses, we next applied SenMayo to available scRNA-seq data from human and murine bone marrow/bone hematopoietic and mesenchymal cells, ascertained the identity of the senescent cells in these analyses, and characterized the communication patterns of senescent hematopoietic or mesenchymal cells with other cells in their microenvironment. Finally, we experimentally validated key predictions from our in silico analyses in a mouse model of aging and following genetic clearance of senescent cells.

Link: https://doi.org/10.1038/s41467-022-32552-1

In a time of rapid progress in biotechnology, the Hippocratic pledge of "first do no harm" kills a lot of people. It just doesn't kill them as directly as more obvious means. Taken to its extreme, "first do no harm" is a strong precautionary principle, it forbids progress, it forbids the testing of new therapies. While we are not at the point of forbiddance yet, regulators have been heading in that direction for years. Officials at the FDA and similar regulatory bodies are willing to accept great ongoing suffering and death in the service of reducing the risk of harm due to new therapies to as close to zero as possible. The costs of regulatory compliance and degree of proof required for novel medical technologies scale upward year after year, and, accordingly, the pace of progress slows while patients continue to die. Medicine in the clinic lags far behind what is possible in the laboratory.

This isn't the best way forward for an era of revolutionary advances in biotechnology, information science, communication technologies. A different paradigm must emerge, one that will lead to more rapid development of new medicines and a lower overall toll of death and suffering. Consider the following, which I will call Distributed Full Disclosure Medical Development, in which information is the currency by which, on an ongoing and incremental basis, the safety and success or failure of therapies can be judged, and patients can make their own informed decisions, guided or unguided by specialists. There are no clinical trials, because there need to be no clinical trials - the entire life span of a therapy to date is the data by which future patients make their decisions. Someone will have to be brave, and be first, but that is no different than today's environment:

1) Anyone can propose, manufacture, and sell a therapy. The only requirement is to publish all of the preclinical data.

2) Any organization can set itself up as a reviewer of therapies.

3) Any provider can offer therapies, provided that the patient signs a disclaimer, agrees to open publication of their medical data, and that data is in fact published.

4) Any organization can set itself up as a clearinghouse and analyst of all of this medical and developmental data.

This is clearly possible in principle. It requires no new technology, only a commitment to the incentives of publishing. Reviewers and clearinghouses steer patients to better providers and therapies, and providers and developers are thus incentivized to prove to reviewers and clearinghouses that what they do is good. Abuses will always happen, people being people, but modern legal systems financially incentivize victims and third parties alike to vigorously attack abusers. Nothing new is needed there. This describes a very normal market in an information age society - and we should perhaps look at the medical markets we have and consider that they are aberrant and strange for our era.

Present day clinical trials leading to regulatory approval, and further studies of approved therapies, form a broken system. It is not full disclosure, because companies keep trade secrets. It is slow and expensive, and data is hidden for years before being only partially released, usually summarized. The infrastructure of clinical trials is an awkward concession to the reality that every medicine must be tested in humans for the first time. People have died when this happens, with the best of preparations. People will continue to die in the future. People will die in a Distributed Full Disclosure Medical Development system. But, I think, far fewer than die now. The primary issue of present regulatory systems, characterized by a central authority wherein "first do no harm" is a goal considerably more important than the development of new therapies, is that the resulting bureaucracy is so slow and expensive that people die waiting on treatments, while development of many potential treatments is never even undertaken, as the onerous requirements make it too expensive to do so. In a better system, cures would be discovered and tested more rapidly. Getting rid of the gatekeeper is necessary.

Yet the medical tourism concerns of the world, medicine absent that primary gatekeeper, also form a broken system. Overseas clinics and regulatory arbitrage is a necessary rebellion against US and EU regulators and their slow, lumbering clinical trial ecosystem, but so far this rebellion has proven just as unable to produce the desired outcome of more rapid, useful progress. There are even more secrets than is the case in the regulated world of medical development. Data is never published, unless extraordinary and beneficial to the clinic. Patients are are more free, but even more in the dark when it comes to making informed choices.

Neither of these systems is likely to change much. The short-term incentives are what they are: no overseas clinic wants to publish anything other than carefully cherry-picked data, and the trend of regulatory bodies in the US and EU continues to be for ever greater costs, ever more burdensome requirements, and ever fewer approved new therapies, in the service of trying to achieve the impossible goal of risk-free new medicine. Yet it is easy enough to describe the principles of a potentially far better system; it can be done in a paragraph or two. In an era of computation, communication, and biotechnology, we are somehow still stuck with the two options of (a) lumbering regulatory systems that kill patients by slowing progress to a crawl, and (b) secretive clinics performing work that is impossible to assess in any useful way. This seems ridiculous, and something that can and should be changed with the advent of a new third way, and with the growth of organizations that encourage and support that third way.

Within a species, variations in the operation of metabolism correlate with later life health and life span. Insulin metabolism is one of the more prominent and well studied examples. Much of this may stem from the lifestyle choices that epidemiology shows explain the majority of the variation in human life expectancy. Become sedentary or overweight and this pushes metabolism into a less optimal, more harmful state. The consequences to health and risk of mortality accrue over a long period of time, but are no less real for it.

The study of aging has long been linked with the study of metabolism, as early theories pointed to the rate of metabolism and by-products of metabolism as drivers of aging processes. The earliest recognized interventions that caused life span extension in model organisms targeted nutritional and metabolic pathways. A more nuanced view of aging mechanisms has since emerged that identifies dysregulated metabolism as one of many hallmarks of aging.

Epidemiologic studies of the oldest old humans, centenarians, strive to identify unifying lifestyle elements, nutritional patterns, and genetic or metabolomic signatures that clearly underlie longevity. Certainly, the female sex confers a longevity advantage, as centenarians are disproportionately female. This pattern of increased female longevity is seen across species; however, its underpinnings are incompletely understood. Social engagement, diet composition, and fasting patterns have been identified as factors that may confer longevity on a population level. Indeed, caloric restriction is known to promote longevity and delay the onset of age-related disease in multiple species. The people of Okinawa, who before the influence of a Western diet ate only 83% of the average calories consumed by the mainland Japanese population, were observed to have a longer life span and lower mortality from coronary artery disease and cancer than mainland Japanese or American people.

Long-lived humans may have some advantage in glucose handling. In one study, human centenarians (older than 100 years of age) had better insulin sensitivity than did younger controls older than 75 years of age. Insulin sensitivity is associated with healthy aging across species, and in fact modifications in glucose signaling pathways were some of the first interventions to lead to life span extension in model systems including yeast and Caenorhabditis elegans. Similarly, inhibition of the growth hormone (GH) axis is associated with longevity in model systems. However, lifelong GH deficiency is also accompanied by smaller body size, which in humans may confer undesirable effects such as adipose tissue accumulation and intellectual deficiency. Body size is typically inversely correlated with longevity (such as in dogs), but this does not seem to be the case in humans.

Link: https://doi.org/10.1172/JCI158451

The constantly changing structure of nuclear DNA, packaged into chromatin, determines which genes are accessible to the machinery of gene expression, which determines protein production, which determines cell behavior and state. Chromatin structure and all of the determinants of that structure, including epigenetic marks such as DNA methylation, change as a cell ages towards the Hayflick limit and cellular senescence, and change in aged tissues versus young tissues. Given the advent of epigenetic reprogramming as a potential strategy for rejuvenation, questions regarding the ways in which epigenetics determines cell function in cellular senescence and aging become more pressing.

Comprehending the role of molecular processes such as DNA damage repair, telomere shortening, nuclear and chromatin changes along with epigenetic alterations which drive aging as well as aging related diseases may hold a key to the "elixir of life." Of late the resurrection of aged cells back to cellular proliferation has garnered attention from various molecular biologists. The use of Yamanaka factors reprograms cells to a partially undifferentiated stage which is shown to ameliorate some of the functions of aged fibroblasts. The transient expression of these factors rescued the levels of H3K9me3 and DNA damage marks such as γ-H2AX. These studies fortify the beneficial role of heterochromatin in protecting the genome from DNA damage and neoplastic transformation.

However, there remain several uncharted domains: Is heterochromatin alone sufficient to extend lifespan? Is the reorganization of the heterochromatin guided by the changed DNA methylome in aged cells? A varied number of histone variants are expressed inside as well as outside of the senescence associated heterochromatin foci (SAHF). What directs them to their specific genomic location upon senescence? The complexity and confusion arise as cells induced by different stress mediated pathways show different epigenetic signatures or varied chromatin organization. Senescent cells found in the pre-cancerous lesions exhibit increased levels of heterochromatic histone modifications (H3K9me2/3 and HP1γ) but lack in SAHF. This discrepancy might be due to the variation in the extent of heterochromatinization of the genome.

We posit that analyzing the biophysical and mechanical nature of aged chromatin polymer in different cell types might provide clues to its natural decay and dysfunction. Despite current technological challenges, even elucidating the half-life or turnover of chromatin factors, including post-translational modifications of nucleosomes, repair factors, chromatin remodelers could be an important start. Knowing these parameters, we can better understand and potentially model how the nuclear landscape changes as cells age.

Link: https://doi.org/10.3389/fcell.2022.943519

Neurogenesis is the production of new neurons from neural stem cell populations, and their integration into neural circuits. Neurogenesis is necessary to memory, learning, and what little regeneration the brain is capable of undertaking following injury. A sizable body of evidence suggests that increased neurogenesis is a good thing, beneficial to brain function, at any adult age. In later life, increased neurogenesis may be capable of compensating for at least some of the damage and dysfunction exhibited by the aging brain. Compensatory therapies are not as useful as treatments that address underlying causes, unfortunately, usually only capable of slowing the progression of a condition.

Today's research materials note an example of this sort of compensatory therapy applied to the progression of cognitive dysfunction in a mouse model of Alzheimer's disease. Such models are quite artificial, as mice do not naturally suffer from anything resembling Alzheimer's disease. The model itself incorporates major assumptions about which mechanisms and forms of pathology are important. One of the major challenges in the field of Alzheimer's research is that it is somewhat unclear as to whether a given result in an animal model is in any way relevant to the natural condition in humans.

Boosting neuron formation restores memory in mice with Alzheimer's disease

Researchers boosted neurogenesis in Alzheimer's disease (AD) mice by genetically enhancing the survival of neuronal stem cells. The researchers deleted Bax, a gene that plays a major role in neuronal stem cell death, ultimately leading to the maturation of more new neurons. Increasing the production of new neurons in this way restored the animals' performance in two different tests measuring spatial recognition and contextual memory.

By fluorescently labeling neurons activated during memory acquisition and retrieval, the researchers determined that, in the brains of healthy mice, the neural circuits involved in storing memories include many newly formed neurons alongside older, more mature neurons. These memory-stowing circuits contain fewer new neurons in AD mice, but the integration of newly formed neurons was restored when neurogenesis was increased.

Further analyses of the neurons forming the memory-storing circuits revealed that boosting neurogenesis also increases the number of dendritic spines, which are structures in synapses known to be critical for memory formation, and restores a normal pattern of neuronal gene expression. Researchers confirmed the importance of newly formed neurons for memory formation by specifically inactivating them in the brains of AD mice. This reversed the benefits of boosting neurogenesis, preventing any improvement in the animals' memory.

Augmenting neurogenesis rescues memory impairments in Alzheimer's disease by restoring the memory-storing neurons

Hippocampal neurogenesis is impaired in Alzheimer's disease (AD) patients and familial Alzheimer's disease (FAD) mouse models. However, it is unknown whether new neurons play a causative role in memory deficits. Here, we show that immature neurons were actively recruited into the engram following a hippocampus-dependent task. However, their recruitment is severely deficient in FAD. Recruited immature neurons exhibited compromised spine density and altered transcript profile. Targeted augmentation of neurogenesis in FAD mice restored the number of new neurons in the engram, the dendritic spine density, and the transcription signature of both immature and mature neurons, ultimately leading to the rescue of memory. Chemogenetic inactivation of immature neurons following enhanced neurogenesis in AD, reversed mouse performance, and diminished memory. Notably, AD-linked App, ApoE, and Adam10 were of the top differentially expressed genes in the engram. Collectively, these observations suggest that defective neurogenesis contributes to memory failure in AD.

This popular science article on the development and present use of epigenetic clocks mentions the view that the clocks will point the way to a better understanding of the causes of aging. I'm dubious that use of the clocks represents a better way forward to that goal than the approach of implementing the various rejuvenation therapies outlined in the SENS proposals. A potential rejuvenation therapy that affects just one potential root cause of aging in isolation will tell us a lot about the importance and validity of that cause; researchers are learning a great deal from the ability to selectively destroy senescent cells, for example. Even good correlations between epigenetic states and aging will, unfortunately, take a long time to pick apart into knowledge of which mechanisms influence those epigenetic states, and to what degree. All along, the challenge of aging has been that looking without intervening tells us little of the behavior of a very complicated, interacting system of many different degenerative processes.

No one knows entirely why epigenetic clocks work. Some but not all of the genes and molecular pathways involved have been identified, and researchers are still learning how DNA methylation patterns affect the behaviors and health of cells, tissues and organs. Researchers have begun seeking biological correlates for epigenetic aging. Perturbations of the biochemical pathways the body uses to sense its need for nutrients slow aging, they recently discovered, in accordance with the effects of calorie-restricted diets on aging. Derailing the workings of mitochondria speeds it up. The clock also tracks the maturation of stem cells. If these processes are connected at a deeper level, epigenetic clocks may reveal unifying mechanisms for aging, researchers wrote in a 2022 paper.

What those unifying mechanisms might be or why methylation status tracks aging so well, however, is yet to be fully determined. "We don't really know if epigenetic clocks are causally linked with aging." Even if they are, epigenetic clocks are almost certainly measuring only part of what occurs during aging. "Whether they are actually measuring more than a single dimension of biological age is not clear. This is part of the problem here - the conflation of epigenetic age with biological age. Those are not equivalent in my view."

Researchers speculate that the methylation changes reflect a loss of cellular identity with age. All cells in the body have the same DNA, so what makes a liver cell a liver cell and a heart cell a heart cell is the pattern of gene expression, which epigenetics controls. As changes in methylation accumulate with age, some of those controls might be lost, replaced by re-emerging developmental programs that should be switched off. Nonetheless, methylation clocks have limited clinical uses at present. People can buy a readout of their biological age from various commercial sources, but not only are the results often inconsistent, they lack clinical relevance because the clocks were meant for group-level analyses in research. They are not built to be predictive at an individual level.

Link: https://www.quantamagazine.org/epigenetic-clocks-predict-animals-true-biological-age-20220817/

You may recall that a small trial of high dose supplementation with glutathione precursors produced what were, for a supplement regimen, sizable benefits in old people. The approach is called GlyNAC, a combination of glycine and N-acetylcysteine in doses approaching 10 grams per day. Here, researchers report on a larger, but still small, clinical trial that produced a similar outcome. Glutathione is important to mitochondrial function, and results appear to proceed from a reduction in the age-related impairment of mitochondria, as well as a reduction in age-related chronic inflammation.

Elevated oxidative stress (OxS), mitochondrial dysfunction, and hallmarks of aging are identified as key contributors to aging, but improving/reversing these defects in older adults (OA) is challenging. In prior studies, we identified that deficiency of the intracellular antioxidant glutathione (GSH) could play a role and reported that supplementing GlyNAC (combination of glycine and N-acetylcysteine [NAC]) in aged mice improved GSH deficiency, OxS, mitochondrial fatty-acid oxidation (MFO), and insulin resistance (IR). To test whether GlyNAC supplementation in OA could improve GSH deficiency, OxS, mitochondrial dysfunction, IR, physical function, and aging hallmarks, we conducted a placebo-controlled randomized clinical trial.

Twenty-four OA and 12 young adults (YA) were studied. OA was randomized to receive either GlyNAC (N = 12) or placebo (N = 12) for 16-weeks; YA (N = 12) received GlyNAC for 2-weeks. Participants were studied before, after 2-weeks, and after 16-weeks of supplementation to assess GSH concentrations, OxS, MFO, molecular regulators of energy metabolism, inflammation, endothelial function, IR, aging hallmarks, gait speed, muscle strength, 6-minute walk test, body composition, and blood pressure. Compared to YA, OA had GSH deficiency, OxS, mitochondrial dysfunction (with defective molecular regulation), inflammation, endothelial dysfunction, IR, multiple aging hallmarks, impaired physical function, increased waist circumference, and systolic blood pressure. GlyNAC (and not placebo) supplementation in OA improved/corrected these defects.

Link: https://doi.org/10.1093/gerona/glac135

Today's open access paper reviews what is known of the connections between epigenetic aging and the nuclear DNA damage that occurs across a lifetime, and particularly in later life. Some of this DNA damage is more evidently connected with the epigenetic regulation that determines the packaging and structure of nuclear DNA, such as the activity of transposable elements, restrained in youth, but unleashed to copy themselves in later life, damaging genes as they do so. It is important to note that the relationship of cause and consequence between nuclear DNA damage and epigenetic change is likely a two-way street, particularly given the comparatively recent discovery that repeated double strand break repair causes epigenetic alterations characteristic of aging.

While nuclear DNA damage raises the risk of cancer, such as via damage to cancer suppression genes, it is fortunately largely irrelevant, occurring in cells that have only a few replications left before hitting the Hayflick limit, and will therefore soon be removed from tissues, or in parts of the genome that are inactive. Outside of the cancer risk, and the epigenetic change noted above, it can be argued that only DNA damage in stem cells and progenitor cells is relevant to aging, as these mutations can spread throughout a tissue. The pattern of mutations in a tissue, some of which will potentially alter cell behavior in damaging ways, is known as somatic mosaicism. Proving that this causes issues beyond cancer risk is ever a challenge, however. A great many harmful processes operate in aged tissues, and determining the relative impact of any one of those processes is very difficult, absent a way to fix it in isolation of all other processes of aging.

Epigenetics, DNA damage, and aging

The biology of aging is very complex, and the heterogeneity of aging is abundantly clear. Over a decade ago, nine hallmarks of aging were identified at the cellular and molecular level. The universality of the hallmarks of aging across species suggests their causal role in driving aging. However, establishing cause and consequence has proved challenging. Notably, more than one of the hallmarks reflect alterations to the nuclear genome, the integrity of which is vital to cell function. Here, we focus on the relationship of two hallmarks of aging affecting the nuclear genome: macromolecular damage and epigenetic alterations.

In eukaryotes, epigenetic modifications are critical because of their effects on gene transcriptional regulation. During development, different cell types establish and maintain specific epigenetic landscapes that dictate their cell fate. With aging, pronounced epigenetic alterations occur, including changes to DNA methylation and histone modifications, two key regulators of gene expression. Concurrent with these changes, spontaneous DNA lesions occur every single day within each of the 10^13 cells that constitute a human body. These lesions stall DNA and RNA polymerases, provoking a DNA damage response (DDR) that halts the cell cycle, enabling DNA repair.

Excessive or chronic DDR triggers irrevocable cell fate decisions, e.g., apoptosis and senescence. These two hallmarks of aging are intimately intertwined: DNA repair alters the epigenome and the epigenome impacts DNA repair efficiency. Furthermore, epigenetic marks to DNA can promote DNA damage. Genotoxic stress (DNA damage) is accepted as playing a causal role in cancer and in aging. Epigenome instability is established to play a causal role in cancer, but the mechanism by which epigenetic changes might play a causal role in aging are not well defined. Given the plethora of epigenetic clocks that correlate with chronological and even biological age, the causal relationship likely exists. Herein, we examine the current state of evidence that epigenetic alterations contribute to driving aging biology. In addition, because epigenetic changes impact genome stability, we explore the relationship between epigenetic marks and DNA damage.

Mitochondria, the power plants of the cell, are the descendants of ancient symbiotic bacteria, and still carry a remnant circular genome, separately from the DNA of the cell nucleus. Some forms of mutational damage to mitochondrial DNA, and the downstream consequences of that damage, are thought to be an important contributing cause of degenerative aging, but what about epigenetic changes? Epigenetic aging in nuclear DNA is a hot topic at the moment, so it is inevitable that attention would turn to the epigenetics of the much smaller mitochondrial genome.

Inflammation is a defining factor in disease progression; epigenetic modifications of this first line of defence pathway can affect many physiological and pathological conditions, like aging and tumorigenesis. Inflammageing, one of the hallmarks of aging, represents a chronic, low key but a persistent inflammatory state. Oxidative stress, alterations in mitochondrial DNA (mtDNA) copy number and mis-localized extra-mitochondrial mtDNA are suggested to directly induce various immune response pathways. This could ultimately perturb cellular homeostasis and lead to pathological consequences.

Epigenetic remodelling of mtDNA by DNA methylation, post-translational modifications of mtDNA binding proteins and regulation of mitochondrial gene expression by nuclear DNA or mtDNA encoded non-coding RNAs, are suggested to directly correlate with the onset and progression of various types of cancer. Mitochondria are also capable of regulating immune response to various infections and tissue damage by producing pro- or anti-inflammatory signals. This occurs by altering the levels of mitochondrial metabolites and reactive oxygen species (ROS) levels.

Since mitochondria are known as the guardians of the inflammatory response, it is plausible that mitochondrial epigenetics might play a pivotal role in inflammation. Thus, strategies aimed at compensating for changes brought about by mitochondrial epigenetics like restoration of dysfunctional mtDNA or TFAM activity might emerge as promising preventive and therapeutic interventions for pathological conditions occurring due to exacerbated inflammation.

Link: https://doi.org/10.3389/fcell.2022.929708

An interesting discussion here on one the less obvious outcomes one might expect to result from a senolytic treatment to clear lingering senescent cells from aged tissues. The heart is one of the least regenerative organs in the body to begin with, but this becomes even more the case with age, as senescent cells accumulate and disrupt the normal processes of tissue maintenance and stem cell function with their inflammatory secretions. The catalog of benefits that might be realized by selectively destroying senescent cells in an old individual is far from complete at the present time, despite the scores of animal studies showing reversal of specific measures of aging and age-related disease.

"As you age, you have an increase in the number of senescent cardiac stem progenitor cells, and these have a reduced potential to proliferate and a reduced potential to differentiate. So, they're no longer able to do what we need them to do. One approach to solving the issues caused by senescent cells is the use of drugs called senolytics that target and kill them. We've used the drugs dasatinib and quercetin to eliminate senescent cells, and we've shown that when you eliminate senescent cells in an aged mouse model, you see a rejuvenation of the heart's regenerative potential. You have activation of the cardiac stem progenitor cells, cardiomyocyte proliferation, and decreased cardiac hypertrophy and fibrosis."

"We have devised these human cell co-culture in vitro systems, where we can test the effects of senescence and also the effects of senolytics on human cells. We've shown that senescent cells can impair survival and proliferation of a variety of cell types found in the heart. When we treat the co-cultures with senolytics to remove the senescent cells, we see an improvement in cell survival, proliferation, and improved angiogenesis. And we do these experiments in a human model, which is so important for us, to show translation."

Link: https://longevity.technology/senolytics-rejuvenate-the-regenerative-capacity-of-the-heart/

We are something like thirty years into the increasingly widespread use of first generation stem cell therapies. Cells are derived from a variety of sources, processed, and transplanted into patients. Near all of these transplanted cells die, but while they survive they secrete signals that suppress inflammation and encourage native cells to change their behavior for the better. It is fair to argue that these treatments have not yet realized the potential originally hoped for, the robust regeneration of damaged tissues. While suppression of inflammation is reliably achieved, regeneration and restored function for organs occurs in only some patients, and to a varying, modest degree.

More generally, not enough is known of how these therapies produce beneficial effects, or of the way in which cells interact in these circumstances. That leads to discussions such as the one offered in today's open access paper, in which clinicians look over their data to make the empirical observation that some sources of cells are better than others for treating specific conditions. Why this might be the case, or even whether it would still be the case in broader datasets, is an open question. Too little is known, much more research is needed, and this is the case decades into the development of this field!

If the original vision for cell therapies is to be realized, then the future of this field must be one in which the challenges of cell survival and cell integration into tissues are solved, allowing the wholesale replacement of damaged and dysfunctional stem cell populations. This may require the rejuvenation of tissues that make up stem cell niches, as at least some of the evidence accumulated to date suggests that stem cell populations can be functional, even in later life, if only protected from age-related changes in the signaling environment provided by the niche and surrounding tissues. That is a somewhat harder problem to solve than issues involving the transplanted cells themselves. But at the end of the day, defeating the challenges of stem cell therapies may require defeating the challenges of degenerative aging.

Stem cell-based therapy for human diseases

From a cellular and molecular perspective and from our own experience in a clinical trial setting, adipose-derived mesenchymal stem cells (AD-MSCs), bone marrow-derived MSCs (BM-MSCs) and umbilical cord derived MSCs (UC-MSCs) exhibit different functional activities and treatment effectiveness across a wide range of human diseases. In this paper, we have provided up-to-date data from the most recently published clinical trials conducted in neuronal diseases, endocrine and reproductive disorders, skin regeneration, pulmonary dysplasia, and cardiovascular diseases. The implications of the results and discussions presented in this review and in a very large body of comprehensive and excellent reviews as well as systematic analyses in the literature provide a different aspect and perspective on the use of MSCs from different sources in the treatment of human diseases.

We strongly believe that the field of regenerative medicine and MSC-based therapy will benefit from active discussion, which in turn will significantly advance our knowledge of MSCs. Based on the proposed mechanisms presented in this review, we suggest several key mechanistic issues and questions that need to be addressed in the future:

1. The confirmation and demonstration of the mechanism of action prove that tissue origin plays a significant role in the downstream applications of the originated MSCs.

2. Is it required that MSCs derived from particular cell sources need to have certain functionalities that are unique to or superior in the original tissue sources?

3. As mechanisms may rely on the secretion of factors from MSCs, it is important to identify the specific stimuli from the wound environments to understand how MSCs from different sources can exhibit similar functions in the same disease and whether or not MSCs derived from a particular source have stronger effects than their counterparts derived from other tissue sources.

4. Should we create "universal" MSCs that could be functionally equal in the treatment of all diseases regardless of their origin by modeling their genetic materials?

5. Can new sources of MSCs from either perinatal or adult tissues better stimulate the innate mechanisms of specific cell types in our body, providing a better tool for MSC-based treatment?

6. A potential 'priming' protocol that allows priming, activating, and switching the potency of MSCs from one source to another with a more appropriate clinical phenotype to treat certain diseases. This idea is potentially relevant to our suggestion that each MSC type could be more beneficial in downstream applications, and the development of such a "priming" protocol would allow us to expand the bioavailability of specific MSC types.

From our clinical perspective, the underlying proposal in our review is to no longer use MSCs for applications while disregarding their sources but rather to match the MSC tissue source to the application, shifting from one cell type for the treatment of all diseases to cell source-specific disease treatments. Whether the application of MSCs from different sources still shows their effectiveness to a certain extent in the treatment of diseases or not, the transplantation of MSCs derived from different sources for each particular disease needs to be further investigated, and protocols need to be established via multicentre, randomized, placebo-controlled phase II and III clinical trials.

The gut microbiome changes with age, a shifting of microbial populations that increases chronic inflammation and reduces the production of beneficial metabolites. These changes may be largely due to the age-related decline of the immune system, responsible for removing unwanted microbes, but significant changes occur early enough in life, in the mid-30s, for there to be other factors involved.

Researchers are actively engaged in mapping the differences between an old microbiome and a young microbiome, work that will likely lend support to various approaches to therapy intended to rejuvenate the gut microbiome, forcing its balance of microbes towards a more youthful configuration. Probiotics are an obvious strategy, but much more data is needed to validate the specifics of such an approach, and it is far from clear that presently available probiotics, even in large amounts, are useful enough to justify a strong focus on their use, versus, say, approaches such as flagellin immunization or fecal microbiota transplantation.

Aging is now the most profound risk factor for almost all non-communicable diseases. Studies have shown that probiotics play a specific role in fighting aging. We used metagenomic sequencing to study the changes in gut microbes in different age groups and found that aging had the most significant effect on subjects' gut microbe structure. Our study divided the subjects (n = 614) into two groups by using 50 years as the age cut-off point for the grouping. Compared with the younger group, several species with altered abundance and specific functional pathways were found in the older group. At the species level, the abundance of Bacteroides fragilis, Bifidobacterium longum, Clostridium bolteae, Escherichia coli, Klebsiella pneumoniae, and Parabacteroides merdae were increased in older individuals. They were positively correlated to the pathways responsible for lipopolysaccharide (LPS) biosynthesis and the degradation of short-chain fatty acids (SCFAs). On the contrary, the levels of Barnesiella intestinihominis, Megamonas funiformis, and Subdoligranulum unclassified were decreased in the older group, which negatively correlated with the above pathways.

Functional prediction revealed 92 metabolic pathways enriched in the older group significantly higher than those in the younger group, especially pathways related to LPS biosynthesis and the degradation of SCFAs. Additionally, we established a simple non-invasive model of aging, nine species (Bacteroides fragilis, Barnesiella intestinihominis, Bifidobacterium longum, Clostridium bolteae, Escherichia coli, Klebsiella pneumoniae, Megamonas funiformis, Parabacteroides merdae, and Subdoligranulum unclassified) were selected to construct the model. The model implied that supplemented probiotics might influence aging. We discuss the features of the aging microbiota that make it more amenable to pre-and probiotic interventions. We speculate these metabolic pathways of gut microbiota can be associated with the immune status and inflammation of older adults. Health interventions that promote a diverse microbiome could influence the health of older adults.

Link: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9359670/

Cancer vaccines work by instructing the immune system to attack a particular cell surface feature characteristic of cancer cells. Cancers tend to subvert the immune system and suppress its activities in and around tumor tissue, however, so improvements in the effectiveness of a vaccine, the degree to which it will rouse the immune system to action, are helpful. Here, researchers present an example of the way in which the present generation of new vaccine technologies can be applied to this goal in the development of improved cancer vaccines.

Researchers had previously designed lipid nanoparticles (LNPs) that targeted gene editing packages to various organs. Targeting is achieved by modifying the chemical structure of the lipids that make up the bubbles, as well as other additives, until the researchers find a combination that prefers to go to the organ of interest. In this case, they found an LNP that concentrated in the lymph nodes after they were injected subcutaneously into mice. The researchers think the LNPs collect molecules from the blood stream on their surface, and those selected molecules bind to specific receptors in the target organ.

The lymphatic system, which includes the familiar lymph nodes that often swell up during an infection, is an important target for vaccines, because that's where immunity against a foreign antigen, or in this case, a cancer antigen, is acquired. If one thinks of the body as a field of battle - against viruses, bacteria, parasites, and tumors - and the B cells and T cells as soldiers, the lymph nodes are the boot camp where the B cells and T cells are trained to be more effective against the enemy. A key element of that training is the participation of dendritic cells and macrophages that introduce the antigens to the T and B cells and help fire them up.

The cancer vaccine works by delivering mRNA, allowing the cells to "read" the mRNA and produce viral antigens, small fragments of the virus that activate the immune system. With more vaccine going to the lymph nodes, researchers discovered that the cancer vaccine was absorbed by about a third of the dendritic cells and macrophages. That's significantly more than obtained with conventional vaccines. Mice with metastatic melanoma that were treated with the lymph-targeted vaccine showed significant inhibition of tumors and a 40% rate of complete response - no tumors - with no recurrence in the long-term when it was combined with another existing therapy that helps prevent cancer cells from suppressing an immune response. All the mice that were in complete remission prevented any new tumors from forming when injected later with metastatic tumor cells, showing that the cancer vaccine led to excellent immune memory.

Link: https://now.tufts.edu/2022/08/15/new-targeted-cancer-vaccines-eliminate-tumors-and-prevent-recurrence-mice

In recent years, there has been an increasing interest in the ability of cells to transfer mitochondria and take up mitochondria from the surrounding environment. In many ways, mitochondria are treated like just another type of extracellular vesicle - except that, of course, mitochondria are much more complex and functional, capable of replication. Researchers have noted examples of cells aiding the function of other cells in this way, and also found that introducing mitochondria in large numbers may form the basis for therapies. Several companies (including Cellvie and Mitrix Bio) are at present working to build the infrastructure needed for widespread use of mitochondrial transplant therapies. There will be clinical trials of the first such therapies in the years ahead, the trajectory seems well established now.

Along the way to those human trials, as interest in mitochondrial transfer grows, we will see more technology demonstrations in animals, such as the one described in today's research materials. The scientists involved have shown that supporting astrocyte cells in the brain will transfer mitochondria to neurons following brain injury, and that this helps to reduce the resulting damage. Further, introducing mitochondria harvested from astrocytes produces benefits. These demonstrations will help to identify the most plausible early uses for mitochondrial transplant therapies.

Brain support cells transfer their mitochondria to fight free radicals

An artery in the brain bursts. Blood rushes into the tissue, inducing free radicals that cause even more damage. The hemorrhage damages mitochondria, the site of energy production in cells. Astrocytes transfer their mitochondria to damaged neurons after a hemorrhage. These healthy mitochondria contain a "healing" peptide called humanin and an enzyme called manganese superoxide dismutase (Mn-SOD) that help neutralize free radicals.

Researchers injected mice with healthy mitochondria after a hemorrhage. The hemorrhage reduced levels of Mn-SOD in the mice brain and increased the number of free radicals. Using molecular tags, the researchers found that the rodents' neurons took up the mitochondria from the bloodstream. The mice who received the treatment showed improved neurological recovery, but the benefits decreased if the mice received mitochondria without the Mn-SOD enzyme. These results reveal mitochondria can transfer between brain cells to improve health and aide recovery.

Transplantation of astrocytic mitochondria modulates neuronal antioxidant defense and neuroplasticity and promotes functional recovery after intracerebral hemorrhage

Astrocytes release functional mitochondria (Mt) that play regulatory and pro-survival functions upon entering adjacent cells. We recently demonstrated that these released Mt could enter microglia to promote their reparative/pro-phagocytic phenotype that assists in hematoma cleanup and neurological recovery after intracerebral hemorrhage (ICH). However, a relevance of astrocytic Mt transfer into neurons in protecting brain after ICH is unclear. Here, we found that ICH causes a robust increase in superoxide generation and elevated oxidative damage that coincides with loss of the mitochondrial enzyme manganese superoxide dismutase (Mn-SOD). The damaging effect of ICH was reversed by intravenous transplantation of astrocytic Mt that upon entering the brain (and neurons), restored Mn-SOD levels and reduced neurological deficits in male mice subjected to ICH.

Using an in vitro ICH-like injury model in cultured neurons, we established that astrocytic Mt upon entering neurons prevented reactive oxygen species-induced oxidative stress and neuronal death by restoring neuronal Mn-SOD levels, while at the same time promoted neurite extension and upregulation of synaptogenesis-related gene expression. Furthermore, we found that Mt genome-encoded small peptide humanin (HN) that is normally abundant in Mt, could simulate Mt-transfer effect on neuronal Mn-SOD expression, oxidative stress, and neuroplasticity under ICH-like injury. This study demonstrates that adoptive astrocytic Mt transfer enhances neuronal Mn-SOD-mediated anti-oxidative defense and neuroplasticity in the brain, which potentiate functional recovery following ICH.

Researchers here present evidence for the proposition that the blood-brain barrier doesn't just become leaky with age, but also causes disruption of neural function in other ways yet to be fully explored. The primary function of the blood-brain barrier is to regulate passage of molecules and cells into the central nervous system, and when that breaks down the consequence is chronic inflammation in brain tissue, contributing to the onset and progression of neurodegenerative conditions. It seems that the harms may start somewhat before the blood-brain barrier is sufficiently compromised to leak, however.

The breakdown of the blood-brain barrier accompanies many neurological conditions, including epilepsy and multiple sclerosis, and neurodegenerative diseases of aging, such as Alzheimer's disease and Parkinson's disease. "We are finding that the barrier is not just a protective check but also a source of regulation. It can cause problems rather than simply being a byproduct of neurodegeneration. We are learning now that there is definitely a two-way street."

The team used fruit fly larvae for their study. While fruit flies do not have the complexity of vertebrate blood-brain barriers, many of the properties are the same, in a system much easier to study. The key cells that provide a barrier for neurons in fruit flies are a specialized glia that function similarly to specialized endothelial cells that form the critical part of the blood brain barrier in higher vertebrates including humans.

The investigation began with a focus on enzymes called metalloproteinases because of their potential to be critical in interactions between glia and neurons. Using a genetic approach to look for what regulated expression of these enzymes, the team identified a pathway that is known as Notch signaling. Notch is found in both fruit flies and humans. It is associated with human diseases of the vasculature, dementia, and stroke. They discovered that Notch signaling in glia regulates the overall structure of the blood-brain barrier. When the signal is blocked, not only is barrier function impaired, but the fundamental work of the nervous system is affected, including neurotransmitter release and muscle contractions.

Under certain conditions, manipulation of Notch signaling affected how neurons fired, even though the blood-brain barrier remained intact. That indicated that there is signaling happening in the blood-brain barrier that is beyond just the maintenance of the barrier function. Breakdown in barrier function may be causing nervous system dysfunction, rather than being correlated with it or even a consequence of other damage.

Link: https://www.eurekalert.org/news-releases/961672

Researchers here discuss the unguarded X hypothesis in the context of gender differences in life span. That these differences exist across species strongly suggests evolutionary, biological origins, rather than the lifestyle and behavioral origins sometimes suggested to explain life span differences in our species. It seems likely that the interaction between evolutionary pressures and mating strategies drives a great deal of the differences between genders, and life span may be included in that list, but exactly how that difference in longevity is produced at the level of cellular biochemistry remains up for discussion, as illustrated here.

Females and males often have markedly different mortality rates and life spans, but it is unclear why these forms of sexual dimorphism evolve. The unguarded X hypothesis contends that dimorphic life spans arise from sex differences in X or Z chromosome copy number (i.e., one copy in the "heterogametic" sex; two copies in the "homogametic" sex), which leads to a disproportionate expression of deleterious mutations by the heterogametic sex (e.g., mammalian males; avian females). Although data on adult sex ratios and sex-specific longevity are consistent with predictions of the unguarded X hypothesis, direct experimental evidence remains scant, and alternative explanations are difficult to rule out.

Using a simple population genetic model, we show that the unguarded X effect on sex differential mortality is a function of several reasonably well-studied evolutionary parameters, including the proportion of the genome that is sex linked, the genomic deleterious mutation rate, the mean dominance of deleterious mutations, the relative rates of mutation and strengths of selection in each sex, and the average effect of mutations on survival and longevity relative to their effects on fitness. We review published estimates of these parameters, parameterize our model with them, and show that unguarded X effects are too small to explain observed sex differences in life span across species. For example, sex differences in mean life span are known to often exceed 20% (e.g., in mammals), whereas our parameterized models predict unguarded X effects of a few percent (e.g., 1-3% in Drosophila and mammals). Indeed, these predicted unguarded X effects fall below statistical thresholds of detectability in most experiments, potentially explaining why direct tests of the hypothesis have generated little support for it.

Our results suggest that evolution of sexually dimorphic life spans is predominantly attributable to other mechanisms, potentially including "toxic Y" effects and sexual dimorphism for optimal investment in survival versus reproduction.

Link: https://doi.org/10.1002/evl3.292

Today's open access paper caught my eye for the assertion that time spent in poor health at the end of life is actually decreasing over the recent period of decades of slowly increased life expectancy. This is not the conventional wisdom, but data is data, at least for this sizable study population. Compression of morbidity, a shortening of the period of age-related disease in later life, is a stated goal for much of the aging research community, but whether or not compression of morbidity is either (a) possible, or (b) already happening in at least some populations is a much debated topic.

If aging is simply slowed outright, then the period of disability and increased mortality could in principle be more drawn out, and less harmful for most of that time. But if aging is postponed rather than slowed then the period of disability would not be lengthened or improved. Given the way in which the relevant human data is recorded, with few fine details, particularly in the earlier, pre-clinical stages of age-related disease, it is hard to determine what exactly is taking place. It seems likely that neither slowing only nor postponing only is a good way to describe the present trend in slowly increased life expectancy, achieved without actively aiming to treat the underlying mechanisms of aging.

How does it all end? Trends and disparities in health at the end of life

Rising life expectancy at older ages has raised concerns that the period of poor health and disability prior to death is growing. Research typically addresses this topic with the implicit assumption that advancing age is the main risk factor for declining health. However, the onset of several health conditions, including end-of-life depression and cognitive decline, is more closely linked to years of life remaining than years lived. Comparing the health of older adults who are the same proximity to death (for example, comparing all adults in their last year of life) may yield different insights than comparing adults who are the same age, but differing distances from death (for example, comparing all 70 year-olds).

In this paper, I examine trends and inequalities in aging from the perspective of time to death, rather than time since birth. I compare three indictors of health - self-rated health (SRH) and two self-reports of disability - in the last 6 years of life among adults dying at ages 65+ across time, sex, age, race, and educational attainment. SRH is a subjective and self-reported indicator of health. While the two disability measures are also self-reported, they serve as more objective assessments of requiring assistance. This study is the first to examine annual trends in SRH at the end of life, as well as the first to produce national estimates of end-of-life SRH for several subpopulations.

Despite concerns about expanding morbidity at the end of life, I find that the amount of time individuals report unfavorable health in the last six years of life declined two months from 1987-2008. To the author's knowledge, this is the first study to examine trends in SRH at the end of life. I also find no change in the length of time spent with at least one end-of-life IADL or ADL limitation from 1997-2008, barring a slight increase in the most recent period.

These findings are generally consistent with prior work that documents an unchanging prevalence of ADL limitations from 1995-2009 in the last 2 years of life. While others use repeated cross sections of the Medicare Current Beneficiaries Survey linked to death records from 1991-2009 to document a decline in the prevalence of ADL and IADL limitations in the last 5 years of life in the 1990's, they find no significant change in the following decade (the main focus of this analysis). However, my findings are in contrast to those by that consider six major chronic conditions and find that the adult disease burden may have grown over a similar period. Perhaps our findings differ because of the operationalization of disability versus chronic conditions. A growing disease burden might not translate to a higher prevalence of reporting one or more limitation, especially if the increases in chronic conditions are among people who already have at least one disability.

This open access paper on epigenetic age and hibernation in bats makes an interesting companion piece to similar research into marmots from earlier in the year. It seems that hibernation may slow epigenetic aging in a range of species, though it may not be enough to explain differences in life span between all similar hibernating and non-hibernating species. Nonetheless, researchers have for some years shown interest in the biochemistry of hibernation in the context of aging. It remains to be seen what there is to learn here, and whether it can form the basis for therapies or enhancements in human medicine.

Comparative analyses of bats indicate that hibernation is associated with increased longevity among species. However, it is not yet known if hibernation affects biological ageing of individuals. Here, we use DNA methylation (DNAm) as an epigenetic biomarker of ageing to determine the effect of hibernation on the big brown bat, Eptesicus fuscus. First, we compare epigenetic age, as predicted by a multi-species epigenetic clock, between hibernating and non-hibernating animals and find that hibernation is associated with epigenetic age. Second, we identify genomic sites that exhibit hibernation-associated change in DNAm, independent of age, by comparing samples taken from the same individual in hibernating and active seasons.

This paired comparison identified over 3000 differentially methylated positions (DMPs) in the genome. Genome-wide association comparisons to tissue-specific functional elements reveals that DMPs with elevated DNAm during winter occur at sites enriched for quiescent chromatin states, whereas DMPs with reduced DNAm during winter occur at sites enriched for transcription enhancers. Furthermore, genes nearest DMPs are involved in regulation of metabolic processes and innate immunity. Finally, significant overlap exists between genes nearest hibernation DMPs and genes nearest previously identified longevity DMPs. Taken together, these results are consistent with hibernation influencing ageing and longevity in bats.

In conclusion, application of a multi-species bat epigenetic clock provides strong evidence that hibernation is associated with slower epigenetic ageing. The multi-species clock explains 94% of the variation in the chronological ages of both hibernating and non-hibernating big brown bats; however, the clock estimates are equal to or greater than the chronological age, suggesting big brown bats age slightly faster than a 'typical' bat, especially during the active period.

Link: https://doi.org/10.1098/rspb.2022.0635

In this interesting paper, researchers investigate the mechanisms by which senolytics can reduce pain in osteoarthritis, while not affecting cartilage degeneration. This outcome appears to involve changes in sensitivity-related signaling that affects the behavior of the peripheral nervous system in and around the damaged areas of the joint. Cartilage is one of the least regenerative tissues in the body. The effective treatment of cartilage damage, it seems, will need more than merely removing the causes of damage to date, but also regenerative therapies to repair the existing damage.

Both clinical and preclinical research suggest that osteoarthritis (OA)-related pain is induced by increased nociceptive input from the joint through alterations in pain signaling pathways in the central and peripheral nervous system. For example, activation of nociceptive neurons in the dorsal root ganglion (DRG) through nerve growth factor (NGF) to activate nociceptive neurons by binding tropomyosin receptor kinase A (TrkA), chemokine (C-C motif) ligand 2 (CCL2), tumor necrosis factor (TNF), and Netrin-1 correlates with OA-related pain. Moreover, these axon guidance proteins induce nociceptive neuron projection locally in multiple joint tissues, including synovium and subchondral bone, leading to an exaggerated pain response.

Currently, it is unknown whether senolytic drugs affect the degree of innervation of sensory nerve fibers in the synovium and subchondral bone and if there are subsequent changes to nociceptive signaling pathways, like CGRP and NGF/TrkA, to alleviate OA-related joint pain. Here, we investigated the therapeutic potential of senolytics against a spontaneously developed OA. Using 21 and 22- month-old mice, we analyzed the effects of two senolytic drugs (ABT263 and the combination of dasatinib and quercetin) on structural alterations (including articular cartilage and subchondral bone degeneration and synovitis) and pain in knee joints. We further analyzed pain-related sensory innervation and axonal growth-promoting factors that stimulate neuronal sprouting in the joints and DRG and knee joint angiogenesis to address putative nociceptive mechanisms by which senolytic treatment reduces OA pain.

Selective elimination of the senescent cells that accumulated in the articular cartilage and synovium by these two drugs did not alter cartilage degeneration and abnormal bone changes during spontaneous OA progression. Treatment reduced thermal and mechanical hyperalgesia associated with OA and peripheral sensitization through decreased expression of axon guidance proteins (nerve growth factor NGF/TrkA) and nociceptive neuron (calcitonin gene-related peptide, CGRP) projection to the synovium, subchondral bone marrow, and dorsal root ganglion, and knee joint angiogenesis. We suggest that systemic administration of ABT263 and the dasatinib and quercetin combination is an exciting therapeutic approach to age-related OA pain.

Link: https://doi.org/10.18632/aging.204204

Senolytic therapies selectively destroy lingering senescent cells in old tissues, improving health as a result. Senescent cells, while never very large in absolute numbers, even in late life, actively maintain a degraded state of tissue and organ function via secretions that provoke chronic inflammation, detrimental alterations to the behavior of normal cells, and harmful remodeling of tissue structure, such as the development of fibrosis. A large number of animal studies have demonstrated rapid rejuvenation and reversal of aspects of specific age-related conditions to result from clearance of senescent cells. The best of the early senolytic approaches, small molecule drugs and plant extracts that sabotage senescent cell resistance to apoptosis, such as the dasatinib and quercetin combination, manage to destroy as many as half of the senescent cells in a given tissue, with the degree of clearance varying widely between therapies and tissues.

Given the animal data, which is far and away the most robust and impressive of all of the approaches to the treatment of aging attempted to date, there is an enthusiasm for human clinical trials. Unfortunately, these early small molecule drugs are largely off-patent or close to it, and so near all of the sizeable funding in the field goes towards the development of new, patentable senolytic therapies rather than the validation of existing low-cost treatments that might be more rapidly brought to the clinic. Still, a number of clinical trials of early, low-cost senolytic drugs are ongoing, as noted by the authors of today's open access paper. In the years ahead, those will be joined by the second generation senolytic therapies under development, hopefully at least marginally better as a result of the effort put into their development, and what has been learned to date about the ways in which early senolytics work. This is all moving far too slowly, however!

Cellular senescence and senolytics: the path to the clinic

The elimination of senescent cells has emerged as a plausible therapeutic strategy for preventing, delaying, or alleviating multiple diseases and age-related dysfunction. Promising results of senolytics in preclinical models suggest therapeutic and preventive opportunities for delaying multimorbidity and increasing healthspan. A key priority should be the identification of reliable, sensitive and specific gerodiagnostics - biomarkers to quantify senescent cell abundance, the senescence-associated secretory phenotype (SASP), and senolysis as well as other pillars of aging.

Fundamental aging mechanisms can be grouped into so-called hallmarks or 'pillars' of aging; these include genomic instability, progenitor cell exhaustion/dysfunction, telomeric and epigenetic changes, dysregulated protein homeostasis, altered nutrient sensing, mitochondrial dysfunction, altered intercellular communication, chronic low-grade inflammation, fibrosis, microbiome dysregulation and cellular senescence. The Geroscience Hypothesis holds that these pillars of aging, including cellular senescence, tend to progress in concert and may be root-cause contributors to the pathophysiology of multiple diseases, age-related dysfunction and loss of resilience. The Unitary Theory of Fundamental Aging Mechanisms builds on the Geroscience Hypothesis by positing that interventions targeting any one fundamental mechanism may target the others. For example, interventions that target cellular senescence tend to attenuate other fundamental aging mechanisms leading to reduced inflammation, attenuated exhaustion of progenitors, decreased fibrosis, alleviated mitochondrial dysfunction, and a partially restored microbiome in experimental animal models of aging and chronic diseases

Based on promising results in preclinical models, over 20 clinical trials of senolytic therapies are completed, ongoing or planned. Because side effects of senolytics in humans are not yet fully known, and to maximize benefit-risk ratios, the first clinical trials are underway in patients with serious health conditions, such as diabetic kidney disease, Alzheimer's disease, frailty and idiopathic pulmonary fibrosis (IPF). The first in-human trial of senolytics (dasatinib and quercetin, D + Q), the Hematopoietic Stem Cell Transplant Survivors Study, is still underway (NCT02652052; first patient dosed on 1 April 2016). The first senolytic clinical trial published was an open-label pilot study in which 14 patients with IPF were treated with intermittent D + Q on 3 days per week for 3 weeks. Results suggested that senolytics improved physical function in these frail patients. Furthermore, post hoc analysis of a study involving 20 patients with IPF showed that urine levels of the 'geroprotective' factor α-Klotho were higher after oral D + Q than before treatment. In an open-label phase 1 pilot study in 9 patients with diabetic kidney disease, a 3-day course of oral D + Q was sufficient to decrease adipose tissue senescent cell burden, inflammation, fibrosis and circulating SASP factors for at least 11 days after the last dose of senolytics, indicating target engagement and suggesting that an intermittent dosing regimen may be effective in humans.

These early data warrant evaluation in larger randomized, double-blind, placebo-controlled trials for senescence-associated disorders and diseases, some of which are underway

Are many of the common neurodegenerative conditions driven in their onset and progression by the consequences of persistent viral infection? The evidence is compelling, but not completely convincing at the present time. Given that these conditions are likely the result of a number of quite different, interacting mechanisms, including viral infection, vascular aging, immune system aging, mitochondrial dysfunction, and aggregation of toxic proteins, amongst others, it is a challenge to produce cut and dried data to show, definitively, the degree to which any one cause contributes. In the case of viral infection, there are studies suggesting yes, and there are studies suggesting no - the usual situation for a complex system in which more work will be needed to better understand what is going on under the hood.

Neurodegenerative diseases (NDs) are fatal chronic diseases of the central nervous system (CNS), including Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and transmissible spongiform encephalopathies (TSEs). A hallmark of NDs is the intracellular or extracellular deposition of cellular proteins into ordered high-molecular weight fibrils, termed amyloid. Amyloid fibrils then act as seeds that bind and convert proteins of the same kind into their abnormal isoforms (seeding). Protein aggregation occurs sequentially in anatomically connected areas, suggesting a progressive spreading throughout the CNS of affected individuals. Approximately 90% of NDs occur sporadically, and only few cases are linked to mutations in aggregation-prone proteins or proteins involved in their processing or trafficking. The etiology of idiopathic NDs remains unknown.

NDs are multifactorial diseases, triggered by enhanced age as well as genetic and environmental risk factors. Pathogens, and especially viruses, are suspected to act as etiological factors in several NDs. An impressive number of studies highlights that viruses, through their capacity to hijack the host cell machinery and induce inflammation, trigger and/or contribute to degenerative processes. Viral infections can activate astrocytes and microglia or induce CNS infiltration by peripheral immune cells, thereby causing neuroinflammation. Some viruses can enter the CNS and affect neurodegeneration via lytic egress from infected neurons by impairing neuronal processes or by inducing neuronal apoptosis. In this review, we discuss how viruses can also directly contribute to disease-associated protein misfolding and subsequent processes of protein aggregate spreading.

Link: https://doi.org/10.1371/journal.ppat.1010670

Many compounds, small molecules, plant extracts, and so forth, have been found to modestly slow aging in mice. Given accumulating evidence from animal studies and human clinical trials, and that a sizable fraction of these compounds are already approved by regulators for other uses, or otherwise readily available, it is inevitably the case that physicians and the population at large will begin make use of these treatments in increasing numbers. This will happen, sometimes ahead of the science, sometimes behind it, sometimes to little benefit to patients, sometimes with enough of a benefit to matter. Navigating the options will become a great deal harder than it was, as we transition from an era in which little to nothing could be done to change the pace of aging, to one in which there are many options, with widely varying degrees of reliability, quality, and proof of reliability and quality.

The majority of people would like to live to the age of 120 years or more if their health remained good and nearly one half would like an unlimited lifespan. About one-third of people would be prepared to take life extension or anti-ageing therapies now. The possibility that a pill might prevent ageing and increase lifespan is tantalising for most people. As a result, anti-ageing and life extension therapies are often the focus for media hype despite the absence of definitive human data.

In this review, the term 'gerotherapeutics' is used to refer to drugs that target ageing biology, and that have been developed using similar approaches to those used to develop drugs for diseases. A major scientific endeavour is underway to find biological switches that can manipulate ageing. This research aims to discover new gerotherapeutic drugs that both reduce the burden of ageing-related diseases, and extend lifespan. There are many ageing-related diseases where the incidence increases exponentially throughout old age, including Alzheimer's disease, some cancers, ischaemic heart disease, ischemic stroke, and chronic obstructive pulmonary disease. The biological changes of ageing are a major risk factor these diseases. The hope is that gerotherapeutic drugs might reduce the impact of these ageing-related diseases with a single therapy.

Over the last two decades there has been a marked increase in the number of interventions reported to increase lifespan, and delay ageing and disease, in laboratory animals. However, the development of gerotherapeutic drugs is still in its infancy, and no gerotherapeutic drug has yet been shown to increase human lifespan or been licenced for an indication related to ageing. 'Anti-ageing' is a term mostly used to promote products that are not regulated or licenced. There are many drugs, supplements and other treatments that are marketed as anti-ageing and can be accessed direct-to-consumer from pharmacies or online. None of these treatments can support their anti-ageing claims with high quality clinical trials equivalent to those that are required for the registration of drugs for the treatment of individual diseases.

There is very little information about how many people are taking anti-ageing therapies and gerotherapeutic drugs or what they are taking. It is likely that most doctors, including geriatricians, will have some or many patients using these treatments without supervision, so will need to have some knowledge about them. This review focuses on gerotherapeutics that have an established basic scientific foundation and/or where there is the possibility of widespread use in the community. It also provides a summary of how these drugs are being discovered, using traditional drug discovery approaches, repurposing, or by investigating populations with exceptional longevity.

Link: https://doi.org/10.1093/ageing/afac156

Senolytic therapies are those that can selectively destroy senescent cells. Clearance of the lingering senescent cells in old tissues has been shown to produce a sizable degree of rejuvenation in animal models, extension of healthy life span, reduction in chronic inflammation, and reversal of aspects of various age-related conditions, some more so than others. The various small molecule senolytic drugs work by stressing senescent cells, or by inhibiting the mechanisms by which senescent cells resist the fate of self-destruction via apoptosis. Senescent cells are primed to enter apoptosis, and only a few lynchpin proteins and their interactions prevent this from happening.

It is suspected that there are sufficient differences between subtypes of senescent cell to make combination senolytic therapies much better than the use of single drugs. Targeting multiple points of intervention in the anti-apoptosis machinery of senescent cells should in principle kill a larger fraction of such cells than targeting any one specific part of these mechanisms. The research community is largely quite reluctant to investigate combination therapies, however, and the industry of medical development is even more so. The incentives placed on research and development by the intersection of regulators, investors, and intellectual property law make it difficult for initiatives intending to use combination therapies to even get off the ground. At present the largest such efforts are funded by philanthropy, and small in comparison to the scope of work that might be usefully undertaken.

Still, a few projects do take place, usually with little funding and a modest scope. Today's open access paper is one such example, in which the authors report on in vitro experiments combining different senolytic compounds that inhibit various members of the BCL-2 family, involved in protecting senescent cells from apoptosis. The researchers convincingly note the existence of senescent cells resistant to the BCL-2 family inhibitor navitoclax due to high expression levels of a BCL-2 family protein that navitoclax does not interact with; these cells can be killed by a different BCL-2 family inhibitor that does interact with that problem protein. We should expect to find that this sort of biochemistry is prevalent in the senolytic space, a good argument for, sooner rather than later, combining senolytic therapies for greater benefit to patients.

Synergism of BCL-2 family inhibitors facilitates selective elimination of senescent cells

Cellular senescence, a complex cellular response to stress characterized by a halt of cell cycle progression, is one factor contributing to aging and age-associated diseases. It is believed that selective elimination of senescent cells can lead to rejuvenation of the aged organism and increase the healthspan, and as a result, clearance of senescent cells can serve as a therapeutic approach to combat many negative aspects of aging. The age-dependent accumulation of senescent cells is caused by age-related attenuated efficiency of the immune system and their higher resistance both to extrinsic and intrinsic pro-apoptotic stimuli, including oxidative stress. While the mechanisms driving senescence are well studied, understanding the mechanisms endowing these cells with increased survival capacity is limited.

The BCL-2 protein family plays a central role in cell death regulation by diverse mechanisms, including apoptosis and autophagy. This protein family, in addition to multidomain pro-apoptotic proteins Bax, Bak, and Bok and BH3-only proteins, also includes the anti-apoptotic proteins BCL-2, BCL-W, BCL-XL, MCL-1, and A1, and is intensively studied as a target for pharmacological intervention in cancer. Researchers have evaluated the contribution of individual members of the BCL-2 family and their combinations to the viability of senescent cells. They found that the increased presence of BCL-W and BCL-XL underlies senescent cell resistance to apoptosis and their combined inhibition induces the death of senescent cells. This mechanism is believed to be a basis for senolytic effects of BCL-2 inhibitors such as ABT-737 or ABT-263 (Navitoclax).

ABT-737 and ABT-263 both display a high affinity for BCL-2, BCL-XL, and BCL-W, but not A1, or MCL-1. In this study, we aimed to search for synergistic selective senolytic effects. We found that combining selective MCL-1 inhibitors with non-MCL1 BCL-2 inhibitors results in marked synergistic effects with higher sensitivity of senescent compared to proliferating cells. These findings indicate that a combination of drugs targeting different BCL-2 family members can benefit for senolytic therapies.

The lack of progress towards effective therapies for Alzheimer's disease based on clearance of amyloid-β, and the relentless focus on that goal for the past two decades, has led to a great deal of alternative theorizing about the mechanisms driving the condition. Some of those theories are less well thought of than others, such as the opinion that rising use of common painkillers is the root cause of Alzheimer's. The paper here provides another example of a view of Alzheimer's disease that probably won't gain much traction in the present environment, but is nonetheless an interesting read. The sheer complexity of the aging brain still allows a great deal of room to interpret the same data in many different ways. The only real proof lies in developing a therapy that does actually produce meaningful results in humans. We can hope that first generation senolytics turn out to be that therapy, but time will tell.

Numerous studies have been attempted to link Alzheimer's disease (AD)-related molecules to the pathogenesis of AD: APOE ε4-associated mechanisms such as amyloid-β (Aβ) clearance and aggregation, cerebral energy metabolism, neuroinflammation, neurovascular function, and synaptic plasticity, and presenilin-related ones such as Aβ production, calcium homeostasis, and neurogenesis. Such heterogeneous and multiple mechanistic pathways may work cumulatively over a lifetime to increase an individual's risk of AD. Nonetheless, the pathogenesis hypothesis needs to make logical connections with several confirmed findings, that is, the existence of both amyloid plaques (APs) and neurofibrillary tangles (NFTs), anatomical characteristics of neurodegeneration. The amyloid hypothesis has long been at the center of discussions. Aβ is believed to be toxic to neurons and have various mechanisms of action.

As an alternative to the Aβ hypothesis, in this paper, I propose that excessive (or aberrant) and maladaptive synaptic plasticity is the cause of AD. Previously, plasticity failure was proposed as a cause of AD. In that hypothesis, AD results if the demand for plastic remodeling exceeds the biological capacity to fulfill it: Familial Alzheimer's disease (FAD)-causing mutations of APP increase the demand for plastic remodeling by shifting the balance of its processing toward more toxic form of Aβ. Another example is the malignant synaptic growth hypothesis, which suggests that AD develops if the positive feedback mechanism during synaptic modification is dysregulated. The authors suggest that Aβ prevents neurons from malignant synaptic growth by impairing the function of plasticity-related synaptic molecules and that FAD-linked mutations produce types of Aβ which have a weaker neuroprotective effect against it. Further, network abnormalities have also been discussed as potential mechanisms of cognitive dysfunction in AD. In these papers, Aβ is considered to be a central molecule causing network abnormalities.

In contrast to the previous discussions, the hypothesis proposed here states that excessive/aberrant synaptic plasticity is a root cause for cognitive dysfunction in AD and that cognitive dysfunction is developed through maladaptive neuronal connections, hyperexcitability of neuronal network and abnormal process of synaptic remodeling. APP is a key player in synaptic plasticity, and in FAD, the mutant APP or presenilin leads to aberrant plasticity through altered APP metabolism and function, which initially manifest as neuronal network abnormalities.

Decades of research do not necessarily support only the amyloid hypothesis, but also can be utilized to hypothesize excessive/aberrant and maladaptive synaptic plasticity as the cause of AD. If this hypothesis is correct, an important goal aimed at delaying the onset of AD and slowing or halting the disease progression is to find ways to adaptively regulate synaptic remodeling without interfering with necessary changes. This requires an understanding of the fundamental mechanism of synapse dynamics, and the characteristics of the stage of synaptic plasticity (formation, maturation, or elimination) at which a person developing AD is affected. Because of heterogeneity between individuals, identifying the stage of synaptic plasticity at which individuals are prone to error is a prerequisite for providing each person the appropriate intervention.

Link: https://doi.org/10.3389/fnagi.2022.913693

I don't pay a great deal of attention to the political lobbying efforts that take place in the community of supporters of aging research, as governmental funding is usually the last to the table, arriving long after the hard work of opening up a new field is done. There are a number of lobbying groups actively working in the US political system, and some single-issue political parties in Europe performing an analogous function. The material here is an example of the work taking place amongst those who lobby, the Alliance for Longevity Initiatives in this case. It is the business of persuading politicians that it is in their short-term interest to divert more funding into useful programs, while hoping that said funding doesn't just get funneled into irrelevant and wasted efforts set up by the politically connected.

A new national poll of registered voters in the United States demonstrates broad bipartisan support for advancing research into longevity treatments that would extend healthy human lifespan. The poll, which was conducted by Public Policy Polling on behalf of The Alliance for Longevity Initiatives (A4LI), found that 70% of respondents support medical research that seeks to treat the cellular aging process as a means to prevent or delay the onset of all age-related chronic diseases. The majority of poll participants also believe that the US government should prioritize funding for this area of research.

However, Americans' support for aging research is in stark contrast to the realities of US biomedical research priorities. Currently, the National Institute of Aging's (NIA) Division of Aging Biology receives just 0.6% of the National Institutes of Health's (NIH) nearly $52 billion budget. Instead, most of the funding goes to specific diseases, such as Alzheimer's and cancer, despite longevity treatments having the potential to combat all age-related conditions at once.

Age-related chronic diseases and conditions have both enormous human and economic costs. Aging is the greatest risk factor for chronic ailments and death. Eighty percent of Americans 65 or older, have at least one chronic condition and 50 percent have at least two. Age-related chronic conditions are also America's most expensive diseases. Approximately 84 percent of all healthcare costs in the US are treatments for chronic diseases. The share of these costs is even higher for patients who receive healthcare through public programs. Ninety-nine percent of Medicare costs and 80 percent of Medicaid expenditures go toward the treatment of chronic diseases. As of 2016, direct healthcare treatment for chronic diseases costs the US $1.1. trillion. This is nearly equivalent to six percent of America's gross domestic product (GDP).

While the cost of age-related chronic conditions is tremendous, the economic benefits of effectively treating aging are even more significant. It is estimated that increasing healthy life expectancy by just one year would be worth $38 trillion in economic returns in the US and by 10 years these savings and additional economic output would accumulate to $367 trillion.

Link: https://a4li.org/2022/08/polling-still-indicates-widespread-bipartisan-support-for-aging-research/

Sepsis is a runaway inflammatory event resulting from infection, in which the lack of resolution to the inflammatory response leads to organ damage and death. One of the lasting consequences for survivors is a suppression of the immune system's effectiveness, and in today's open access paper researchers draw parallels between this state and the natural aging of the immune system leading to immunosenescence, a loss of the capacity to destroy pathogens and errant cells alike.

Aging does make sepsis worse. The immune system is already in a state of chronic inflammation as a result of the damage of aging: pro-inflammatory secretions of senescent cells, molecular debris from dying or stressed cells that immune cells take for evidence of an attack, and so forth. It is thus less resilient, more susceptible to entering a runaway cytokine storm of the sort provoked in sepsis. Further, because the aged immune system is also less capable, immunosenescent, the suppression of its effectiveness following sepsis can be that much worse, and, further, it is less capable of clearing dangerous infectious agents before they can replicate to the point of causing sepsis.

Immunosenescence: A Critical Factor Associated With Organ Injury After Sepsis

Sepsis is an intricate, heterogeneous, and highly fatal syndrome, which is responsible for life-threatening organ dysfunction due to the immune regulation disorder. The third international consensus definition of sepsis and septic shock (Sepsis 3.0) recommended the sequential organ failure assessment (SOFA) to assess sepsis and hence predict the subsequent prognosis. While the old definitions of sepsis greatly emphasized infection, Sepsis 3.0 focused on the dysregulation of the body's response to infection and organ dysfunction. Furthermore, the organ damage scored by SOFA focuses on organs like lungs, heart, liver, kidneys, and brain. Surviving sepsis is associated with chronic, long-term consequences in host protective immunity. Additionally, researchers observed that most of the survivors suffered from issues like nervous system disturbances and cognitive dysfunction throughout their life span.

Since several similarities are found between immunosuppression after sepsis and immunosenescence, researchers hypothesized that these two factors might be associated with the progressive failure of immune functions. In sepsis, an increase in the number of myeloid-derived suppressor cells (MDSCs) was associated with the regulation of the function of other immune cells, and excessive inflammation was blocked. It has been suggested that MDSCs play a paradoxical role in sepsis: these cells may increase the production of proinflammatory cytokines during emergency myelogenesis and be also potently immunosuppressive. MDSCs may induce immunosenescence in the remodeled immune system. Therefore, we were interested in analyzing the effect of immunosenescence on sepsis, including the effect on the parenchymal organs. Here we review the possible relationship between septic injury-related organs and immunosenescence and analyze the possible mechanisms of immunosenescence after sepsis, which may shed some light on the delayed consequences of sepsis.

The TAME clinical trial, still not started, intends to assess the ability of metformin to marginally slow aging in humans. Back at the start of this initiative, it required a long process of negotiation on the part of the trial organizers with the FDA to produce an endpoint that was agreed upon to sufficiently represent aging. To my mind, the TAME trial initiative has already achieved what needs to be achieved: to get the FDA to agree that there is a way to run trials to treat aging. One doesn't actually need to run the trial, and there is in fact little point in running the trial. Metformin is almost certainly a marginal treatment, and attention should be directed instead towards senolytics and other approaches that have much, much better animal data to support their effects on the mechanisms of aging and late life health.

In 2013, Nir Barzilai and two other researchers got a grant from the National Institute on Aging to develop a roadmap to conduct, for the first time in history, a clinical trial that targets aging. They planned to test metformin, a drug that had been approved in the '90s for treating diabetes, and that was shown in epidemiological studies to prevent against conditions like heart attacks, cancer, and Alzheimer's. It also turned out to be very safe, with few, generally mild side effects. And it's dirt cheap: just six cents per dose.

The biggest obstacle they had was the Food and Drug Administration. The federal regulator adheres to a "one disease, one drug" model of approval. And because the agency does not recognize aging as a disease, there's no path forward for a drug to treat it. And even if there was, it's impractical to do a lifespan study - it would take decades and be astronomically expensive. The solution then would be to use biomarkers as a proxy, as researchers have with other treatments. Barzilai's plan was to launch a new kind of gold-standard trial, designed to prove that the onset of multiple chronic diseases, or comorbidities, associated with aging can be delayed by a single drug: metformin. The ambitious effort aimed to track 3,000 elderly people over five years to see if the medicine could hold off cardiovascular disease, cancer, and cognitive decline, along with mortality.

In 2015, he and a group of academics from more than a dozen top-tier universities met with the FDA to get its blessing for their Targeted Aging with Metformin, or TAME, trial. And to many people's surprise, the agency agreed. All that was left was funding it. Because metformin is a generic drug from which no one could make any money, the trial's sponsor wouldn't be a pharmaceutical company, but AFAR. A trial of the scale researchers were proposing would cost between $30 million and $50 million. The National Institutes of Health offered up just a small portion, about $9 million, toward the difficult but important task of screening for the best biomarkers for assessing if the aging process is actually being slowed. The rest of the money, Barzilai was convinced, could be raised from philanthropists. But despite interest from several people - at one point, Barzilai said, the Israeli American businessman Adam Neumann offered to pay for it all, before his WeWork empire evaporated - the required funds never materialized. "Those big billionaires, they want moonshots, they want a scientific achievement that will make people say 'wow'. TAME is not a moonshot. It's not even about scientific achievement really, it's more about political achievement. Metformin is a tool to get aging as an indication."

Link: https://www.statnews.com/2022/08/09/anti-aging-projects-funding-much-discussed-trial-overlooked/

The best approach to stroke is to prevent it from happening, a goal that implies a robust way to control and reverse atherosclerosis, the development of fatty lesions that narrow and weaken blood vessels. There is still only limited progress towards more meaningful treatments for atherosclerosis, unfortunately, and so the research community remains very interested in finding ways to limit the damage that occurs following a stroke, or enhance regeneration of damaged brain tissue. The immune system plays an important role in the post-stroke environment, and researchers here report on an interesting discovery, a population of immune cells that appears important in limiting the damage of stroke in the days following the event.

Immune response plays an important role in stroke. As soon as a blood clot wedges itself in a blood vessel, the brain sends an "SOS" signal to activate the immune system. This rapid immune response aims to clear out the cell debris, limit brain damage, and kick-start brain repair processes. However, the function of the immune system is diverse and complex, and different types of immune cells may play distinct beneficial or detrimental roles in a damaged brain.

This study identified a novel subset of CD8+ regulatory-like T cells, or CD8+TRLs, as "first responders" to stroke. Attracted to the site of ischemic injury by a unique "homing" signal released by dying brain cells, CD8+TRLs reach the brain within 24 hours after stroke onset, where they release molecules that provide direct neuroprotective effects, as well as limit inflammation and secondary brain damage. "Creating shelf-stable and ready-to-use CD8+TRLs or developing a cocktail of neuroprotective signaling molecules released by those cells once they reach the brain could present effective future therapies against stroke and offer hope to hundreds of thousands of patients who are ineligible for treatments available to them currently."

CD8+TRLs enter the brain much faster than any other regulatory immune cells. Within 24 hours after researchers depleted these special CD8+TRLs from the bloodstream of stroke mice, the size of the brain region affected by ischemia expanded by 50% compared to animals whose CD8+TRL levels remained intact. Even more reassuringly, mice who received a transfusion of purified CD8+TRLs prepared in the lab fared better and recovered faster than those who were untreated for over five weeks. These unique CD8+TRLs, therefore, serve as early responders to rally defenses after stroke and may collaborate with other immune cells to safeguard the brain for a long time.

Link: https://www.upmc.com/media/news/080122-protectionagainststroke

Nicotinamide adenine dinucleotide (NAD) is central to mitochondrial function, but declines with age. Mitochondria are the power plants of the cell, producing chemical energy store molecules to power cellular processes. When mitochondria run down, everything suffers. Thus a great deal of attention has been given over the years to approaches that might help to boost mitochondrial function in old individuals: mitochondrially targeted antioxidants; increasing NAD levels; transplantation of mitochondria; copying mitochondrial genes into the nucleus to provide resistance against mitochondrial DNA damage. The small molecule approaches widely deployed to date are arguably all marginal, at best on a par with structured exercise programs when it comes to improvement of health.

Nonetheless, attempting to improve mitochondrial function by the use of small molecules to restore youthful NAD levels has a long history, going back decades prior to the point at which researchers realized that the interventions were raising NAD levels. The primary approach here is to use vitamin B3 derivatives, and those have been employed at high doses in clinical trials for a long time. Only in more recent years have researchers started to focus on how the compounds derived from vitamin B3, such as niacin, nicotinamide riboside, and nicotinamide mononucleotide, interact with the synthesis and recycling of NAD, and deliberately aimed at raising NAD levels for therapeutic effect.

Today's paper reports on a small study that shows some benefit to nicotinamide mononucleotide supplementation in old patients. It is like other studies in that one might expect similar benefits from exercise, and also it is as interesting for what was not improved as it is for what was. We should expect to see more studies much like this, though it is worth remembering that, taken as a whole, looking over the range of trials conducted over decades, the evidence for NAD upregulation to be useful isn't as good as this small study might make it look. Larger trials have tended to fail to show significant impact on the treated conditions.

Chronic nicotinamide mononucleotide supplementation elevates blood nicotinamide adenine dinucleotide levels and alters muscle function in healthy older men

Aging- and age-related diseases have been shown to be closely related to decreased NAD+ levels. In animal studies, the administration of intermediate NAD+ metabolites, such as nicotinamide (NAM), nicotinamide mononucleotide (NMN), or nicotinamide riboside (NR), has been shown to increase NAD+ concentrations, which helped improve the health and extend the lifespan of the experimental animals. Thus, the potential of intermediate NAD+ metabolites in improving tissue rejuvenation in humans has led to multiple clinical trials on NR and NMN.

The results of NR clinical trials have been reported. In these trials, NR (100-2000 mg/day) was administered to healthy participants or individuals with obesity for a maximum of 12 weeks. Most NR clinical trials have reported the safety of NR administration and the elevation of NAD+ or NAD+ -related metabolites in the blood. The most recent report showed that NR increases the fat-free body mass in participants with obesity, although no effect was observed on insulin sensitivity, mitochondrial function, and hepatic and intramyocellular lipid accumulation.

Recently, for the first time, the safety of single-day NMN oral administration was reported in humans. Moreover, while the drafting of this paper was underway, a 10-week, randomized, placebo-controlled, double-blind trial to evaluate the effect of NMN supplementation on metabolic function in 25 postmenopausal women with prediabetes was reported, in which NMN supplementation increased muscle insulin sensitivity, insulin signaling, and remodeling in women with prediabetes who are overweight or obese. Furthermore, the effects of NMN supplementation combined with exercise training have been reported in healthy amateur runners aged 27-50 years. NMN dose-dependently increased the ventilatory threshold and improved aerobic capacity during exercise. However, evidence of the effects of human interventions with NMN remains limited for older adults.

Therefore, to elucidate the safety and efficacy of NMN administration in older adults, we conducted a placebo-controlled, randomized, double-blind, parallel-group study with the administration of 250 mg of NMN to 42 healthy men aged 65 years or more for 12 weeks. We demonstrated that NMN oral supplementation at 250 mg/day in healthy older men for 12 weeks was safe and well-tolerated and significantly increased the levels of NAD+ and NAD+-related metabolites in whole blood. Furthermore, NMN administration partly improved muscle performance, evaluated using gait speed and grip strength, in healthy older men. Conversely, no difference was observed in the indicators of vascular functions, such as assessed blood pressure and flow-mediated dilation. Chronic NMN supplementation did not affect the visceral or liver or spleen fat mass distribution. Likewise, NMN administration did not affect the homeostatic model assessment of insulin resistance (HOMA-IR), an indicator of hepatic insulin sensitivity in blood analysis. Adiponectin and interleukin 6 (IL-6), which are also related to insulin sensitivity, were unaffected by NMN administration. Lastly, the intervention exerted no observable effect on overall cognitive function.

Senolytic therapies to clear lingering senescent cells in aged tissues improve a great many age-related conditions in animal models, among them intervertebral disc degeneration. Researchers here note the association of this effect with the deterioration of the microvasculature that delivers nutrients to disc tissue. As always, it is a challenge to determine whether or not the mechanism is significant in comparison to, say, the effects of inflammatory signaling generated by senescent cells on the same disc tissues. Nonetheless, the small blood vessel networks present throughout the body do deteriorate with age, their density decreasing, and thus also their ability to supply tissues with oxygen and nutrients. This is likely harmful to cell and tissue function throughout the body, and so it is interesting to see senescent cells implicated specifically in this issue.

With the increase of age, the function and interaction of three unique intervertebral disc (IVD) compartments: the central nucleus pulposus (NP), the circumferential annulus fibrosus (AF), and the cranial and caudal cartilaginous endplates (CEP) continue to deteriorate, which is difficult to avoid. Normal IVD is the largest avascular structure in human body and exchanges metabolites via diffusion from the adjacent capillary bed penetrating the subchondral bone of the endplate and the capillaries around the fibrous ring. The main nutrient supply of the IVD comes from the bony endplate vasculature, and material exchange between the vertebral body and the IVD is carried out through the diffusion of the cartilaginous endplate, which is the nutrient supply route of the disc cells.

As life span increases, so does the cartilaginous endplate osteosclerosis changes, accompany with the number of microvessels under the bony endplate gradually decreases, and the permeability disappears, resulting in the imbalance of energy metabolism of nucleus pulposus cells. Consequently, microvessels under the bony endplate and nutrient availability at the bone-disc interface decreases may be a key factor of intervertebral disc degeneration (IDD) that could not be neglected.

During IVD degenerative process, there are inevitable interactions between the human IVD cells and adjacent non-IVD cells, including endothelial cells (ECs) which play a major part in vascular structure formation. The senescent vascular endothelial cellular accumulation, which leads to the altered cellularity, vascular regression, and extracellular matrix composition, might set the IVD on a slow course toward degeneration. Additionally, there is a positive association of the vascular endothelial cellular senescence with the decrease of microvasculature in the marrow space of the bony endplate, which can hinder transport from nutrient supply to the disc or result in changes in cell phenotype, even death.

In this study, the relationships between endothelial cellular senescence in the marrow space of the bony endplate and IVD degeneration were investigated using the aged mice model. Preliminary results showed that senolytics alleviate endothelial cellular senescence in the marrow space of the bony endplate as evidenced by reduced senescence-associated secretory phenotype. In the aged mice model, we found decreased height of IVD accompanied by vertebral bone mass loss and obvious changes to the endplate subchondral vasculature, which may lead to the decrease in nutrition transport into IVD. These findings may provide evidence that senolytics can eliminate the senescent cells and facilitate microvascular formation in the marrow space of the bony endplate. Targeting senescent cellular clearance mechanism to increase nutrient supply to the avascular disc suggests a potential treatment value of senolytics for IVD degenerative diseases.

Link: https://doi.org/10.3389/fcell.2022.853688

Diabetics tend to develop retinopathy and macular edema, disrupting retinal structure and function, and leading to progressive and presently irreversible blindness. The presence of senescent cells is likely a significant contribution to this process, the retina negatively affected by the pro-inflammation, pro-growth signals produced by these errant cells. UNITY Biotechnology, one of the earliest biotech companies working on senolytics to clear senescent cells, has been pursuing the strategy of local administration of small molecule senolytic drugs, using low doses to only destroy senescent cells in one area of the body. This is an approach that failed for osteoarthritis in the knee, but appears to be working for macular edema in the eye. Local administration of senolytics in human clinical trials is an expensive way to test whether or not the impact of the inflammatory signaling of senescent cells is localized to a meaningful degree, a topic on which there is some debate, and in which the answers may differ considerably from tissue to tissue.

UNITY Biotechnology, a biotechnology company developing therapeutics to slow, halt, or reverse diseases of aging, today announced 12-week and 18-week data from its Phase 2 BEHOLD study of UBX1325, a senolytic Bcl-xL inhibitor, in patients with diabetic macular edema (DME).

At 18 weeks after a single UBX1325 injection, the mean change in best corrected visual acuity (BCVA) of UBX1325-treated subjects was an increase of 6.1 ETDRS letters, representing an improvement of +5.0 ETDRS letters compared to sham-treated subjects. In addition, patients treated with UBX1325 maintained central subfield thickness (CST) compared to sham-treated patients who demonstrated progressive worsening of CST (i.e., increased retinal thickness) through 18 weeks. The separation of UBX1325-treated patients from sham-treated patients at 18 weeks in measures of both visual function and retinal structure following a single UBX1325 injection suggests that one dose could have a durable therapeutic effect. The current standard of care for DME with the leading anti-VEGF therapeutic requires 3-5 monthly loading doses followed by every 8-week dosing, imposing a significant treatment burden on patients.

"The 12- and 18-week results are especially impressive considering that UBX1325 was given as a single injection in a patient population in which anti-VEGF treatment was no longer providing optimal benefit. The vision gains observed are greater than what has been previously reported with the standard of care in similar patient populations, and the durability of effect suggests that UBX1325 could address the large unmet need for longer-lasting, disease-modifying treatments for patients with DME. These data represent an important and exciting step in validating the senolytic therapeutic concept that is core to UNITY's platform."

Link: https://ir.unitybiotechnology.com/news-releases/news-release-details/unity-biotechnology-announces-positive-data-phase-2-behold-study

The gut microbiome is important in long-term health. At a guess, its influence on health may be on a par with, say, the state of physical fitness exhibited by an individual. The relative sizes of microbial populations change over a lifetime, and in detrimental ways. Inflammatory microbes and those producing harmful metabolites increase in number, while useful metabolite production declines. This occurs for a range of reasons, easy enough to list, but hard to put in an order of relative importance. For example, the intestinal mucosal barrier declines in effectiveness; the immune system becomes less capable of suppressing problematic microbial populations; diet tends to change with age; and so forth.

At present the only definitively lasting way to beneficially alter the gut microbiome is fecal microbiota transplantation, such as from a young individual to an old individual. Methods such as probiotics can produce benefits, but do not last very long, and are also far from a complete solution. Can more be done to apply fine degrees of control to the composition and function of the gut microbiome without full transplantation of a new microbiome? In the research materials below, researchers suggest an intriguing approach based on engineering native microbes. At the end of the day, however, that full reset via fecal microbiota transplantation may just be the best approach to an aging microbiome, and not just because it can be implemented now.

Engineering the Microbiome to Potentially Cure Disease

Numerous diseases are associated with imbalance or dysfunction in gut microbiome. Even in diseases that don't involve the microbiome, gut microflora provide an important point of access that allows modification of many physiological systems. Modifying to remedy, perhaps even cure these conditions, has generated substantial interest, leading to the development of live bacterial therapeutics (LBTs). One idea behind LBTs is to engineer bacterial hosts, or chassis, to produce therapeutics able to repair or restore healthy microbial function and diversity.

Existing efforts have primarily focused on using probiotic bacterial strains from the Bacteroides or Lactobacillus families or Escherichia coli that have been used for decades in the lab. However, these efforts have largely fallen short because engineered bacteria introduced into the gut generally do not survive what is fundamentally a hostile environment. The inability to engraft or even survive in the gut requires frequent re-administration of these bacterial strains and often produces inconsistent effects or no effect at all. The phenomenon is perhaps most apparent in individuals who take probiotics, where these beneficial bacteria are unable to compete with the individual's native microorganisms and largely disappear quickly.

In a proof-of-concept study, researchers report overcoming that hurdle by employing native bacteria in mice as the chassis for delivering transgenes capable of inducing persistent and potentially even curative therapeutic changes in the gut and reversing disease pathologies. The research team showed that they can take a strain of E. coli native to the host and engineer it to express transgenes that affect its physiology, such as blood glucose levels. The modified native bacteria were then reintroduced into the mouse's gut. After a single treatment, the engineered native bacteria engrafted throughout the gut for the lifetime of the treated mice, retained functionality and induced improved blood glucose response for months. The researchers also demonstrated that similar bacterial engineering can be done in human native E. coli.

Intestinal transgene delivery with native E. coli chassis allows persistent physiological changes

Live bacterial therapeutics (LBTs) could reverse diseases by engrafting in the gut and providing persistent beneficial functions in the host. However, attempts to functionally manipulate the gut microbiome of conventionally raised (CR) hosts have been unsuccessful because engineered microbial organisms (i.e., chassis) have difficulty in colonizing the hostile luminal environment.

In this proof-of-concept study, we use native bacteria as chassis for transgene delivery to impact CR host physiology. Native Escherichia coli bacteria isolated from the stool cultures of CR mice were modified to express functional genes. The reintroduction of these strains induces perpetual engraftment in the intestine. In addition, engineered native E. coli can induce functional changes that affect physiology of and reverse pathology in CR hosts months after administration. Thus, using native bacteria as chassis to "knock in" specific functions allows mechanistic studies of specific microbial activities in the microbiome of CR hosts and enables LBT with curative intent.

The longest lived mice to date are those in which growth hormone signaling is disrupted, such as via growth hormone receptor knockout. While larger species tend to be longer lived, within a given mammalian species greater body size (and thus greater growth hormone activity) appears to reduce life expectancy. The effect is much more pronounced in short-lived species such as mice than in long-lived species such as our own, however. An inherited loss of function mutation in growth hormone receptor in humans produces Laron syndrome in a small population, but these individuals do not appear to live any longer than the rest of us.

Mice with genetic growth hormone (GH) deficiency or GH resistance live much longer than their normal siblings maintained under identical conditions with unlimited access to food. Extended longevity of these mutants is associated with extension of their healthspan (period of life free of disability and disease) and with delayed and/or slower aging. Importantly, GH and GH-related traits have been linked to the regulation of aging and longevity also in mice that have not been genetically altered and in other mammalian species including humans.

Available evidence indicates that the impact of suppressed GH signaling on aging is mediated by multiple interacting mechanisms and involves trade-offs among growth, reproduction, and longevity. Life history traits of long-lived GH-related mutants include slow postnatal growth, delayed sexual maturation, and reduced fecundity (smaller litter size and increased intervals between the litters). These traits are consistent with a slower pace-of-life, a well-documented characteristic of species of wild animals that are long-lived in their natural environment. Apparently, slower pace-of-life (or at least some of its features) is associated with extended longevity both within and between species.

This association is unexpected and may appear counterintuitive, because the relationships between adult body size (a GH-dependent trait) and longevity within and between species are opposite rather than similar. Studies of energy metabolism and nutrient-dependent signaling pathways at different stages of the life course will be needed to elucidate mechanisms of these relationships.

Link: https://doi.org/10.3389/fendo.2022.916139

Here, researchers discuss what is known of the role of senescent cells, and the chronic inflammation that they create, in the aging of the lung. The first human trials of senolytic therapies to selectively destroy senescent cells were aimed at reversal of idiopathic pulmonary fibrosis. There is a good evidence for the growing presence of senescent cells to disrupt tissue maintenance and produce fibrosis as a result, the deposition of excessive, scar-like collagen structures that harm tissue function. There is a little that can be done to reverse fibrotic disease in the clinic, but animal studies showing improvement following clearance of senescent cells have given some hope for progress on this front.

Cellular senescence, a coordinated cellular response to stress characterized by permanent cell cycle exit and the development of an elaborate secretory profile, is intricately linked with aging. It is well-appreciated that the number of senescent cells increases with age, and the removal of senescent cells through various mechanisms has been shown to improve both healthspan and median lifespan in mice. The senescent cell secretory profile, commonly referred to as the senescence-associated secretory phenotype (SASP), is considered one of the major mechanisms by which senescent cells impact their resident tissues. The SASP - which frequently encompasses cytokines, chemokines, and growth factors - is thought to mediate its effects through multiple mechanisms, including direct action on tissue-resident stem cells and immune cell recruitment.

The human lung has an elaborate epithelial structure to accomplish its numerous functions, which include mucus production and clearance, antimicrobial defense, surfactant production, and the facilitation of gas exchange. Maintenance and repair of the epithelium requires proper functioning of airway epithelial stem cells. These stem cells are both supported by and responsive to signals from their niche cells, which usually include, but are not limited to fibroblasts, endothelial, and resident immune cells. Emerging data have demonstrated that cells of the lung stem cell niche can express cytokines and growth factors that overlap with SASP factors, and that these secreted factors can alter stem cell behavior, thus offering a potential mechanism through which the aging niche impacts stem cell function.

Here we explore the mechanisms by which senescent cells develop in the aging lung, and how these cells contribute to both physiologic aging and aging-associated lung diseases. We give particular attention to mechanisms by which senescent cells interact with the lung stem cell niche, and how senescent cell interaction with the immune system can modulate not only tissue immune cell composition but also immune cell function. Finally, we explore the potential contribution of senescence to the pathogenesis of some of the most common age-related diseases in the lung, highlighting the therapeutic implications of unraveling the intersection between senescence and inflammation in the aging lung.

Link: https://doi.org/10.3389/fcell.2022.932723

I recall being surprised by the study from a few years ago showing that early epigenetic clocks are insensitive to physical fitness, as demonstrated in twin studies using fit versus sedentary twin pairs. Given that a higher epigenetic age than chronological age, epigenetic age acceleration, correlates with increased mortality, and fitness status is similarly well correlated with mortality, it seems interesting that the machine learning approaches used to generate the clocks from raw epigenetic data by age managed to produce this outcome. Today's study is similarly surprising, and perhaps more so. It suggests that epigenetic age is not strongly correlated with inflammatory status, and yet it is well demonstrated that increased chronic inflammation in aging drives all of the common age-related conditions, raises mortality risk, and is in general an important component in degenerative aging.

The true promise of epigenetic clocks (and similarly, transcriptomic and other clocks) is to be able to test potential rejuvenation therapies, determining quickly and efficiently whether or not they work, and how good they are relative to other options. As things stand today the research and development communities spend far too much time and effort on marginal therapies. Some process by which poor approaches are cost-effectively winnowed out early on in the development process is very much needed. Ideally, an epigenetic clock measurement would be taken before and after an intervention is attempted, either in mice or in human trials, and provide an unambiguous result. Unfortunately, epigenetic clocks cannot be used in this fashion for so long as they have these gaps, unknown until discovered, in which important aspects of aging are not well reflected in epigenetic age.

Inflammation and epigenetic ageing are largely independent markers of biological ageing and mortality

Limited evidence exists on the link between inflammation and epigenetic ageing. We aimed to 1) assess the cross-sectional and prospective associations of 22 inflammation-related plasma markers and a signature of inflammaging with epigenetic ageing; 2) determine whether epigenetic ageing and inflammaging are independently associated with mortality. Blood samples from 940 participants in the Melbourne Collaborative Cohort Study, collected at baseline (1990-1994) and follow-up (2003-2007) were assayed for DNA methylation and 22 inflammation-related markers, including well-established markers (e.g., interleukins and C-reactive protein) and metabolites of the tryptophan-kynurenine pathway. Four measures of epigenetic ageing (PhenoAge, GrimAge, DunedinPoAm and Zhang) and a signature of inflammaging were considered.

Associations were assessed using linear regression, and mortality hazard ratios (HR) were estimated using Cox regression. Cross-sectionally, most inflammation-related markers were associated with epigenetic ageing measures, although with generally modest effect sizes and explaining altogether between 1% and 11% of their variation. Prospectively, baseline inflammation-related markers were not, or only weakly, associated with epigenetic ageing after 11 years of follow-up. Epigenetic ageing and inflammaging were strongly and independently associated with mortality, e.g. inflammaging: HR=1.41, which was only slightly attenuated after adjustment for four epigenetic ageing measures: HR=1.35. Although cross-sectionally associated with epigenetic ageing, inflammation-related markers accounted for a modest proportion of its variation. Inflammaging and epigenetic ageing are essentially non-overlapping markers of biological ageing and may be used jointly to predict mortality.

Researchers here provide evidence for the inflammatory burden of infection to accelerate the aging of the hematopoietic system responsible for generating blood and immune cells. A greater exposure to infectious disease throughout life may be causing presently irreversible damage in the stem cell populations that produce the immune system. It is already known that restoration of these stem cell populations is an important target for the rejuvenation of the aged immune system, along with regeneration of the thymus and clearance of misconfigured and damaged populations of immune cells. It is unclear as to which of the many potential approaches to rejuvenation of hematopoietic stem cells will first succeed to a useful degree, but it seems likely that some form of cell therapy will be needed, an outright replacement of worn, damaged, and missing cells with a new and competent population.

Blood stem cells in the bone marrow provide a lifelong replenishment of the different cell types making up the blood system. In addition, they are also of capable of making new stem cells, in a process called "self-renewal". In older people, diseases of the hematopoietic system often occur, such as anemia or certain forms of blood cancer. Such diseases are thought to be caused by an age-associated decline in stem cell self-renewal. However, mouse models housed under highly controlled, pathogen-free conditions, rarely spontaneously develop such age-related diseases.

According to experts, the cause of this age-related loss of function of the hematopoietic system is a chronic low-grade inflammatory condition called inflammaging, that only develops in later life and impairs the function blood stem cells. "However, the question that we wanted to answer was whether inflammation and infections in early life can permanently damage blood stem cells and thus promote aging of the blood system. We have therefore carried out time-consuming experiments to determine for how we observe an inhibitory effect on stem cell function following infection and inflammation, and came to the surprising conclusion that we never see any evidence of stem cell recovery, suggesting that this process is long-lasting or perhaps even irreversible."

The researchers subsequently identified the cause of the dysfunctional hematopoiesis: Blood stem cells failed to self-renew as they were forced to divide in response to the inflammatory stimuli. The long-term consequence of a lack of self-renewal is that the hematopoietic system becomes exhausted. "This observation in mice contradicts common doctrine: we had previously believed that, after inflammatory challenge, blood stem cells revert into a so-called dormant state that preserves their capacity for self-renewal."

Link: https://www.dkfz.de/en/presse/pressemitteilungen/2022/dkfz-pm-22-43-Inflammation-accelerates-aging-of-the-hematopoietic-system.php

As practiced in the laboratory, heterochronic parabiosis is the surgical joining of the circulatory systems of an old and young mouse. The older mouse shows signs of rejuvenation, the younger mouse shows signs of accelerated aging. This has led to a great deal of debate and further research into mechanisms; the present weight of evidence favors the improvements in the old mouse to result from a dilution of harmful factors, such as damaged albumin, in the aged bloodstream, rather than by any provision of pro-regenerative factors carried in your blood but not in old blood. Researchers here show that heterochronic parabiosis actually fails to extend life span in the older mice, an interesting addition to the present body of evidence.

A new study in which young and old mice were surgically joined such that they shared blood circulation for three months showed that the old mice did not significantly benefit in terms of lifespan. In contrast, the young mice that were exposed to blood from old animals had significantly decreased lifespan compared to mice that shared blood with other young mice. Heterochronic parabiosis is a research tool used to assess the effect of organs and of blood-borne factors on young and old animals. Less controlled than direct blood exchange, parabiosis is a model of blood sharing between two surgically connected animals.

Researchers used heterochronic parabiosis between young and old mice and the isochronic controls for three months. They then disconnected the animals and studied the effects of being joined on the blood plasma and animal lifespan. "The most robust and interesting result of this study is the fact of a significant decrease in the lifespan of young mice from heterochronic parabiotic pairs. This data supports our assumption that old blood contains factors capable of inducing aging in young animals. Finding and selective suppression of aging factor production in the organism could be the key research field for life extension."

Link: https://home.liebertpub.com/news/can-exposure-to-young-blood-increase-lifespan/4941

Scores of animal studies provide compelling evidence for cellular senescence to contribute meaningfully to many age-related conditions, and yet more such studies demonstrate rapid and sizable rejuvenation via targeted removal of senescent cells in old animals using varieties of senolytic therapy. Senescent cells are created constantly in the body, the result of cells reaching the Hayflick limit on replication, tissue injury, or encountering cellular damage or toxicity. When an individual is young, these newly senescent cells are near all removed by a combination of programmed cell death and the actions of the immune system. Later in life, this balance between creation and destruction shifts, however, particularly because the immune system becomes less capable. As a result senescent cells begin to accumulate in tissues throughout the body.

While the absolute numbers of senescence cells do not become very large in most tissues, they are highly active. When maintained over time, the secreted molecules produced by senescent cells contribute to chronic inflammation, detrimental changes in cell function, pathological alterations in tissue structure, and more. This is an active maintenance of ever more degraded tissue function, leading into all of the common fatal age-related diseases. Thus removing senescent cells can allow tissues to rapidly recover to a better, more youthful state. This makes the targeted destruction of senescent cells a very desirable goal in the treatment of aging.

Cellular senescence: a key therapeutic target in aging and diseases

Aging is a complex process driven, at least in part, by hallmarks of aging, including cellular senescence, genomic instability, telomere attrition, epigenetic alterations, loss of proteostasis, deregulated nutrient sensing, mitochondrial dysfunction, stem cell exhaustion, and altered intercellular communication. Of these hallmarks, cellular senescence has been directly implicated as a key driver of aging and age-related diseases. Senescent cells (SnCs) are characterized by stable exit from the cell cycle and loss of proliferative capacity, even in the presence of mitogenic stimuli. In addition to replicative senescence caused by telomeric erosion and induction of a DNA damage response, cellular senescence can be induced by other stressors, including but not limited to epigenetic changes, genomic instability, mitochondrial dysfunction, reactive metabolites, oxidative stress, inactivation of certain tumor suppressor genes, oncogenic- and therapy-induced stress, and viral infections.

Although SnCs are growth arrested in the cell cycle, they are still metabolically active. Many SnCs secrete a wide spectrum of bioactive factors, including inflammatory cytokines, chemokines, growth factors, matrix metalloproteinases, lipids, nucleotides, extracellular vesicles, and soluble factors, termed the senescence-associated secretory phenotype (SASP).

Cellular senescence is thought to have evolved as an antitumor mechanism where the SASP induced by oncogene-induced senescence recruits immune cells to facilitate SnC removal. nCs play an essential role in multiple physiological processes, including embryogenesis, cellular reprogramming, tissue regeneration, wound healing, immunosurveillance, and tumor suppression. However, SnCs can also contribute to the pathology of many chronic diseases, including diabetes, cancer, osteoarthritis, and Alzheimer's disease. SnCs accumulate with age in most tissues, and SASP factors can act to induce secondary senescence, thus propagating and enhancing the SnC burden. The SASP also serves to sustain and enhance inflammaging, whereby enhanced chronic, low-grade systemic inflammation occurs in the absence of pathogenic processes.

Cellular senescence not only contributes to aging but also plays a causal role in numerous age-related diseases. SnC accumulation frequently occurs at pathogenic sites in many major age-related chronic diseases, including Alzheimer's and cardiovascular diseases, osteoporosis, diabetes, renal disease, and liver cirrhosis. Notably, transplanting a small number of SnCs into young healthy animals recapitulates age-related impaired physical functions. This supports the threshold hypothesis, which proposes that once the SnC burden increases beyond sustainability in a tissue, it activates age-related pathological changes and eventually results in disease.

The deleterious effects of SnCs in aging and many age-related diseases are likely mediated by increased SASP expression. SASP factors, such as TGF-β family members, VEGF, and chemokines, are known to accelerate senescence accumulation by spreading senescence to neighboring cells. The SASP crosstalk with immune cells, including NK cells, macrophages, and T cells, exacerbates both local and systemic inflammation. Proteases and growth factors in the SASP are known to disrupt tissue microenvironments and promote cancer metastasis. Fibrogenic factors and tissue remodeling factors in the SASP contribute to fibrosis in multiple tissues, including skin, liver, kidney, lung, cardiac tissue, pancreas, and skeletal muscle.

Klotho is a longevity-associated protein; more of it slows aging, less of it accelerates aging, at least in animal studies. While researchers have spent considerable effort investigating the effects of klotho on the brain, as it improves cognitive function, it seems likely that its effects arise via improved kidney function in old age. Loss of kidney function, and thus clearance of metabolic toxins and waste from the bloodstream, is harmful to tissues throughout the body. Manipulation of klotho may be a good way to assess just how much harm is generated by the age-related decline of the kidneys.

The subject of this review is Klotho (kl), which is an antiaging gene, and the corresponding protein α-Klotho (henceforth denoted Klotho or KL). The gene was first identified in mice in 1997. Deficiency of the protein results in a syndrome that has several features of aging, as observed in mutant mice with a full knockout of the Klotho gene (Kl-/-). Klotho-deficient mice exhibit stunted growth, renal disease, hyperphosphatemia, hypercalcemia, vascular calcification, cardiac hypertrophy, hypertension, organ fibrosis, multi-organ atrophy, osteopenia, pulmonary disease, cognitive impairment and short lifespan. Overexpression of the gene has the opposite effects, lengthening survival.

Klotho insufficiency appears to play a role in human aging and, specifically, in many of the diseases that are associated with aging. Klotho expression declines with age, renal failure, diabetes, and neurodegenerative disease. The age-related decline in serum levels appears to be similar in men and women; and reference values have recently been reported. Notably, a recent study of American adults showed that low serum Klotho levels correlate with an increased all-cause death rate.

Klotho can exist as a membrane-bound coreceptor for fibroblast growth factor 23 (FGF23), or a soluble endocrine mediator with many functions. Age-related deterioration of renal function results in Klotho insufficiency, and hyperphosphatemia that contributes greatly to the aging phenotype. Klotho protects the kidney and promotes phosphate elimination. Remarkably, independent of FGF23, it inhibits at least four pathways that have been linked to aging in various ways. Klotho blocks or inhibits transforming growth factor β (TGF-β), insulin-like growth factor 1 (IGF-1), nuclear factor κB (NF-κB), and Wnt/β-catenin.

Consequently, Klotho exerts major effects on several biological processes relevant to aging and disease: 1) FGF23-dependent phosphate, calcium, and vitamin D regulation. 2) Antioxidant and anti-inflammatory activities. 3) Prevention of chronic fibrosis. 4) Protective effects against cardiovascular disease. 5) Anti-cancer (tumor suppressor) activities. 6) Metabolic regulatory functions relevant to diabetes. 7) Anti-apoptotic and anti-senescence functions; stem cell preservation. 8) Protection against neurodegenerative disease (Alzheimer's and other).

Link: https://doi.org/10.3389/fragi.2022.931331

Researchers here review what is know of links between hypoxia and the onset of inflammation in age-related disease. Hypoxia in tissues can arise for a range of reasons in aging, and the processes of regulation that respond to localized hypoxia, primarily in order to induce regrowth of blood vessels to the affected region, may be meaningfully detrimental when consistently triggered. Inflammation is involved in this response, while chronic inflammation is a well-known feature of aging, driving numerous forms of tissue dysfunction.

When tissues are subjected to acute injury resulting in ischemia/hypoxia, cells adapt to the hypoxic environment by inducing the expression of a number of adaptive genes and regulating post-translational modifications. These adaptive changes in tissue cells in hypoxic environments are controlled by the HIF family. The dysregulation or overexpression of HIF-1α induced by hypoxia is associated with many pathological processes, such as cardiovascular diseases, metabolic diseases, and tumors. For example, in lung diseases, HIF-1α induces the expression of the vascular endothelial growth factor, ROS, and inducible nitric oxide synthase (iNOS) through multiple signaling pathways and a broad target gene profile, promoting an increased inflammatory response. This leads to endothelial cell dysfunction and leukocyte adhesion, promoting the proliferation of pulmonary artery smooth muscle cells (PASMCs) and oxygen delivery to hypoxic regions.

At the same time, senescence may also be involved in promoting the expression of HIF-1α. During hypoxia and aging, the hypoxic signaling pathway interacts with the sirtuin, AMPK, and NF-κB signaling pathways. For example, hypoxia induces an inflammatory response in cells, and the activation of the NF-κB pathway in endothelial cells facilitates the release of cellular inflammatory factors and acts as positive feedback for HIF-1. There is an interconnection between HIF and the sirtuin family. SIRT1 and HIF-1α jointly regulate mitochondrial senescence, and SIRT1 has a regulatory effect on HIF-1α activity; however, the specific regulatory mechanism has been controversial. The evidence has shown that SIRT1 deletion or inactivation under hypoxic conditions leads to reduced hypoxic HIF-1α accumulation, accompanied by increased HIF-1α acetylation, that SIRT1 assists in stabilizing the HIF-1α protein through direct binding and deacetylation, and that the upregulation of SIRT1 may prevent premature cellular senescence and the development of many chronic diseases associated with aging.

Further, AMPK is an important regulator of energy metabolism, resilience, and cellular proteostasis, and hypoxia can activate AMPK directly or indirectly. However, the activation capacity of AMPK signaling decreases with age, which impairs the maintenance of cellular homeostasis and accelerates the aging process, thus triggering a variety of aging-related diseases.

Link: https://doi.org/10.3390/ijms23158165

Sizable contingents in the aging research community and longevity industry like to assure us that greater human longevity is not in fact the goal of the growing level of investment in research and development of means to treat aging, or even desirable for that matter. It is a strange phenomenon. Cynically, one might suspect that those working on approaches based on cellular stress response upregulation, mimicking calorie restriction, that cannot in fact do much to extend life in longer-lived species such as our own, and will at best incrementally improve late-life health, are trying to make their work look better to the groups that funded it.

Regardless of motivation, I think that propagating this sort of viewpoint is harmful to the future of the field. While it might be harder of late to make this argument given the existence of Altos Labs, I would say that downplaying longevity as a goal can actively discourage greater public understanding of, and greater investment in, approaches that are not based on cellular stress response upregulation, such as the SENS view of rejuvenation, and which can in principle extend the healthy human life span to a meaningful degree by directly addressing the root causes of aging.

The Buck Institute, Where the Promise of Aging Research Isn't Longevity

The leaders of the Buck Institute for Research on Aging want you to know that they're not going to make you immortal. Even if they could, they wouldn't necessarily want to. Because extending life just to spend a few more years on Earth is not the point. But if their field has something deeper and better to deliver, they have reached the moment when they really have to prove it - which is what they are furiously working to do.

Longevity medicine has already generated several lifetimes' worth of hype and hogwash. There have been opportunistic (or narcissistic) promises of 500-year lifespans that captured the popular press even as reasonable scientists labored for legitimate discoveries in the background. Now, leaders in the field are busy shaking off the shadow of immortality salesmen as they set up for a new stage of growth. Their science, they say, is almost mature enough to deliver real therapies. And the Buck Institute - a small, independent research center in a California suburb almost no one's heard of - wants to lead the field into maturity.

Yet what experts there and elsewhere say the field will deliver may not be what you'd expect - especially if you've been listening to its fanboys. The real promise of longevity science, they argue, is not a longer life - it's a better one. It takes very little spark to start Eric Verdin, the Buck Institute's President and CEO, talking a streak about the possibilities of longevity research - but unlike those who promise imminent miracles, he tempers his predictions with scientific caution. And his predictions are not about finding eternal youth; they're about fighting the diseases that shorten and darken the later years of our regular lifetimes. "I don't think it's a stretch to think we could bring everyone to 95 healthy. The field is not talking about this enough. We're only talking about how we are going to get the tech guys to live to 150, but that's not where the real urgency is."

Verdin predicts that the first approved therapy from geroscience will come within five years, though he won't forecast exactly when a full paradigm shift for healthspan will follow. "Some people have called me conservative or a dream killer, but let's underpromise and overdeliver. I can tell you this field will overdeliver, but I don't know when."

In recent years, researchers have become a great deal more interested in analysis of the various microbiomes that populate the human body. The gut microbiome is clearly influential on long-term health, and changes in detrimental ways with age. There are many other niches of the body in which microbes dwell, however. Here researchers take a look at the microbes that can be found in the bloodstream of healthy individuals. This also can be seen to change with age, and we might suspect that these changes are harmful in some way. The challenge lies in demonstrating that to be the case, of course.

Metagenomic approaches for studying microbial genomes are being used to determine the potential roles of the gut microbiome, skin, and blood in chronic inflammatory diseases. According to the inflammatory theory, inflammation underlies many chronic diseases, which means that lipopolysaccharides (LPS) from inflammatory cytokines and bacteria are present in the blood. This gives rise to the probability that bacteria act as inflammatory sources and might be present in the blood even in a healthy state. Evidence of a dormant blood microbiota comes from its direct assessment using culture-independent methods, including the detection of blood (or tissue) microbial macromolecules such as the 16S ribosomal RNA (rRNA) gene and direct visualization of cells using ultramicroscopic methods. Since human blood has traditionally been thought to be a completely sterile environment composed only of blood cells, platelets, and plasma, the presence of microbes in the blood has consistently been interpreted as an indication of infection. Although it is a controversial concept, there is increasing evidence for the existence of a healthy human blood microbiota.

Although evidence indicating the presence of a microbial component in the blood of healthy human individuals is steadily accumulating, the influence of age on healthy human blood microbiota composition remains ambiguous. Aging affects both the host and microbiome physiologically, and host-microbiome interactions may affect aging. Most contemporary research has focused on age-related microbiomes in the human gut. The aim of this study was to demonstrate the presence of a blood microbiota in healthy individuals and to identify bacteria at the phylum and class levels using next generation sequencing data.

Using 37 samples from 5 families, we extracted sequences that were not mapped to the human reference genome and mapped them to the bacterial reference genome for characterization. Proteobacteria account for more than 95% of the blood microbiota. The results of clustering by means of principal component analysis showed similar patterns for each age group. We observed that the class Gammaproteobacteria was significantly higher in the elderly group (over 60 years old), whereas the relative abundance of the classes Alphaproteobacteria, Deltaproteobacteria, and Clostridia was significantly lower. In addition, the diversity among the groups showed a significant difference in the elderly group. This result provides meaningful evidence of a consistent phenomenon that chronic diseases associated with aging are accompanied by metabolic endotoxemia and chronic inflammation.

Link: https://doi.org/10.3390/jpm12060939

The SENS Research Foundation is hosting an online presentation of their work next month, a virtual Ending Aging Forum. If you are interested in the projects presently underway at the Foundation, and in allied labs, then mark your calendars. While the SENS view of aging as a process of damage accumulation, accompanied by a set of specific approaches to be taken to produce rejuvenation, has diffused somewhat into the broader longevity industry, that industry remains largely working on metabolic manipulation to slightly slow aging, not actual repair of damage. There is still a role for organizations focused on the SENS approach to aging and rejuvenation, accelerating the path towards meaningful rejuvenation therapies.

Come spend a wonderful and thought provoking time with the team at SENS Research Foundation. This virtual event is your opportunity to hear first-hand about the latest advances that our in-house researchers are making toward new rejuvenation biotechnologies, along with some of our young scientists-in-training and outside researchers whose research we fund. In addition to the formal presentations, you'll have the opportunity to talk one-on-one with the scientists and other members of our team, as well as with citizens, donors, and activists who dream of and work for a future free of degenerative aging.

The virtual event will have a Conference Hall, where feature presentations are made, along with project-specific Research Booths and booths for scientific posters presented by our students that break down different research projects. In the Expo Room, attendees can also meet and talk one-on-one or in small groups with the team and other supporters, or watch videos in which our team members and scientists-in-training introduce themselves and what drew them to this Mission. Join us to learn and celebrate how far we've come, and to catch a glimpse of the future we're building!

Link: https://www.sens.org/endingagingforum/

Recently, I had the occasion to make one of my very infrequent trips to the emergency room. As always the case to date, I get to walk out afterwards, after a very long period of hurry up and wait. Not everyone is so fortunate. One of the things one tends to find in emergency rooms is old people. So many more of life's slings and arrows become an emergency when one is frail, and old people are increasingly frail. Fall over? Emergency room. Sudden infection? Emergency room. And so on and so forth.

Nurses and doctors are inordinately overworked, and there is a long backstory to this state of affairs in which the American Medical Association, generations of regulators, and hospital owners all play the villain in turn. Emergency rooms are a great place to watch the consequences of this in action. A hospital as an entity is caring in the aggregate. There are formal systems of triage, but a great deal more informal triage based on which of the human wheels are presently squeaking. People fall through the cracks in ways large and small.

Waiting is what one does, largely, in an emergency room. A great deal of waiting. Particularly if one walks in and has every prospect of walking back out again. The older woman across from me in the waiting room did not walk in. She was in a wheelchair, and frail to the point at which walking was out of the question. She was alone. The nurses had wheeled her out at some point after intake, and there she was, waiting like the rest of us. In her case, increasingly unhappy in the stoic, quiet way of the elderly. The nurse had left her bag slung over the back of her wheelchair, in such a way as to be inaccessible to a frail older person, unable to apply the modest amount of strength to turn and lift it over. Trivial for you and me, impossible for her.

It was hard to tell that she was unhappy. It didn't show in her face. But after a few times of noticing that she tried to tug at the bag strap, and with no relative or friend in evidence, left alone, I went over to offer assistance. Perhaps others there might have had I not, but none did. I lifted off the bag, put it carefully in her lap, and left her to it. She rooted around, took out slippers and dropped them to the floor - which may as well have been on the other side of the ocean for her, inaccessible, and beyond reach. Then found her phone and started working with it. At least a frail person has that!

Unfortunately that turned out not to be the case. A little while later she caught my attention and asked me to call her house. She was difficult to understand, in part because of accent and the COVID-19 rules that lead to everyone still being masked in hospitals, but any conversation was difficult for her. She did not say much, and was slow with what she did say. It wasn't always clear that she understood me. Still, she gave me a number, and I called it. It was out of service, I told her as much, and she seemed to grasp why it wasn't working for me. She then fumbled with her memory, half-trying variations on the number, but not completing any of them.

I asked about her phone, a modern iPhone. Did she have the number in her address book? The phone had a lock code, the usual panel of numbers to enter. She tried that, as she had been, and the phone promptly locked her out for five minutes. Modern security at work. As we waited for that timer to complete, I talked to her, retrieved her slippers and put them on, as she indicated that this was desired. She did not really respond meaningfully to much else of what I said. At one point, she told me clearly that she did not feel well. I flagged a passing staffer and asked him to find someone, and nothing came of that by the time the phone was accessible again. Caring in the aggregate!

I watched her try to enter the phone code again, and she did it in a way that strongly suggested that she did not recall the code at all, or was perhaps not grasping the nature of the lock screen, entering the numbers in ascending order until the iPhone locked her out again, for longer this time. At that point, I went to find an actual nurse myself, and wouldn't take no for an answer. To her credit, the nurse put away what she was doing and came out to see what could or should be done, and had the good idea to look in the intake records for a phone number to call.

The old woman was wheeled away, and I didn't see her again. I walked out somewhat later, the more fortunate and less age-damaged of the two of us. I am not a physician and cannot diagnose dementia, but aspects of the interaction were those of someone who no longer has the full function of their brain. Just considering the physical, she was frail to the point of being unable to support herself, but that in combination with mental deterioration, leading to no longer being able to recall a phone number or even work a modern phone, is a sobering thing to see. Left on her own, she was helpless, and someone had simply left her there.

Fundamentally, this is why we advocate for greater research into the means to treat aging, to produce rejuvenation therapies based on the most plausible approaches to that goal. No-one should find themselves in the position of the old woman I met in that emergency room, a prisoner of her own old age, a shadow of who she once was, left alone and at the whim of those who cared only when prompted to do so.

Researchers here report on their efforts to improve on the ability of spermadine to modestly slow aging in short-lived species, producing new derived molecules with larger effects on the cellular maintenance process of mitophagy. Mitophagy clears damaged and worn mitochondria, and is known to decline in effectiveness with age. A range of approaches that somewhat improve mitochondrial function, including mitochondrially targeted antioxidants such as mitoQ and compounds that raise NAD+ levels such as nicotinamide riboside, may produce their effects via boosted mitophagy.

The related publicity materials for this research note that the academic program has spun out into a new startup, but to my eyes this work is unlikely to result in anything that will greatly move the needle on health and life span in humans. This part of the field, in which upregulation of cellular maintenance processes modestly slows aging in short lived species, has consistently failed to produce anywhere near the same gains in long-lived species. Spermadine is in this category, even given the attempts to produce decent human data for its effects in our species, and a moderately better version of spermadine will most likely still be in this category.

Impaired mitophagy is a primary pathogenic event underlying diverse aging-associated diseases such as Alzheimer's and Parkinson's diseases and sarcopenia. Therefore, augmentation of mitophagy, the process by which defective mitochondria are removed, then replaced by new ones, is an emerging strategy for preventing the evolvement of multiple morbidities in the elderly population.

Based on the scaffold of spermidine (Spd), a known mitophagy-promoting agent, we designed and tested a family of structurally related compounds. A prototypic member, 1,8-diaminooctane (VL-004), exceeds Spd in its ability to induce mitophagy and protect against oxidative stress. VL-004 activity is mediated by canonical aging genes and promotes lifespan and healthspan in C. elegans. Moreover, it enhances mitophagy and protects against oxidative injury in rodent and human cells. Initial structural characterization suggests simple rules for the design of compounds with improved bioactivity, opening the way for a new generation of agents with a potential to promote healthy aging.

Link: https://doi.org/10.1080/15548627.2022.2078069

A diet containing red meat comes with a higher risk of atherosclerosis and consequent cardiovascular disease, this much is well known. Researchers here look through epidemiological data in order to assess which are the more relevant of the mechanisms known to contribute to this relationship between diet and the development of fatty lesions in blood vessel walls. Their analysis suggests cholesterol level is not a relevant link, while mechanisms leading to increased chronic inflammation are important, as is the fact that red meat leads to a gut microbiome that produces significant TMAO, a metabolite that in turn negatively affects cardiovascular health.

Over the years, scientists have investigated the relationship between heart disease and saturated fat, dietary cholesterol, sodium, nitrites, and even high-temperature cooking, but evidence supporting many of these mechanisms has not been robust. Recent evidence suggests that the underlying culprits may include specialized metabolites created by our gut bacteria when we eat meat. A new study of 3,931 U.S. men and women over age 65 shows that higher meat consumption is linked to higher risk of atherosclerotic cardiovascular disease (ASCVD) - 22 percent higher risk for about every 1.1 serving per day - and that about 10 percent of this elevated risk is explained by increased levels of three metabolites produced by gut bacteria from nutrients abundant in meat. Higher risk and interlinkages with gut bacterial metabolites were found for red meat but not poultry, eggs, or fish.

In this community-based cohort of older U.S. men and women, higher intakes of unprocessed red meat, total meat (unprocessed red meat plus processed meat), and total animal source foods were prospectively associated with a higher incidence of ASCVD during a median follow-up of 12.5 years. The positive associations with ASCVD were partly mediated (8-11 percent of excess risk) by plasma levels of TMAO, gamma-butyrobetaine, and crotonobetaine. The higher risk of ASCVD associated with meat intake was also partly mediated by levels of blood glucose and insulin and, for processed meats, by systematic inflammation but not by blood pressure or blood cholesterol levels. Intakes of fish, poultry, and eggs were not significantly associated with ASCVD.

"We identified three major pathways that help explain the links between red and processed meat and cardiovascular disease - microbiome-related metabolites like TMAO, blood glucose levels, and general inflammation - and each of these appeared more important than pathways related to blood cholesterol or blood pressure. The study also argues for dietary efforts as a means of reducing that risk, since dietary interventions can significantly lower TMAO."

Link: https://now.tufts.edu/2022/08/01/research-links-red-meat-intake-gut-microbiome-and-cardiovascular-disease-older-adults

The usual progression of ways to tinker with metabolism in order to affect the pace of aging is much as follows: (a) identify an interesting mechanism associated with a single gene; (b) create mouse lineages in which the expression of this gene is manipulated in a controlled way via genetic engineering, to observe the outcomes; (c) use some form of gene therapy to overexpress or knock down that gene in mice, and note differences in life span and manifestations of aging; (d) search the drug databases for small molecules that might affect expression of the gene of interest without causing too many undesirable side-effects; (e) produce animal studies to show that the small molecule approach produces the same outcome as the genetic studies, but to a smaller degree.

If further development is then undertaken, it typically picks up from the small molecule demonstration, which is almost always unimpressive in comparison to the gene therapy. The economics of development still heavily favor working with small molecules, however, to the point at which producing a marginal therapy that is less likely to help patients is an acceptable cost of doing business. This is particularly the case since early investors typically make their returns, and are on to the next project, well before the issues associated with marginal effect sizes arise in phase II or phase III clinical trials. It is a broken system, and the obvious fix, that most small molecule development should in fact be gene therapy development, is slow in arriving. Gene therapies must fall in cost by a sizable amount to be competitive in this way.

Today's open access paper is an example of step (e) noted above in ongoing research into the role of CISD2 in aging. Researchers have in in the past demonstrated that CISD2 decreases in expression with age, and that producing mice that overexpress CISD2 extends their life span. This effect may arise because CISD2 influences autophagy and mitochondrial function, but like most longevity-associated genes, it participates in many cellular processes, and picking apart the relevant from the irrelevant is a challenging task. Here, researchers are trying to manipulate CISD2 with non-genetic means, and in doing so produce the predictably modest extension of life span in mice. If autophagy and other stress response mechanisms are the primary way in which CISD2 upregulation produces life extension, then it is unlikely to have any meaningful effect on life span in humans. Even given that the intervention in this study was started in late life, it is well known that this sort of calorie restriction mimetic approach works very much better in short-lived species than in long-lived species such as our own.

Hesperetin promotes longevity and delays aging via activation of Cisd2 in naturally aged mice

The human CISD2 gene is located within a longevity region mapped on chromosome 4q. In mice, Cisd2 levels decrease during natural aging and genetic studies have shown that a high level of Cisd2 prolongs mouse lifespan and healthspan. Here, we evaluate the feasibility of using a Cisd2 activator as an effective way of delaying aging. Hesperetin was identified as a promising Cisd2 activator by herb compound library screening. Hesperetin has no detectable toxicity based on in vitro and in vivo models. Naturally aged mice fed dietary hesperetin were used to investigate the effect of this Cisd2 activator on lifespan prolongation and the amelioration of age-related structural defects and functional decline. Tissue-specific Cisd2 knockout mice were used to study the Cisd2-dependent anti-aging effects of hesperetin. RNA sequencing was used to explore the biological effects of hesperetin on aging.

Three discoveries are pinpointed. Firstly, hesperetin, a promising Cisd2 activator, when orally administered late in life, enhances Cisd2 expression and prolongs healthspan in old mice. Secondly, hesperetin functions mainly in a Cisd2-dependent manner to ameliorate age-related metabolic decline, body composition changes, glucose dysregulation, and organ senescence. Finally, a youthful transcriptome pattern is regained after hesperetin treatment during old age.

Hesperetin is the first compound we have tested as a proof-of-concept for the hypothesis that a Cisd2 activator will have an anti-aging effect. Our findings provide an experimental basis for using Cisd2 as a molecular target for the screening and development of novel compounds that are able to activate Cisd2 pharmaceutically with the goal of translating these drugs into clinical interventions that can be used in geriatric medicine. Most importantly, hesperetin can be rapidly delivered systematically to multiple organs and tissues in vivo. Additionally, it has no detectable in vivo toxicity after long-term oral administration for 6-7 months in mice, specifically when supplemented in food at a dose of 100 mg/kg/day, which has a human equivalent dose of 491 mg/60 kg/day. Accordingly, it will be of great interest to develop hesperetin as a medicinally or nutritionally functional food for preventive purposes related to extending healthy lifespan and/or therapeutic purpose related to treating age-related diseases.

The characteristic loss of muscle mass and strength that occurs with age, sarcopenia, is accompanied by increased mortality risk where it is more pronounced. This may be because the causes of sarcopenia, such as loss of stem cell function, chronic inflammation, and so forth, have many other detrimental consequences, contributing to numerous fatal age-related conditions. This study illustrates the point, providing evidence for a weak hand grip strength to correlate with a shorter remaining life expectancy.

Muscle strength is a powerful predictor of mortality that can quickly and inexpensively be assessed by measuring handgrip strength (HGS). What is missing for clinical practice, however, are empirically meaningful cut-off points that apply to the general population and that consider the correlation of HGS with gender and body height as well as the decline in HGS during processes of normal ageing. This study provides standardised thresholds that directly link HGS to remaining life expectancy (RLE), thus enabling practitioners to detect patients with an increased mortality risk early on.

Relying on representative observational data from the Health and Retirement Study, the HGS of 8,156 survey participants aged 50-80 years was z-standardised by gender, age and body height. We defined six HGS groups based on cut-off points in standard deviation (SD) from the mean; we use these as predictors in survival analyses with a 9-year follow-up and provide RLE by gender based on a Gompertz model for each HGS group.

Even slight negative deviations in HGS from the reference group with have substantial effects on survival. RLE among individuals aged 60 years with standardised HGS of up to -0.5 SD from the mean is 3.0/1.4 years lower for men/women than for the reference group, increasing to a difference of 4.1/2.6 years in the group with HGS of -0.5 SD to -1.0 SD from the mean. By contrast, we find no benefit of strong HGS related to survival. Survival appears to decrease at much higher levels of muscle strength than is assumed in previous literature, suggesting that medical practitioners should start to become concerned when HGS is slightly below that of the reference group.

Link: https://doi.org/10.1136/bmjopen-2021-058489

Persistent viral infection may be an important contributing cause of Alzheimer's disease, either because the amyloid-β associated with Alzheimer's disease is a part of the innate immune response, and infection thereby increases production, or because persistent infection drives the chronic inflammation that disrupts the biochemistry of brain tissue. If viral infection does drive Alzheimer's disease, it may go some way towards explaining why the disease doesn't correlate with lifestyle factors such as weight, activity, and so forth, anywhere near as well as is the case for other common age-related conditions. It all sounds plausible, and the various mechanisms that may be involved certainly exist, but the supporting evidence from patient data is so far mixed, despite a few quite compelling studies. The hypothesis is by no means concretely demonstrated, but researchers here suggest that pathology may require multiple viruses, a possible explanation for confounding data in studies that only focus on one type of viral infection.

Using a three-dimensional human tissue culture model mimicking the brain, researchers have shown that varicella zoster virus (VZV), which commonly causes chickenpox and shingles, may activate herpes simplex (HSV), another common virus, to set in motion the early stages of Alzheimer's disease. Normally HSV-1 - one of the main variants of the virus - lies dormant within the neurons of the brain, but when it is activated it leads to accumulation of tau and amyloid beta proteins, and loss of neuronal function, signature features found in patients with Alzheimer's.

Researchers re-created brain-like environments in small 6 millimeter-wide donut-shaped sponges made of silk protein and collagen. They populated the sponges with neural stem cells that grow and become functional neurons capable of passing signals to each other in a network, just as they do in the brain. Some of the stem cells also form glial cells, which are typically found in the brain and help keep the neurons alive and functioning.

The researchers found that neurons grown in the brain tissue can be infected with VZV, but that alone did not lead to the formation of the signature Alzheimer's proteins tau and beta-amyloid - the components of the tangled mess of fibers and plaques that form in Alzheimer's patients' brains - and that the neurons continued to function normally. However, if the neurons already harbored quiescent HSV-1, the exposure to VZV led to a reactivation of HSV, and a dramatic increase in tau and beta-amyloid proteins, and the neuronal signals begin to slow down. "It's a one-two punch of two viruses that are very common and usually harmless, but the lab studies suggest that if a new exposure to VZV wakes up dormant HSV-1, they could cause trouble."

Link: https://www.eurekalert.org/news-releases/960389

Today I'll point out a pair of interviews with researchers Judith Campisi and Dena Dubal, in which they discuss quite different aspects of aging. Campisi's research has a heavy focus on cellular senescence in aging. Cells become senescent constantly in the body, most because they hit the Hayflick limit on replication imposed upon the somatic cells that are the overwhelming majority of cells in our tissues. Cells can also become senescent because of damage, or encouraged into senescence by the signaling of other, nearby senescent cells. Once senescent, cells are normally quickly removed by the immune system or programmed cell death mechanisms, but the balance between creation and destruction is disrupted with age, allowing the number of senescent cells to grow. These cells secrete a potent mix of signals that produce chronic inflammation and disruption of tissue structure and function, an important contribution to degenerative aging.

Dubal, on the other hand talks about the well known gender difference in longevity. There are many, many theories as to why women life longer than men. It is a feature of species with mating patterns like our own, so it is unlikely to result from anything particularly human, such as median male versus median female lifestyle choices peculiar to our species, such as smoking. Evolution interacts with mating strategies to favor women in this way. Under the hood, identifying the mechanisms involved in the comparative longevity of women suffers from the same issue as many other areas in aging - everything changes with age! While the principle differences between male and female tissues are well known and easily enumerated, it is very challenging to link those fundamental differences to specific changes in the pace of aging or late life mortality. This remains an actively debated topic.

Why Do We Get Old, and Can Aging Be Reversed?

Campisi: Many of the processes that happen during aging really happen as a consequence of the declining force of natural selection. That is, there was no natural selection for these diseases. The process we study, cellular senescence, it's now clear - and certainly in mouse models - that this process, the cellular process, drives a large number of age-related diseases, everything from macular degeneration, to Parkinson's disease, cardiovascular disease, and even late-life cancer, but it evolved to protect young organisms from cancer. So we certainly don't want to stop it when we're young.

Senescence is a state that the cell enters, in which it adopts three new traits. One of them is it gives up almost forever, almost forever, the ability to divide. It will tend to resist dying. And most important, it tends to secrete a lot of molecules that can have effects on neighboring cells, and also in the circulation. Not that many cells have been studied when they become senescent. And almost everything else we know about senescence is slowly changing as we learn more and more about different cell types and different ways that cells enter senescence.

There are still very few of them even in very old and very diseased tissue. A few percent at the most. So why do people think this has anything to do with aging? That has to do with the third thing that happens when cells become senescent is they begin to secrete a large number of molecules that have biological activity outside the cell. And that means that those senescent cells can call immune cells to the site where they are, it can cause neighboring cells to fail to function. And it basically causes a situation that is classically termed chronic inflammation.

If you eliminate senescent cells, it is possible to do one of three things to an age-related pathology: You either make it less severe, or you postpone its onset, or - and this is, of course, the one we all love - in a few cases, you can even reverse that pathology.

Dubal: in every society that records mortality across the world, women live longer than men. From Sierra Leone, where lifespan is lower, to Japan and Sweden, where lifespan is much longer. But here's a really interesting piece of information: When we look historically across multiple countries and societies, at times of extreme mortality, like famine and like epidemics, the girls will live longer than the boys and the women will live longer than the men. And this, this really suggests to us that there is a biologic underpinning for female longevity, because even when there is very high and equal stress in the environment with very high mortality, the girls are outliving the boys and the women are outliving the men. There's some very, very sad and really remarkable times that, that demonstrate this including the Irish famine and many, many other examples in our world history.

If we think about this, biologically, why there could be sex differences and human longevity. One has to do with chromosomes, our genetics, our genetic code, and every single one of our cells in our bodies. And that is that female mammals and certainly female human mammals have two X chromosomes in every cell. One of them is inactivated during development, but there are two X chromosomes, and that is the sex chromosome complement of women and girls. In contrast, boys and men have one X and one Y chromosome. And so here already at the outset, there is a very clear and striking difference in our genetics. And so with this difference, and XX in females compared to XY in males, there, there arises for biologic reasons, for sex differences in longevity. One is that in males, there's a presence of a Y. And it is thought, although not experimentally shown, that maybe there are toxic effects or deleterious effects of the presence of a Y chromosome.

Further, all the mitochondria in all of your cells are inherited from our mothers. So in the process of cellular division and the creation of a zygote, mothers pass on their mitochondria, not fathers. And so this becomes really important because mitochondria can only undergo evolution in a female body. Males will never pass their mitochondria on. And so at the end of the day, what that predicts is that mitochondrial function is more evolved to female physiology, when compared to male physiology. And this may make a difference with aging when things begin to go awry. The female cells may be more fit because their mitochondria are more evolved to the female cells compared to male cells.

The brain is in principle capable of far more repair than it actually undertakes in practice. This is generally true of most tissues, since the processes and pathways of developmental growth still exist. New neurons can be produced by neural stem cells, and the synaptic connections between neurons can be rearranged to bypass damage, where possible. It is all a matter of finding the right points of control for cellular activities. With that in mind, researchers here demonstrate a way to upregulate neuroplasticity and show that, this approach produces improved function in mice, even comparatively late in the treatment of stroke damage.

In addition to neuroprotective strategies, neuroregenerative processes could provide targets for stroke recovery. However, the upregulation of inhibitory chondroitin sulfate proteoglycans (CSPGs) impedes innate regenerative efforts. Here, we examine the regulatory role of PTPσ (a major proteoglycan receptor) in dampening post-stroke recovery. Use of a receptor modulatory peptide (a mimetic of the PTPσ regulatory wedge region with a TAT domain to facilitate membrane penetration) or PTPσ gene deletion leads to increased neurite outgrowth and enhanced neural stem cell migration in vitro.

Post-stroke ISP treatment results in increased axonal sprouting as well as neuroblast migration deeply into the lesion scar with a transcriptional signature reflective of repair. Lastly, peptide treatment post-stroke (initiated acutely or more chronically at 7 days) results in improved behavioral recovery in both motor and cognitive functions. Therefore, we propose that CSPGs induced by stroke play a predominant role in the regulation of neural repair and that blocking CSPG signaling pathways will lead to enhanced neurorepair and functional recovery in stroke.

Link: https://doi.org/10.1016/j.celrep.2022.111137

An epigenetic clock produces an epigenetic age from a patient blood or tissue sample. These clocks are trained on data from many individuals at varying ages. When the measured epigenetic age is greater than chronological age, in other words that their biochemistry looks more like that of older people from the training data, this is referred to as epigenetic age acceleration, and is thought to represent a more rapid progression of degenerative aging. Numerous studies have correlated epigenetic age acceleration with risk of specific age-related conditions. Here, researchers correlate it with odds of survival to late life. The worse the epigenetic age acceleration, the worse the odds of survival.

To our knowledge, this cohort study is the first study examining the association between epigenetic age acceleration (EAA) and healthy longevity among older women. In this racially and ethnically diverse cohort of older women, increased EAA as measured by Horvath, Hannum, PhenoAge, and GrimAge clocks was associated with lower odds of survival to age 90 years with intact mobility. Results were similar when including intact cognitive functioning.

Among 1813 women, there were 464 women (mean age at baseline, 71.6 years) who survived to age 90 years with intact mobility and cognitive functioning, 420 women (mean age at baseline, 71.3 years) who survived to age 90 years without intact mobility and cognitive functioning, and 929 women (mean age at baseline, 70.2 years) who did not survive to age 90 years. Women who survived to age 90 years with intact mobility and cognitive function were healthier at baseline compared with women who survived without those outcomes or who did not survive to age 90 years. The odds of surviving to age 90 years with intact mobility were lower for every 1 standard deviation increase in EAA compared with those who did not survive to age 90 years as measured by Horvath (odds ratio 0.82), Hannum (odds ratio 0.67), PhenoAge (odds ratio 0.60), and GrimAge (odds ratio 0.68) clocks.

This cohort study's findings suggest that EAA may be a valid biomarker associated with healthy longevity among older women. Our results suggest that EAA may be used for risk stratification and risk estimation for future survival with intact mobility and cognitive functioning within populations. Future studies could usefully focus on the potential for public health interventions to reduce EAA and associated disease burden while increasing longevity.

Link: https://doi.org/10.1001/jamanetworkopen.2022.23285

Today's open access review paper looks over a selection of what I would consider to be largely unpromising small molecules, each with evidence for their ability to slow aging, but very modestly and unreliably in most cases. Looking at the bigger picture, for much of the public it is still surprising to hear that the pace of aging can be adjusted via any form of therapy, so there is probably a role for simple, low-cost small molecule drugs in the process of education that leads to more serious efforts aimed at producing the means of human rejuvenation. Still, entirely too much effort is devoted towards small molecules that have inconsistent animal data (such as metformin), and also small effect sizes (such as metformin), and further are probably outpaced by the benefits of exercise - metformin again, but near all of the panoply of other calorie restriction mimetics that function via upregulation of cellular stress responses such as autophagy.

There are small molecules that are worth the effort, however. For example, senolytic therapies that selectively destroy senescent cells and produce rapid rejuvenation in animal models. This is far more interesting than the marginal slowing of aging produced by improved cell maintenance, not least because a single senolytic treatment results in lasting improvement as a result of the reduced burden of senescent cells. That said, there is at present a great deal more interest in the research and development community in producing small molecule drugs that alter metabolism to modestly slow aging, which have to be taken continuously over time, and which are unlikely to do better than lifestyle choices. A change in priorities is very much needed if we are to realize the promise of treating aging in our lifetimes.

Pharmacological Approaches to Decelerate Aging: A Promising Path

Aging is the principal risk factor for many illnesses such as cancer, cardiovascular disorders, and neurodegenerative diseases like Alzheimer's disease. Therefore, most elderly are being treated for a variety of chronic diseases and are suffering from side effects of the drugs. Only a 2% hindrance in the progression of aging, comparing with treatment of a disabling illness such as cancer would end up to a 10 million rise in healthier individuals and saving a large amount of budget. Hence, identifying smart therapeutic options that uphold the process of aging on one hand and simultaneously cease or decelerate the progression of age-related illnesses is of great significance.

The mTOR inhibitor rapamycin was first identified as an antifungal metabolite. The role of mTOR signaling pathway in longevity and extend of life span has been studied in numerous species. In general, inhibition of the mTOR pathway, either genetically or pharmacologically, has shown to increase lifespan in different species. The antiaging effects of rapamycin are exerted through various mechanisms, but the main route of action of rapamycin on the aging process is through inhibition of mTOR pathway. SIRT1 and AMPK occurs following inhibition of mTOR, so rapamycin can also be indirectly effective in the aging process by activating SIRT1 and AMPK following inhibition of the mTOR pathway. As known, mortality rate from infectious diseases is higher in older ages, which may be due to reduced immune function in old ages. One of the mechanisms by which the immune system is rejuvenated is the activation of autophagy. Inhibition of mTOR pathway can increase autophagy and therefore may be effective in increasing immune function during the aging process.

Resveratrol belongs to the polyphenol family exerting medical properties. The antiaging effect of resveratrol is exerted through several mechanisms. Resveratrol mimics the effects of caloric restriction (CR) and shows positive effects of CR in the aging process. It can have antiaging effects by inducing inhibitory effects on inflammation, improving mitochondrial function, suppressing oxidative stress, and regulating apoptosis. Another antiaging mechanism of resveratrol is through the activation of SIRT1. Activation of SIRT1 increases the antioxidant capacity of tissues and improves mitochondrial function.

Metformin is a biguanide and antidiabetic for the first-line treatment of type 2 diabetes. Metformin can lower plasma glucose levels and reduce the amount of glucose absorbed by the body and the amount of glucose produced by the liver. Metformin also enhances tissue sensitivity to insulin. Antiaging effects of metformin are governed by several mechanisms. In general, metformin activates AMPK and inhibits mTOR, downregulates IGF-1 signaling, reduces insulin levels, and inhibits electron transport chain (ETC) and mitochondrial complex 1.

Lithium is an alkali metal that is present in trace amounts in the body. The antiaging effect of lithium may be related to autophagy regulation, increasing telomere length, and enhancement of mitochondrial function in the brain. Inositol monophosphatase (IMPase) and glycogen synthase kinase-3 (GSK-3) contribute to the role of lithium in the regulation of autophagy.

Spermidine is a natural polyamine that is essential for cell proliferation and growth. Spermidine, as a polycation, binds to molecules such as DNA, RNA, and lipids, so it can play an important role in cellular functions. Spermidine affects autophagy, inflammation, DNA stability, transcription, and apoptosis. According to previous studies, spermidine can cause autophagy in multiple organs such as the liver, heart, and muscles. Spermidine induces autophagy by regulating the expression of autophagy-related genes such as Atg7, Atg15, and Atg11. Increased expression of elF5A and transcription factor EB (TFEB) by spermidine also induces autophagy.

Pterostilbene is an analogue of resveratrol from blueberries, which is obtained by both natural extraction and biosynthesis. Pterostilbene has anti-inflammatory, antioxidant, and antitumor effects. In a study investing the effect of pterostilbene on sepsis-induced liver injury, it was found that pterostilbene activates SIRT1, so it can also affect FOXO1, p53, and NF-κB. Pterostilbene also decreases the levels of inflammatory cytokines such as TNF-α and IL-6, decreases myeloperoxidase (MPO) activity, and increases Bcl-2 expression. Accordingly, pterostilbene can have anti-inflammatory and antiapoptotic effects.

Melatonin is a hormone in the pineal gland that affects many physiological functions. Melatonin secretion gradually decreases with aging. One of the antiaging mechanisms of melatonin is due to its antioxidant effects and reduction of oxidative stress, which leads to improved mitochondrial function. Melatonin has the ability to scavenge toxic free radicals and decrease reactive oxygen species (ROS) and can indirectly stimulate antioxidant enzymes such as GPx, glutathione reductase (GRd), and SOD. Melatonin also exerts its antiaging effects by increasing SIRT1 expression.

Acetylsalicylic acid or aspirin is obtained from the bark of the willow tree. Aspirin has a variety of medical uses. One of the main uses is to prevent secondary cardiovascular diseases. It also has analgesic and antitumor properties. The antiaging effects of aspirin on C. elegans, mice, and Drosophila melanogaster have been investigated. Lifespan increases when germ cell progenitors become ablated. One of the proposed antiaging mechanisms of aspirin is through its effect on the reduction of germline stem cells. Another proposed mechanism is improving intestinal barrier function by restricting the K63-linked ubiquitination and preventing intestinal immune deficiency.

Fisetin is a natural compound in the category of flavonoids. Fisetin can reduce age-related decline in brain function. This action can also be due to its antioxidant and anti-inflammatory effects. Fisetin can have a direct antioxidant effect and maintain mitochondrial function in the existence of oxidative stress and increase glutathione levels in cells. It has also anti-inflammatory effects against microglial cells by inhibition of 5-lipoxygenase and decreasing the production of lipid peroxides and inflammatory products. Fisetin can prevent neuroinflammation, neurodegeneration, and memory impairment by reducing oxidative stress. These functions are mediated by preventing the accumulation of ROS, inhibiting inflammatory cytokines, and regulating endogenous antioxidant mechanisms. Fisetin has senolytic effects as well by inhibiting the PI3K/AKT pathway. Downstream molecules of the mentioned pathway are involved in different parts of cellular processes by acting on the Akt/mTOR pathway that eventually leads to elimination of senescent cells. A study in mice found that taking fisetin reduces oxidative stress and inflammation and removes senescent cells; thus, tissue homeostasis is restored and lifespan is increased.

Researchers here link lower levels of glutamine with rising activation of mTOR signaling in aging, showing that it increases the burden of cellular senescence and impairs the cellular maintenance processes of autophagy. Either glutamine supplementation or mTOR inhibition addresses these specific defects. This is an interesting addition to what is known of the role of mTOR in aging, an area of active interest, with numerous mTOR inhibitor small molecule drugs presently under development. If the less costly and more readily available approach of glutamine supplementation can produce much the same benefits, that is a promising development.

Glutamine is a conditionally essential amino acid involved in energy production and redox homeostasis. Aging is commonly characterized by energy generation reduction and redox homeostasis dysfunction. Various aging-related diseases have been reported to be accompanied by glutamine exhaustion. Glutamine supplementation has been used as a nutritional therapy for patients and the elderly, although the mechanism by which glutamine availability affects aging remains elusive.

Here, we show that chronic glutamine deprivation induces senescence in fibroblasts and aging in Drosophila melanogaster, while glutamine supplementation protects against oxidative stress-induced cellular senescence and rescues the D-galactose-prompted progeria phenotype in mice. Intriguingly, we found that long-term glutamine deprivation activates the Akt-mTOR pathway, together with the suppression of function. However, the inhibition of the Akt-mTOR pathway effectively rescued the autophagy impairment and cellular senescence caused by glutamine deprivation.

Collectively, our study demonstrates a novel interplay between glutamine availability and the aging process. Mechanistically, long-term glutamine deprivation could evoke mammalian target of rapamycin (mTOR) pathway activation and autophagy impairment. These findings provide new insights into the connection between glutamine availability and the aging process.

Link: https://doi.org/10.3389/fphar.2022.924081

Acarbose is one of a few diabetes medications shown to modestly slow aging in short-lived species. Researchers here take a look at the evidence for this effect on life span to be mediated by changes in the gut microbiome. The gut microbiome changes with age: the relative numbers of harmful microbes increasing, contributing to the chronic inflammation of aging, while relative numbers of beneficial microbes decreases, causing a reduction in metabolites known to help tissue function. Directly changing the gut microbiome to a more youthful configuration via fecal microbiota transplantation has been shown to improve health and extend life in laboratory species, so it is not unreasonable to hypothesize that some of the pharmaceutical approaches that slow aging act at least in part by adjusting the gut microbiome.

The existing literature provides evidence that acarbose can affect the life span. This review links inflammation, mitochondria, and telomeres with the gut microbiota, illustrating individual mechanisms involved in acarbose-associated life span extension. Acarbose improves the immune system, inflammatory response, and mitochondrial function by affecting the gut microbiota. Acarbose supplementation is a cost-effective method for delaying aging given its potential health-restorative effects and limited side effects. This offers hope for analyzing the use of acarbose to improve health and reduce the risk of age-related diseases.

Additional experiments should be undertaken to verify our speculations; for instance, which bacteria affect the length of telomeres and mitochondrial function after acarbose intervention needs to be studied. The role of acarbose in affecting telomere length by regulating the gut microbiota should be investigated with a more rigorous scientific approach.

The present review describes several mechanisms by which acarbose affects the life span through the gut microbiota by considering different viewpoints and provides a new theoretical basis for the mechanism of acarbose-extended life spans. Hitherto, to the best of our knowledge, no other reviews have explained the mechanisms underlying life span extension by acarbose based on the perspective of gut microbiota. In general, many factors that affect the life span and mechanisms of acarbose that can help extend the life span of humans remain to be studied.

Link: https://doi.org/10.14336/AD.2022.0117

Today I'll point out a couple of papers on the topic of why SARS-CoV-2 is so much more severe in the old. There has been a great deal of discussion about the age-related nature of COVID-19 mortality these past few years, though near entirely within the scientific community. The more severe cases involve runaway inflammation, and old people already suffer a raised level of chronic inflammatory signaling, making them that much more vulnerable to cytokine storm events in which the immune system runs wild to cause severe pathology and death. Sepsis is a similar problem, similarly age-related for reasons relating to increased vulnerability.

It isn't just a higher base level of inflammatory signaling with age, however. Nor is it only inflammatory signaling coupled with immunosenescence, the growing inability of the adaptive immune system to engage effectively with pathogens. Infectious diseases that are shrugged off in youth would be serious threats to the old and frail even if immunosenescence was the only consequence of aging. Unfortunately many other aspects of aging also conspire to make an old person more vulnerable to inflammatory infectious disease. This has long been well illustrated by the mortality that attends every winter influenza season, COVID-19 was an unneeded lesson. And yet the broader public is still largely unaware that working towards rejuvenation therapies is perhaps the best, most cost-effective way to prevent these continued losses of life.

Inflammaging at the Time of COVID-19

Most people infected with SARS-CoV-2 have a self-limiting infection and do recover; others experience more severe disease, with 10% of patients requiring intensive care unit (ICU) admission. The case-fatality rate of COVID-19 is approximately 1.5%. Most COVID-19-related deaths have occurred in those 60 years and older, and an even higher mortality was registered among the oldest old (ie, ≥80 years). The presence of a least 1 underlying chronic condition (eg, cancer, diabetes, hypertension, obesity, cardiovascular disease, cerebrovascular disease) is a major risk factor for death. Older adults are more susceptible to SARS-CoV-2 infection, more prone to develop severe COVID-19, and more frequently admitted to ICUs, with consequent increased mortality.

An extraordinary proliferation of studies suggests that SARS-CoV-2 infection unleashes an abnormal inflammatory response, the so-called cytokine storm. Indeed, severe COVID-19 in hospitalized patients is characterized by high circulating levels of C-reactive protein (CRP), interleukin (IL)-6, tumor necrosis factor alpha (TNF-α), and lymphopenia. The abnormal inflammatory response, along with hypercoagulability and defective viral clearance, contributes to the development of severe pneumonia and acute respiratory distress syndrome (ARDS), with subsequent end-organ damage, multiorgan system failure, and eventually death. Although severe COVID-19 disproportionally affects older people, systemic inflammation during SARS-CoV-2 infection is detected in patients of all ages, including children, in whom a severe multisystem inflammatory syndrome has been described. This implies that COVID-19-induced inflammation is not per se sufficient at inducing negative health outcomes. This article provides a pathophysiologic view of COVID-19 in older adults within the frame of inflammaging, with a focus on antiinflammatory treatments for acute and postacute disease.

How can Biology of Aging Explain the Severity of COVID-19 in Older Adults

Aging has been identified as one of the most relevant risk factors for poor outcomes in COVID-19 disease, independently from the presence of preexisting diseases. The COVID-19 mortality risk sharply increases for elderly subjects, as showed by the reports of China, Italy, and the United States. In particular, in Italy, case fatality rate for patient aged 40 to 49 years or younger was reported of about 0.4% or lower, 1% among those aged 50 to 59 years, 3.5% in those aged 60 to 69 years, 12.8% in those aged 70 to 79 years, to 20.2% from 80 years and older.

Age is not only an important predictor for mortality, but it is also associated with higher disease severity, in terms of increased hospitalization rates, length of hospital stay, need for intensive care, and invasive mechanical ventilation. Since now, different mechanisms responsible for worse outcomes in the elderly have been suggested, which include the remodeling of immune system, the higher prevalence of malnutrition and sarcopenia, the increased burden of multimorbidity, and, to a lesser extent, the direct effects of age on the respiratory system and hormonal profile. The interplay between all these causes, rather than the individual pathophysiological mechanism, explains the increased severity of the disease with age.

This paper is, more or less, a complaint that the research community still knows far too little of the relative importance of different mechanisms of aging. That is fair enough, certainly true. The authors put that complaint in the context of the current prevalent attitude of using the hallmarks of aging as a checklist for development of therapies to intervene in aging, which in some cases (such as the dysregulation of nutrient sensing) is also fair enough. Not all of the hallmarks are evidently good places to intervene, as they are most likely far downstream of the causes of degenerative aging. That said, I do feel that the authors are deliberately ignoring the copious in vivo evidence for the efficacy of clearing senescent cells in the service of making their point, however. Given the many studies showing rapid reversal of diverse forms of age-related pathology in mice following treatment with senolytic drugs, it is a little ridiculous to suggest that we really don't know much about whether nor not removing of senescent cells is meaningfully beneficial.

The critical outstanding question is: Can aging processes be slowed down? Evidence in nature suggests a positive answer to this fundamental question. For instance, similar pathobiological changes associated with aging develop over very different time scales in different mammalian species. While it may take 70 years for a senile cataract to develop in a human, similar age-related changes develop in horses within 20 years, in dogs within 10 years, and in mice in even only 2 years. Analogous considerations also apply to many other age-related alterations (hair greying, muscle loss, etc.). Although the biology underlying these differences in aging rate are not well understood, these examples demonstrate that similar aging phenomena in comparable tissues can develop over very different absolute time scales. Therefore, there seems to be some plasticity that could be harnessed, in theory, for slowing down the aging process.

Much of what is currently thought to be known about the biological underpinnings of the aging process has been presented in concepts like the "hallmarks of aging" which summarize processes claimed to be involved in driving organismal aging phenomena. Here, we carefully examine the evidence presented in favor of such links between these processes and aging. As we will explain in detail below, we identify limitations that are often grounded in the choice of models and/or the way aging is measured. We conclude by outlining experimental designs that are suited to overcome these current limitations and that can be used to address if and to what extent putative aging regulators are in fact involved in regulating organismal aging rate.

Aging research essentially deals with a many-to-many mapping problem. There are changes in many age-sensitive phenotypes (collectively representing the aging process, i.e., the transition of a young adult organism to an aged one) that could, in theory, each be influenced by a large set of regulators. Advances in aging research will critically depend on a better definition of this problem. In conclusion, aging research will benefit from a better definition of how specific regulators map onto age-dependent change, considered on a phenotype-by-phenotype basis. Resolving some of these key questions will shed more light on how tractable (or intractable) the biology of aging is.

Link: https://doi.org/10.1038/s41380-022-01680-x

LDL particles carry cholesterol from the liver throughout the body via the circulatory system. As the prevalence of oxidative molecules rises with age, a consequence of inflammation and mitochondrial dysfunction, ever more of these LDL particles become oxidized. This allows them to interact with cells in novel ways that contribute to atherosclerosis, the formation of fatty deposits in blood vessel walls, either by overwhelming them with additional cholesterol uptake, aggravating the lysosomal recycling system, or interacting with specialized receptors such as LOX-1 in ways that spur inflammatory behavior. Here, researchers report that one of the receptors known to be involved in these processes is also important to cancer metastasis - and so the same oxidative stress of aging that contributes to atherosclerosis is also contributing to a greater risk of severe cancer via this mechanism.

Cancer is the uncontrolled growth of body cells leading to the formation of tumors, triggered by the accumulation of mutations in a cell's genome. In order to become malignant, metastasizing cancer, tumor cells go through a series of transformations involving interactions between the body's immune system and the tumor. However, many mechanistic details in this process are still unclear, making the prevention and treatment of cancer notoriously difficult. However, there is growing evidence that in tumor progression to metastasis, inflammation of blood vessel-lining endothelial cells is a key process.

Researchers showed that metastasizing tumors, in contrast to non-metastasizing ones, accumulate proteoglycan molecules; these, in turn, attach to and accumulate LDL to the walls of blood vessels. The bound LDL becomes oxidized. There are also high levels of its receptor, called LOX-1, in the endothelial cells of metastasizing tumors. This, they found, causes these cells to produce inflammation signals that attract neutrophils. They then proved that in mice, the suppression of LOX-1 can significantly reduce tumor malignancy, and also that LOX-1 overexpression caused an increase in signaling molecules attracting neutrophils.

The study also points to a promising approach for treating and preventing malignant cancer - and cardiovascular disease - by targeting neutrophil recruitment to endothelial cells. "The number of patients with cancer who die not of cancer, but of cardiovascular events, is increasing. Targeting the LOX-1/oxidized LDL axis might be a promising strategy for the treatment of the two diseases concomitantly."

Link: https://www.global.hokudai.ac.jp/blog/a-common-mechanism-for-cancer-metastasis-and-atherosclerosis/

It is fair to say that everything changes with age, every aspect of cellular biochemistry. That doesn't mean that researchers can point to any specific change and say that it is important, however. It could be far downstream from underlying causes. It could be hard to fix in comparison to those causes. It may be shown to detrimentally affect a range of vital cellular processes, but those mechanisms could turn out to be minor and unimportant in comparison to others. The major challenge in aging research is exactly that everything changes. It is thus very hard to determine the importance of any given change, given that it takes place in this complex environment of interacting dysfunction, chains of cause and consequence, a network falling into failure.

Lipid rafts are assemblies that constantly form and break down in and around the cell membrane, a complex little world in and of itself. The cell membrane influences everything to do with cell signaling, uptake of materials from the environment, export of materials from the cell, and a good many other things besides. Thus any changed aspect of the cell membrane, such as altered behavior of lipid rafts, will also influence these line items. But is it important?

That is a hard and expensive question to answer. Theorizing costs little, however, and thus we see a great deal of theorizing. Today's open access paper is good example of a fairly aggressive joining of dots with little to no support for the importance of the proposed mechanisms as a target for intervention. Which is, sadly, business as usual in the matter of aging: the only practical way to prove that any given approach is a good approach is to try it. Unfortunately, building the means to try it in the context of something as complex as lipid raft behavior gets us right back to hard and expensive again.

Crosstalk between Lipid Rafts and Aging: New Frontiers for Delaying Aging

Lipid rafts (LRs) are microdomains (10-200 nm) with a short life, and their components, such as sphingolipids, cholesterol, and proteins, are assembled to function and disassemble quickly afterward. The components and sizes of LRs are not constant, and they can merge with each other to become larger when necessary. As hubs for signal transduction, LRs contain various signal proteins. Because signal transduction is essential for aging processes, the relationship between LRs and aging has attracted increasing attention. Aging drastically affects the components and functions of LRs. Further, considering the evidence, the influences of LRs on the hallmarks of aging are apparent. Many of these hallmarks contribute to the development of sustained inflammatory stage and aging. Hence, attempts to "cure" aging should involve amelioration of inflammaging (chronic, sterile, low-grade inflammation during aging), which can be achieved by regulating LRs.

Modulation of cholesterol is one way to regulate LRs, as cholesterol is a critical constituent of LRs. Most cellular cholesterol exists in the membrane and is enriched in LRs. Depleting cholesterol can disrupt the form of LRs and reduce the content of LRs, suggesting that cholesterol-lowering drugs such as statins, can alleviate inflammaging to anti-aging by inhibiting the formation of LRs. As expected, clinical results have demonstrated that new statin use is associated with a decreased death rate among American veterans (75 years and older).

However, one of the frequently reported adverse reactions of statins is memory impairment and cognitive decline. Coincidentally, Alzheimer's disease, which is characterized by cognitive and memory deterioration, is associated with reduced levels of cholesterol and LRs in the frontal cortex. Based on these results, we speculate that the adverse effects of statins on memory and cognitive alterations may partly be due to their cholesterol-lowering effects and hindered formation of LRs. Therefore, when using statins to delay aging, it is recommended to adopt some pharmaceutical modifications to increase the polarity of the statins or to choose hydrophilic statins instead of lipophilic statins for making them selective and inaccessible to the central nervous system, thus reducing their side effects.

Overall, aging has been proven modifiable, and some drugs for slow aging have been discovered. For example, rapamycin inhibits mTOR activation to delay aging; senolytics can target and eliminate senescent cells; sirtuin activators, which enhance sirtuin activity; Nicotinamide adenine dinucleotide (NAD) precursors that can supply cellular NAD levels; antidiabetic drugs such as metformin and acarbose; and non-steroidal anti-inflammatory drugs, can also be used. However, none of drugs target LRs to delay aging, making it a future objective. Overall, targeting LRs will be a novel strategy for prolonging life, and statins might be promising candidates for new anti-aging agents.

Mapping the regulation of improved muscle strength resulting from exercise may lead to interventions that increase or mimic these beneficial effects of exercise. Here, researchers report on a part of their investigation of proteins involved in regulating the response to exercise. They do not show that the new regulatory protein discovered in their work can be manipulated to enhance the effects of exercise on muscle strength, but they do show that it is important by removing it in mice to produce the outcome of greatly reduced muscle function.

Exercise induces signaling networks to improve muscle function and confer health benefits. To identify divergent and common signaling networks during and after different exercise modalities, we performed a phosphoproteomic analysis of human skeletal muscle from a cross-over intervention of endurance, sprint, and resistance exercise. This identified 5,486 phosphosites regulated during or after at least one type of exercise modality and only 420 core phosphosites common to all exercise.

One of these core phosphosites was S67 on the uncharacterized protein C18ORF25, which we validated as an AMPK substrate. Mice lacking C18ORF25 have reduced skeletal muscle fiber size, exercise capacity, and muscle contractile function, and this was associated with reduced phosphorylation of contractile and Ca2+ handling proteins. Expression of C18ORF25 S66/67D phospho-mimetic reversed the decreased muscle force production. This work defines the divergent and canonical exercise phosphoproteome across different modalities and identifies C18ORF25 as a regulator of exercise signaling and muscle function.

Link: https://doi.org/10.1016/j.cmet.2022.07.003

Researchers here identify distinctive markers for a population of regulatory T cells that act to protect at least some types of tumor tissue from the rest of the immune system. Cancers subvert the immune system in a range of ways, making it blind to cancer cells, and even making immune cells assist in the growth of the cancer. In principle destroying these protective, subverted immune cells could produce a renewed attack on a tumor, or at the very least make it more vulnerable to present therapies, particularly those that encourage immune cells to attack cancer cells.

Some types of T cells work to calm their over-active brethren. Known as regulatory T cells, or T-regs, they typically tamp down inflammation, quieting that mob and thereby protecting nearby healthy tissues. In tumor tissue, researchers found a different flavor of T-regs. These immune-suppressing cells, swarming in tumor-environment specimens, were different from T-regs found elsewhere in the body. Their cell surfaces are marked by two distinct protein receptors. These specially marked T-regs were particularly good at tamping down inflammation, expanding in number and protecting the tumor cells from attack by other types of T cells.

To a casual observer, the T-regs from the tumor samples would look no different from those found elsewhere in the body. But the team used new techniques that allow scientists to identify characteristics of tens of thousands of individual cells in a sample, and advanced computing methods to sift through data. It allowed them to spot two types of receptor proteins on the surfaces of T-regs collected from the tumor. The telltale proteins have names only a scientist could love: IL-1R1 and ICOS. "What makes these cells unique is that they express both those proteins. You just don't see that co-expression on other T-reg cells."

One reason this pair of proteins may have been overlooked by researchers previously is that they occur in human T-regs, not in those of mice. Much of laboratory work in immunology relies on mouse models of the immune response, but this study focused on human tissues, taken from patients who either had cancer or non-cancerous lesions. Researchers hypothesize that these tumor-resident T-regs have been tricked by cancer into working for the wrong team. Surrounded by T cells searching for cancer cells to destroy, the tumors acquired an ability to either attract or generate a blanket of these ICOS/IL-1R1-bearing T-regs. Exactly how they did so is not clear, but their impact is to build up an immunosuppressive environment, protecting the tumor from ordinary T cells doing their jobs.

Link: https://www.fredhutch.org/en/news/center-news/2022/05/regulatory-t-cells-solid-tumors.html