Fight Aging! Newsletter, September 25th 2023

Fight Aging! publishes news and commentary relevant to the goal of ending all age-related disease, to be achieved by bringing the mechanisms of aging under the control of modern medicine. This weekly newsletter is sent to thousands of interested subscribers. To subscribe or unsubscribe from the newsletter, please visit:

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A Call for Matching Donors for the LEV Foundation "Robust Mouse Rejuvenation 2" Fundraiser

The Longevity Escape Velocity (LEV) Foundation was founded by Aubrey de Grey to address an important missing aspect of the ongoing work to produce treatments that target the underlying mechanisms of aging. While the research and development community has made sizable strides in the past decade, and the first rejuvenation therapies now exist in at least prototype form, it remains the case that next to no-one is conducting combination studies that use two or more of these interventions. When considering therapies that can repair forms of the cell and tissue damage that cause aging, it seems plausible that two different therapies will be additive, producing larger results than either alone.

The LEV Foundation is presently conducting the Robust Mouse Rejuvenation 1 Study, and is raising funds for the next study in line, Robust Mouse Rejuvenation 2, testing other promising interventions to prove that there is synergy between very different forms of repair therapy. These studies, and the many more like them that should be running throughout the research community and industry, but are not, will form the first foundation for the next few decades of medical practice. It has always been apparent that there would be a toolkit of many rejuvenation therapies, each addressing some aspect of aging, and that these therapies would be used in combination. But that conjecture still requires concrete proof to convince the industry and the medical community.

Many of the Fight Aging! audience have in the past supported the SENS Research Foundation annual fundraisers, some of you by offering matching donations to encourage others to donate. It worked well, and collectively our community has raised a great deal of funding over the past decade to support the growth of rejuvenation biotechnology research under the SENS umbrella, helping to fund many promising research programs that went on to spawn biotech startups. All those who have done so in the past, I encourage you to reach out and offer your support again to the LEV Foundation in their present important work, and help make the Robust Mouse Rejuvenation 2 study a reality.

Below, see Aubrey de Grey's comments on current efforts at the LEV Foundation, and a call for matching donors to help with the soon to be launched fundraiser:

A decade ago, five indisputably mainstream luminaries of geroscience published a paper that remains, by far, the most highly-cited publication in the entire field this century: "The Hallmarks of Aging". It had its roots in a paper that I and my collaborators published more than a decade earlier: "Time to talk SENS: Critiquing the Immutability of Human Aging", and laid to rest the debate as to whether the divide-and-conquer, damage-repair approach that the earlier paper introduced was feasible. What remained was to implement it.

Inevitably, some of the component interventions in the SENS rejuvenation biotechnology program are much more challenging to implement than others. That is why, while the field has mostly focused on the lower-hanging fruit, SENS Research Foundation has focused on filling that vacuum by targeting the hardest types of damage to repair, since no divide-and-conquer approach can succeed otherwise.

Now, however, the field has reached a new phase of implementing the SENS program. While the themes that SRF have pursued remain relevant, and are now much better funded as a result of Richard Heart's admirable initiative of 2021 that added 27 million to SRF coffers, it has also become possible to move to the final phase of the implementation of divide-and-conquer, namely the combining - in mice, for now - of interventions that individually show considerable promise.

That is why my new organisation, LEV Foundation, is focusing on combination studies as its flagship research program. I continue to provide regular updates on social media regarding the first such study, which we at LEVF are terming "Robust Mouse Rejuvenation 1", as the study progresses towards the point at which interesting differences emerge in the mortality of the cohorts.

Importantly, there is a long list of promising interventions not included in our current study, and which I and the LEVF team are eager to incorporate into a second study: Robust Mouse Rejuvenation 2. We are now focused on raising the funds for this new project, which like our first study will continue to identify the best combinations, antagonistic interactions, and sex and age differences in the degree to which each intervention can impact aging.

The specifics of the second study are being finalized, and we have conducted extensive work to narrow the options down, as I outlined in my presentation at LEVF's Dublin conference. Many of the remaining decisions, both between these options and concerning their details, come down to cost. Thus it continues to be the nature of our work that every offer of financial support counts. We are immensely grateful to those who have made our past work possible, and those who continue to make our future plans possible. Please reach out if you can help to make a difference!

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Leaking Gut, Leaking Blood Vessels, Leaking Blood Brain Barrier

In today's open access paper, researchers attempt to throw a big tent over three distinct issues in the aging of the body and brain. Firstly, the intestinal barrier fails, allowing bacteria and bacterial metabolites into tissue and the circulation, where they can provoke dysfunction and inflammation. Secondly, blood vessels become leaky, harming surrounding tissues by allowing excessive fluid, inappropriate molecules and cells to escape. Lastly, the blood-brain barrier leaks; this is a more specialized barrier layer surrounding blood vessels in the brain, and when it leaks, the passage of unwanted cells and molecules into the brain again produces dysfunction and inflammation.

Can one really draw a circle around these three quite different phenomenon and talk about a unified "leaky syndrome", as the authors of today's paper do? Perhaps so if these issues largely begin with intestinal barrier dysfunction, allowing gut microbes and their inflammatory metabolites into the bloodstream to cause increased dysfunction in blood vessel walls. That this is the primary issue has yet to be determined, but given that we are entering an era in which the aged gut microbiome is both accurately measurable and can be rejuvenated via techniques such as fecal microbiota transplant, flagellin immunization, and so forth, I'd imagine much more will be known a decade from now.

Treating Leaky Syndrome in the Over 65s: Progress and Challenges

Aging is a natural process associated with decreased physiologic function in all organs, i.e. it not only affects our immune system, but also affects all tissues and cells, resulting in increased risk of several chronic diseases and vulnerability to death. The gut microbiome is now recognized as one of the key elements to maintaining host health1 and contributing to disease progressions such as high abundance of pathogenic bacteria (such as Escherichia coli, Staphylococcus aureus, and Clostridium difficile) and low abundance of short-chain fatty acid producing bacteria such as Bifidobacterium, Faecalibacterium, Roseburia. Several studies over the past few years revealed that the gut microbiome and its composition changes with age which could have significant implications on overall health during aging, however, the mechanisms by which it impacts the biology of aging remain largely unknown.

The microbiome is composed of diverse microbes i.e., bacteria, archaea, viruses, eukaryotic microbes, and fungi, that have lived in and around our body since birth. The gut and skin are the most extensively colonized regions of our body, while other areas including the mouth, eyes, ears, and reproductive organs also harbor dense populations of specific microbes. These microbes establish a symbiotic relationship with the host, playing a crucial role in regulating essential functions such as protection against pathogens, immunomodulation, and maintaining the structural integrity of the gut mucosal barrier, indicating a strong association between abnormalities in gut microbiota and the development of a wide range of diseases including autoimmune disorders, depression, and neurodegenerative diseases such as Alzheimer's disease and metabolic disorders.

However, the mechanisms by which the microbiome contributes to the development of these diseases are unclear. There can be several mechanisms but inflammation is a key suspect. Low-grade inflammation is often higher in older adults but the source of inflammation remains largely elusive. Growing evidence indicates that gut dysbiosis, characterized by an imbalance in gut microbial composition, tends to escalate with age. This dysbiosis, in turn, contributes to increased gut permeability, often referred to as "leaky gut". This heightened permeability facilitates the passage of pro-inflammatory substances such as bacterial toxins and lipopolysaccharide (LPS) from the gut lumen into the bloodstream or mucosal immune system, thereby triggering inflammation. Elevated inflammation is also known to increase the permeability of other epithelial and endothelial barriers such as intestinal epithelia (leaky gut), blood vessel endothelia (leaky vessels), blood-brain barrier (BBB) (leaky brain), and others, and collectively called "leaky syndrome". The link between leaky syndrome with chronic inflammation and microbiome dysbiosis in aging biology remains poorly understood.

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The Lack of Consensus on Approaches to Aging as a Flaw to be Fixed

It can be argued that the largest challenge facing the development of means to treat aging as a medical condition is that there is, as of yet, no useful consensus position on how to measure aging, how to define aging, or which of the countless measurable aspects of biochemistry that change with age are the most appropriate targets for therapy. This means that any given research group or biotech startup has a lot of leeway to argue that their approach is the right one - and it might take twenty years to establish the effects of their therapies on long-term health and life span, even given a successful development program. There is a shotgun approach underway, in which the research and development communities try many different things and see how it goes, only limited by their ability to persuade sources of funding to support the work. I imagine that this will continue for the foreseeable future, given just how long it takes to assess the efficacy of a given approach to therapy.

From a funding perspective, should the first generation of therapies to slow and reverse aspects of aging start to produce very promising data on long-term health by the end of the 2030s, there will be thereafter be funding for just about every option on the table to treat aging. The hype cycles will come and go, and it may well be the case that enough funding to try all of the available options will in fact be needed. It seems to me that the most straightforward way to reverse engineer the biology of aging, to decide on which of the many identified mechanisms are the most important, the closest to being root causes, is to produce prototype and first generation therapies for all of the plausible approaches to rejuvenation, the various means of repair of cell and tissue damage, and compare the resulting benefits in human trials. It won't be a fast process, but likely faster than the other options on the table.

We need to shift the focus of aging research to aging itself

The field of aging is at a precipice. Attention and funding are increasingly focused on this area, and exciting, fundamentally important findings are being reported literally every day. As the great promise of targeting aging comes into sharper focus, we are rapidly approaching the point where we must face the elephant in the room: We lack any semblance of a consensus on the nature of aging or, more fundamentally, on the essence of this process. Taking steps to resolve these foundational issues in aging biology will enable us to advance this field to the next level.

As a field, we claim to study aging - but what, in essence, do we study? What is that most basic, fundamental feature of the process that we call aging? Is it functional decline, damage accumulation, increased mortality rate, continuation of development, increased biological age, decrease in the strength of natural selection, the totality of age-related changes, loss of homeostasis, loss of information, their combination, or something else? After organisms reach adulthood, all of these features seemingly go hand in hand, but their coordination is not perfect, and there must be one underlying, explanatory feature that leads to the others. What is it, and can we truly advance the field without identifying it?

Aging biology is exponentially growing as a field, and talented scientists are designing and carrying out many elegant studies. However, in many ways, we are attempting to construct a building without a foundation. One can see this by the lack of clear answers to some of the most basic questions: When does aging begin? To what extent, if any, is biological age dynamic and potentially reversible? Which biomarkers are most appropriate to measure biological age, and do any of them actually measure aging directly?

To begin answering these questions and ensuring the future success of this field, we propose two critical concepts on which aging biologists can actively focus their collective attention: the essence of aging and the nature of aging. To be clear, we are not suggesting that either a formal definition or a unified theory of aging is an immediate need for the field. The essence and nature of aging represent more fundamental concepts, from which we envision that a consensus definition and theory of aging may proceed in the future. In the immediate term, these concepts may serve as building blocks to form the basis of our understanding of aging biology.

We define the "essence of aging" as the most basic, essential, explanatory, and causative feature of biological aging. It is the underlying driving force of the manifestations of advanced age, such as frailty, loss of function, and age-related diseases. Identifying the essence of aging is critical if we wish to study and target aging itself, rather than its later-stage manifestations. Many aging biologists invoke the hallmarks or pillars of aging as a basic starting point for conceptually framing aging biology. However, the essence of aging, in our minds, represents a more fundamental concept underlying these and other characteristics of aging. In the same way that the Hallmarks of Cancer can be reduced to a single essence - mutations - we should be able to, and should strive to, distill a single essence of aging that drives all of the hallmarks/pillars and higher-level manifestations of aging.

We define the "nature of aging" as the inherent properties and dynamics that characterize aging as a biological phenomenon. The nature of aging is conceptually related to critical outstanding questions in the field, such as the behavior of biological age over the life course; the point at which aging begins; and the extent to which aging of a subset of cells or tissues impacts the aging of surrounding or distant cells/tissues. The nature of aging is a much broader concept than the essence of aging, but understanding the nature of aging is no less critical to our ability to target this process.

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Medical Control of Hypertension Largely Removes Increased Risk of Dementia

The increased blood pressure of hypertension is very damaging. So much so that blunt therapies that override regulatory systems controlling blood pressure, reducing blood pressure without in any way addressing the underlying causes of hypertension, can reduce mortality and incidence of age-related disease. Hypertension is a downstream consequence of forms of age-related cell and tissue damage that also cause many other forms of dysfunction. But a sizable fraction of their contribution to degenerative aging is mediated by increased blood pressure.

Hypertension turns biochemical issues in aging into physical trauma to tissues. It causes pressure damage such as rupture of capillaries to delicate structures necessary to tissue function in the kidney, brain, and elsewhere. It accelerates the progression of atherosclerosis, in which fatty lesions form in blood vessel walls. It contributes to destructive remodeling of heart muscle. Further, hypertension speeds the progression of neurodegenerative conditions leading to dementia, the subject of today's open access meta-analysis. The data demonstrates the point made above, that controlling hypertension makes a sizable difference to the risk of suffering dementia, a measure of just how much damage raised blood pressure does to the brain when sustained over time.

Use of Antihypertensives, Blood Pressure, and Estimated Risk of Dementia in Late Life: An Individual Participant Data Meta-Analysis

The utility of antihypertensives and ideal blood pressure (BP) for dementia prevention in late life remains unclear and highly contested. This study assessed the associations of hypertension history, antihypertensive use, and baseline measured BP in late life (older than 60 years) with dementia. Longitudinal, population-based studies of aging participating in the Cohort Studies of Memory in an International Consortium (COSMIC) group were included. Participants were individuals without dementia at baseline aged 60 to 110 years and were based in 15 different countries. Participants were grouped in 3 categories based on previous diagnosis of hypertension and baseline antihypertensive use: healthy controls, treated hypertension, and untreated hypertension. Baseline systolic BP (SBP) and diastolic BP (DBP) were treated as continuous variables.

The key outcome was all-cause dementia. Mixed-effects Cox proportional hazards models were used to assess the associations between the exposures and the key outcome variable. The association between dementia and baseline BP was modeled using nonlinear natural splines. The main analysis was a partially adjusted Cox proportional hazards model controlling for age, age squared, sex, education, racial group, and a random effect for study. Sensitivity analyses included a fully adjusted analysis, a restricted analysis of those individuals with more than 5 years of follow-up data, and models examining the moderating factors of age, sex, and racial group.

The analysis included 17 studies with 34,519 community dwelling older adults (58.4% female) with a mean age of 72.5 ± 7.5 years and a mean follow-up of 4.3 ± 4.3 years. In the main, partially adjusted analysis including 14 studies, individuals with untreated hypertension had a 42% increased risk of dementia compared with healthy controls (hazard ratio 1.42) and 26% increased risk compared with individuals with treated hypertension (hazard ratio 1.26). Individuals with treated hypertension had no significant increased dementia risk compared with healthy controls. The association of antihypertensive use or hypertension status with dementia did not vary with baseline BP. There was no significant association of baseline SBP or DBP with dementia risk in any of the analyses. There were no significant interactions with age, sex, or racial group for any of the analyses.

In conclusion, this individual patient data meta-analysis of longitudinal cohort studies found that antihypertensive use was associated with decreased dementia risk compared with individuals with untreated hypertension through all ages in late life. Individuals with treated hypertension had no increased risk of dementia compared with healthy controls.

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Results from Human Clinical Trials Do Not Support Metformin as a Longevity Drug

The SENS Research Foundation staff have carried out the public service of extensively discussing and dismantling the evidence commonly cited in support of metformin as a way to modestly slow aging, showing that said evidence is problematic, to say the least. Metformin might make life modestly better for diabetics, but it doesn't slow aging. This view of the human data matches the poor quality of the animal model data, in which metformin makes a poor showing in comparison to the robust data for a modest slowing of aging that is produced by the use of, say, mTOR inhibitors, or the practice of calorie restriction.

Regardless of what you, I, the SENS Research Foundation staff, or just about anyone else thinks of the merits of metformin and the problems with human studies of metformin, the TAME trial to assess the use of metformin to treat aging will forge ahead. Regardless of whether it succeeds or (as I expect) fails, the point of the TAME trial is to pave the way, to have browbeaten the FDA into accepting a trial design in which the target is aging, not any specific disease of aging. That has essentially taken place. The next well-funded group will try that same trial design with mTOR inhibitors, or plasma dilution, or senolytics, or small molecule reprogramming agents. Sooner or later, it will become commonplace to run trials that target aging, rather than development programs sidetracking into the treatment of specific age-related disease while hoping for off-label use to take off.

More Studies on Metformin and Survival

In an earlier five-part series, I laid out the reasons to be skeptical that metformin would pan out as a longevity therapeutic. The centerpiece of the second post in the metformin series was a 2014 observational study, which is the one study that is most often cited as evidence that metformin slows aging in humans. A press release that accompanied the Bannister paper wrongly stated that it showed that "Type 2 diabetics can live longer than people without the disease" if they take metformin.

But as other scientists had pointed out before me, the study had a design flaw that first unintentionally selected only the healthiest diabetic patients (those on metformin) and compared them to patients whose blood sugar was harder to get under control (those on second-line diabetes medications) as well as to a random assortment of the nondiabetic population. Their study design then unwittingly but systematically pushed subjects who were taking metformin "off the books" as soon as their diabetes got worse. This methodological artifact created the illusion that metformin users lived longer lives than nondiabetics, because it meant that the study would only count metformin users as metformin users if they managed to stay healthy.

In the months since I wrote the original blog post explaining this, I've become aware of two other studies asking the same core question but using different methods - and they both find that, as you would expect, people on metformin for diabetes are shorter-lived than people without diabetes. Because these studies address this question more directly than any of the studies discussed in that blog post, we'll review them here. In summary, the metformin users were clearly dying more often than the nondiabetic population. The long-term effect on metformin was better than going untreated as a diabetic, but its benefits were clearly not even enough to get them back on the miserable course of "normal" aging, let alone to have a real anti-aging effect.

We shouldn't stop looking for hidden benefits in common medications - and if we find good evidence that such a drug might slow something as terrible as degenerative aging, it may be worth it to follow that signal up with clinical trials. But with metformin, a story that emerged in cell culture and some poorly-designed animal and human observational studies have led many smart people astray. And even if metformin had turned out to be as effective as it seemed to be in some of the early studies of metformin in abnormally short-lived animals, the implied potential benefits for aging humans would have been pretty modest. It would garner an aging humanity a far greater gain if the media, many advocates, and scientists would redirect the resources and attention that have gone into metformin into developing therapies that directly repair the damage in aging tissues.

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Increased Mortality Associated with High Blood Pressure that Declines While Remaining Above the Normal Range

Researchers here note the phenomenon in which blood pressure declines in very late life, in the last few years. In studying a Chinese population, they find that the greatest mortality risk attends those whose blood pressure is initially high and then begins to decline while still remaining above the normal range. The consensus of recent years is that lower is better, as the raised blood pressure of hypertension causes pressure damage and disruption of normal tissue maintenance throughout the body. Study data appears to support this hypothesis. Nothing is ever simple, of course, and two different individuals can exhibit quite different degrees and manifestations of cardiovascular aging in late life.

Optimal blood pressure (BP) management strategy among the elderly remains controversial, with insufficient consideration of long-term BP trajectory. In this study, we included 11,181 participants older than 60 at baseline (mean age, 80.98 ± 10.71) with 42,871 routine BP measurements from the Chinese Longitudinal Healthy Longevity Survey. Latent class trajectory analysis and Cox proportional hazard model were conducted to identify trajectory patterns and their associations with mortality. Furthermore, we also applied mixed-effects model to identify terminal BP trajectories among the elderly.

Compared with stable at normal high level trajectory, excess systolic BP (SBP) trajectory with decreasing trend was associated with a 34% (hazard ratio, HR = 1.34) higher risk of all-cause mortality. Considering the competing risk of non-CVD death, excess BP trajectory with decreasing trend had a more pronounced effect on cardiovascular disease (CVD) mortality, in which HR was 1.67. Similar results were also found in diastolic BP (DBP), pulse pressure (PP), and mean arterial pressure (MAP) trajectories. We further conducted a mixed-effects model and observed that SBP and PP trajectories first increased and began to decline slightly six years before death. In contrast, DBP and MAP showed continuous decline 15 years before death.

In conclusion, long-term BP trajectory was associated with all-cause mortality, especially CVD mortality. Keeping a stable BP over time may be an important way for CVD prevention among the elderly.

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Inflammaging in the Aged Kidney

With age, the immune system becomes simultaneously less capable (immunosenescence) and more active and inflammatory (inflammaging). This constant, low-grade, unresolved inflammatory activity is driven by a range of different mechanisms. For example, senescent cells energetically secrete pro-inflammatory signals, and their numbers grow with age in tissues throughout the body. Further, age-related issues in cell function can lead to fragments of DNA from mitochondria and the nucleus leaking into the cytoplasm, where they trigger innate immune mechanisms intended to detect pathogens. Constant, unresolved inflammation is harmful to cell and tissue function, as illustrated by this paper, focused on the kidney. Control of inflammation much be a part of any comprehensive toolkit of approaches to slowing and reversing degenerative aging.

Even during physiologic aging, the kidney experiences a loss of mass and a progressive functional decline. This is clinically relevant as it leads to an increased risk of acute and chronic kidney disease. The kidney tubular system plays an important role in the underlying aging process, but the involved cellular mechanisms remain largely elusive. Kidneys of 3-, 12- and 24-month-old male C57BL/6J mice were used for RNA sequencing, histological examination, immunostaining, and RNA-in-situ-hybridization. Single cell RNA sequencing data of differentially aged murine and human kidneys was analyzed to identify age-dependent expression patterns in tubular epithelial cells. Senescent and non-senescent primary tubular epithelial cells from mouse kidney were used for in vitro experiments.

During normal kidney aging, tubular cells adopt an inflammatory phenotype, characterized by the expression of MHC class II related genes. In our analysis of bulk and single cell transcriptional data we found that subsets of tubular cells show an age-related expression of Cd74, H2-Eb1 and H2-Ab1 in mice and CD74, HLA-DQB1 and HLADRB1 in humans. Expression of MHC class II related genes was associated with a phenotype of tubular cell senescence, and the selective elimination of senescent cells reversed the phenotype. Exposure to the Cd74 ligand MIF promoted a prosenescent phenotype in tubular cell cultures.

Together, these data suggest that during normal renal aging tubular cells activate a program of 'tubuloinflammaging', which might contribute to age-related phenotypical changes and to increased disease susceptibility.

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Chronic Pain Conditions in the Context of Aging

Chronic pain conditions are poorly understood, often incorrectly diagnosed or dismissed by medical practitioners, and, generally, have only poor and unreliable options for treatment. Given that aging degrades the function of all bodily systems, it is no surprise to find a significant incidence of chronic pain in older adults. It is an open question as to the degree to which similar mechanisms are at play to those causing chronic pain in younger adults, and whether useful information can be obtained by comparing the biochemistry of similar conditions in old and young individuals. Unfortunately there remains a lack of understanding as to what is actually going on under the hood in these diverse conditions, leading to a great deal of suffering in a large patient population.

Chronic pain is one of the most common, costly, and potentially debilitating health issues facing older adults, with attributable costs exceeding 600 billion annually. The prevalence of pain in humans increases with advancing age. Yet, the contributions of sex differences, age-related chronic inflammation, and changes in neuroplasticity to the overall experience of pain are less clear, given that opposing processes in aging interact.

This review article examines and summarizes pre-clinical research and clinical data on chronic pain among older adults to identify knowledge gaps and provide the base for future research and clinical practice. We provide evidence to suggest that neurodegenerative conditions engender a loss of neural plasticity involved in pain response, whereas low-grade inflammation in aging increases central nervous system sensitization but decreases peripheral nervous system sensitivity. Insights from preclinical studies are needed to answer mechanistic questions. However, the selection of appropriate aging models presents a challenge that has resulted in conflicting data regarding pain processing and behavioral outcomes that is difficult to translate to humans.

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In Search of Immune System Differences in Long-Lived Mammals

What are the mechanisms that allow long-lived mammals to be long-lived? It remains to be seen as to whether it will be cost-effective and of sizable benefit to isolate specific genetic differences that can be used as a basis for therapies in humans, but it isn't a terrible idea to conduct the search. Clearly cancer suppression is an interesting topic, and one it might well be possible to build novel therapies based on the study of whales and elephants. Another good place to start is the operation of the immune system. The age-related decline of immune function is clearly important to the onset and progression of age-related disease. We might well ask how long-lived mammals maintain functional immune systems for a much longer period of time than shorter-lived but otherwise quite similar species.

Although immunosenescence may result in increased morbidity and mortality, many mammals have evolved effective immune coping strategies to extend their lifespans. Thus, the immune systems of long-lived mammals present unique models to study healthy longevity. To identify the molecular clues of anti-immunosenescence, we first built high-quality reference genome for a long-lived myotis bat, and then compared three long-lived mammals (i.e., bat, naked mole rat, and human) versus the short-lived mammal, mouse, in splenic immune cells at single-cell resolution.

A close relationship between B-cell:T-cell ratio and immunosenescence was detected, as B-cell:T-cell ratio was much higher in mouse than long-lived mammals and significantly increased during aging. Importantly, we identified several iron-related genes that could resist immunosenescence changes, especially the iron chaperon, PCBP1, which was upregulated in long-lived mammals but dramatically downregulated during aging in all splenic immune cell types. Supportively, immune cells of mouse spleens contained more free iron than those of bat spleens, suggesting higher level of reactive oxygen species (ROS)-induced damage in mouse.

PCBP1 downregulation during aging was also detected in hepatic but not pulmonary immune cells, which is consistent with the crucial roles of spleen and liver in organismal iron recycling. Furthermore, PCBP1 perturbation in immune cell lines would result in cellular iron dyshomeostasis and senescence. Finally, we identified two transcription factors that could regulate PCBP1 during aging. Together, our findings highlight the importance of iron homeostasis in splenic anti-immunosenescence, and provide unique insight for improving human healthspan.

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Different Invasive Bacterial Species are Found in Alzheimer's Brains versus Normal Brains

Research into the effects of the human microbiome on health and aging has progressed quite rapidly in recent years. It now costs little to sequence a sample to determine the which bacterial species are present and in what proportions. With age, the intestinal barrier, blood vessels, and blood-brain barrier begin to leak, allowing greater passage of microbes into the body. Additionally, the immune system declines in function, reducing the ability to clear these microbes from tissues.

In the case of patients with Alzheimer's disease, researchers are finding that the gut microbiome exhibits characteristic differences when compared with old people without this condition. The work here shows that this difference extends to the microbes leaking into the brain. This may indicate that specific immune dysfunction is present in Alzheimer's disease, favoring certain microbial species, or more likely, that changes in the microbiome provide an important contribution to the onset and progression of this form of dementia. The precise details as to why this is the case, over and above merely considering increased inflammation, remain to be determined.

When biomes turn unhealthy, either by invasion of outside pathogens, or a major change in the relative numbers of the microbial species present, a dysbiosis, or imbalance in the microbiota, occurs. This dysbiosis can alter human metabolism and cause inflammation, which has been linked to the tissue damage seen in ulcerative colitis, rheumatoid arthritis, and many other chronic inflammatory diseases. Studying 130 samples from the donated brains of 32 people - 16 with Alzheimer's and 16 age-matched controls without the disease, researchers found bacterial flora in all the brains- but the Alzheimer's brains showed profoundly different bacterial profiles when compared to their age-matched controls.

The group used full-length 16s ribosomal RNA gene sequencing, a technique that can detect any and all bacterial species present in a sample. In this process, the researchers pinpointed disease-specific sets of bacteria in almost all of the Alzheimer's-affected brains, suggesting these groups of bacteria are strong predictors of the disease. The authors detected five brain microbiomes, four that are hypothesized to be present at different times in the evolution of the Alzheimer's-afflicted brains. The authors said it is likely that the observed Alzheimer's microbiomes evolve to become more pathogenic as the disease progresses with the later stages characterized as a pathobiome. The authors hypothesize that the brain begins with a healthy biome, but as the disease develops, the healthy biome is supplanted as a new set of microbes replace the original healthy ones with the eventual emergence of the Alzheimer's pathobiome.

Samples from both sets of brain samples were drawn from the frontal and temporal lobes and entorhinal cortex. Based on the random distribution of microbiomes requiring delivery all over the brain, the results were consistent with failure in one or more of the brain's networks; however it too soon to tell if the observed distribution patterns result from a leaky blood-brain barrier, the brain's glymphatic system, or synaptonemal transmission that allowed bacteria, including Cutibacterium acnes (formerly called Proprionibacterium acnes), Methylobacterium, Bacillus, Caulobacter, Delftia, and Variovora to enter the brain. In Alzheimer's brain samples, the researchers noted, these pathogenic bacteria appeared to have overpowered and replaced Comamonas sp. bacteria, which are associated with a dementia-free brain.

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Aging Rate Indicators as Speedometers for Aging Research

Is it possible to measure the pace of aging at any given moment? Are there biomarkers that reveal not the biological age of the individual, but rather how fast that biological age is changing? The field is presently focused on developing measures of biological age, such as the extensive work on epigenetic clocks. Some information about pace of aging might be inferred from whether biological age is higher or lower than chronological age, assuming a biological age measurement that is actually accurate, something that still a topic for contention. But that doesn't say anything about the momentary pace of aging at any given time. That information would certainly prove useful in the context of testing interventions that adjust the pace at which aging proceeds. It isn't all that interesting in the context of interventions that reverse aging, such as by repairing the underlying cell and tissue damage that causes aging. In that case, pace of aging becomes irrelevant. The desire to measure the pace of aging reflects a bias towards merely slowing aging rather than achieving rejuvenation, and that is certainly the character of much of the field, sad to say.

Researchers interested in the biology of aging, and its potential modification by antiaging drugs, have devoted a substantial amount of community effort to the search for possible biomarkers of aging, conceived as quantifiable traits that can reveal the biological age of an individual animal. The central framework here is that such biomarkers might change monotonically through some relevant portion of adult life, might discriminate younger from older adults, might predict mortality risk at some useful distance from ultimate date of death, and, crucially, might serve, individually or collectively, as surrogate endpoints for studies of putative antiaging diets, drugs, or polymorphic alleles. Like an odometer in a car, biomarkers or weighted combinations of biomarkers might in principle reveal how far along the aging trajectory an individual organism has already proceeded. Odometers do not reveal the speed at which a car is currently traveling. A low-mileage or high-mileage car might be going quickly or slowly. Speed and distance traveled are independent and unconnected measures of a vehicle's state.

This essay presents the concept of aging rate indicators (ARIs) as speedometers for aging research. In principle, an ARI is a quantitative trait or measurement, an endpoint, which discriminates slow-aging mice from normal mice; it measures how quickly the aging process is proceeding in an individual organism. (The definition carefully takes no position on whether ARIs might also discriminate fast-aging animals from normal ones, a topic that will be deferred for another occasion). An ideal ARI would make this discrimination regardless of the age at which it is measured, at least within the portion of adult life where serious diseases are rare and mortality risk is minimal. The critical feature of an idealized ARI, the critical test of a candidate ARI, is that it should be modulated, in the same direction, by antiaging perturbations, whether the slowed aging and extended lifespan are caused by genetic factors, by dietary intervention, or by lifespan-increasing drugs.

It is helpful to consider the differences between ARIs and the more familiar biomarkers of aging. If a measurement - an estimate of collagen cross-linking, a score of visual acuity, or reflex speed, an index combining levels of DNA methylation at several sites, a T cell subset ratio, and so on - is proposed as a biomarker of aging, it is expected to show age-related change in adults, that is, to distinguish young, middle-aged, and older adults. Evaluation of an endpoint as a candidate ARI involves an entirely different set of criteria. Evidence that a candidate ARI changes with age is quite beside the point, because ARIs are taken to be measures of the pace or speed at which aging is currently occurring, and not as indices of how much a given subject has already aged, in the past. In such a framework, estimates of ARIs made in young adults are expected to be highly informative, because these individuals may actually be aging at different rates; for example, one might be on a calorie-restricted (CR) diet, or carry a mutant growth hormone receptor (GHR) allele, or be in a rapamycin treatment cohort. The key criterion for a putative ARI is that it should be modified, in a consistent direction, by most or all genes, diets, and drugs that are known, on independent evidence, to slow the signs of aging, postpone late-life illnesses, and increase lifespan.

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Synaptic Dysfunction Precedes the Death of Neurons in Parkinson's Disease

Parkinson's disease is characterized by the loss of dopamine-generating neurons, with the inflammatory pathology leading up to that issue thought to be driven by the spread of misfolded α-synuclein. Dysfunctional mitochondrial quality control can make these dopamine-generating neurons more vulnerable to the underlying pathology, however, and thus a fraction of Parkinson's disease arises in people with mutations that cause this sort of dysfunction. That has directed researchers towards mitochondrial function as an important factor in the progression of the condition, but it will probably turn out to be more useful to focus on the deeper causes, such as inflammation and cell dysfunction driven by α-synuclein aggregation.

Degeneration of dopaminergic neurons is widely accepted as the first event that leads to Parkinson's. But the new study suggests that a dysfunction in the neuron's synapses - the tiny gap across which a neuron can send an impulse to another neuron - leads to deficits in dopamine and precedes the neurodegeneration. The study investigated patient-derived midbrain neurons, which is critical because mouse and human dopamine neurons have a different physiology and findings in the mouse neurons are not translatable to humans.

Imagine two workers in a neuronal recycling plant. It's their job to recycle mitochondria, the energy producers of the cell, that are too old or overworked. If the dysfunctional mitochondria remain in the cell, they can cause cellular dysfunction. The process of recycling or removing these old mitochondria is called mitophagy. The two workers in this recycling process are the genes Parkin and PINK1. In a normal situation, PINK1 activates Parkin to move the old mitochondria into the path to be recycled or disposed of. It has been well-established that people who carry mutations in both copies of either PINK1 or Parkin develop Parkinson's disease because of ineffective mitophagy.

Two sisters had the misfortune of being born without the PINK1 gene, because their parents were each missing a copy of the critical gene. This put the sisters at high risk for Parkinson's disease, but one sister was diagnosed at age 16, while the other was not diagnosed until she was 48. The reason for the disparity led to an important new discovery. The sister who was diagnosed at 16 also had partial loss of Parkin, which, by itself, should not cause Parkinson's.

As a result, the scientists realized that Parkin has another important job that had previously been unknown. The gene also functions in a different pathway in the synaptic terminal - unrelated to its recycling work - where it controls dopamine release. With this new understanding of what went wrong for the sister, scientists saw a new opportunity to boost Parkin and the potential to prevent the degeneration of dopamine neurons. "We discovered a new mechanism to activate Parkin in patient neurons. Now, we need to develop drugs that stimulate this pathway, correct synaptic dysfunction and hopefully prevent neuronal degeneration in Parkinson's."

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Many Researchers and Companies Will Aim to Produce Small Molecule Reprogramming Therapies

The typical path for any program in biomedical research and development is to first demonstrate interesting results in animal studies using forms of genetic engineering or gene therapy, and then find small molecules that adjust the same mechanism. Small molecules are never as good as genetic manipulations, the size of the effect is always smaller, usually much smaller, and there are inevitably side-effects. Small molecule development is much easier to conduct, however, more familiar to investors and regulators and program managers, a well-trodden path. Thus while the future of medicine is gene therapy, in search of large effect sizes and no side-effects, the present industry remains near entirely focused on small molecules. Given the popularity of reprogramming as an approach to treat aging, an increasing number of research groups and companies are working to find small molecules that induce reprogramming to some degree, an alternative to gene therapies that induce expression of the Yamanaka factors. Based on the discoveries to date, it seems plausible that they will succeed.

Two weeks ago, longevity biotech startup emerged from stealth with 4 million in funding, and setting itself an ambitious goal to be in a Phase 3 trial for a healthspan-extending intervention by the end of the decade. With the clock ticking, the company is already working to map rejuvenation biology across the entire human genome over the next 12 months. Having completed an initial screen of around 1,000 genes, says it has already identified several new potential rejuvenation targets.

The company is based on the idea of triggering the self-rejuvenation mechanism of pluripotent stem cells to gain insight into the cellular drivers of aging and rejuvenation. Crucially, has found a way to shortcut the screening process required to identify rejuvenation drivers across the entire human genome. "We have been able to create a paradigm in the lab, where we override the repair programs, and force-age the stem cells, so that their rejuvenation capabilities kick in again." The company uses unbiased CRISPR screens on large samples of stem cells to identify gene candidates that are causally relevant for cell rejuvenation. then identified some existing, approved drugs that could potentially be used against the targets identified in the first screen. "We looked at whether these drugs could beneficially modulate aged neurons - we found that they did, and if we combined them the results got even better. So, now we have this end-to-end validation in vitro - from being able to identify rejuvenation genes, which are essentially controlling repair processes, through to activating those repair processes in aged cells. It's a completely unbiased way to understand every process that's involved in restoring the aging hallmarks."

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A Selection of Mechanisms Relevant to Atherosclerosis

Atherosclerosis is the growth of fatty lesions in blood vessel walls, leading eventually to a rupture and blockage to cause a heart attack or stroke, and along the way causing narrowing of blood vessels sufficient to lead to heart failure and dysfunction elsewhere in the body as the supply of blood to tissues is reduced. Today's paper on this topic is a little disorganized, something of a random assembly of thoughts on mechanisms relevant to the development of atherosclerosis. Atherosclerosis is the single largest cause of human mortality, and attempts to treat contributing mechanisms have so far not stopped it from being the single largest cause of human mortality. So perhaps it is something that we should all be putting more thought into, and broadening the range of development programs in an attempt to produce more meaningful therapies.

Atherosclerosis is chronic arterial inflammation caused by both conventional and unconventional risk factors that result in plaque development in the vascular intima. Inflammation starts with the activation of NLRP3 inflammasomes, which results in the production of proinflammatory cytokines IL-1 and IL-18, acting via the autocrine, paracrine, or endocrine pathways. IL-1 has been demonstrated to promote its own gene expression in a variety of cell types through an amplification loop known as autoinduction. IL-1 increases endothelial dysfunction, leukocyte-endothelial cell adhesion, procoagulant activity, and neutrophil recruitment, all of which contribute to atherogenesis and plaque ruptures.

Aging is one of the strongest risk factors for atherosclerosis which increases the morbidity and mortality of patients. Understanding the mechanisms of the age-related increase in atherosclerotic diseases can better guide prevention and therapy in this risk group, since it is unclear whether aging itself increases the susceptibility to atherosclerotic diseases and their severity. In this review, we present two main areas in which aging promotes atherosclerosis. The first group of factors is those outside of the vascular system, such as the impact of age on the clonal hematopoiesis of indeterminate potential (CHIP) differentiation of hematopoietic cells in the myeloid cell lineages. The second group of factors is the vascular intrinsic ones, such as the effect of aging on vascular bioenergetics due to impairment of mitochondrial function, mitophagy (removal of damaged mitochondria), and an impact on inflammation in vessels. In addition, mitochondrial DNA damage, which is an early event of atherogenesis in apolipoprotein deficient (ApoE) mice, can result in mitochondrial dysfunction, leading to proatherogenic processes such as inflammation and apoptosis.

The vascular endothelium, as an integral component of the cardiovascular system intimately interfacing with the blood, plays a crucial role in maintaining systemic homeostasis. It acts as a lining of the cardiovascular system, forming a particular barrier to various molecules. It assumes multifaceted functions within the human body, being intricately responsive to a myriad of external stimuli present in the surrounding environment. The vascular endothelium plays a regulatory role in vascular muscle contraction, relaxation, smooth muscle proliferation, and the expression of adhesion molecules or chemotactic factors. These factors are responsible for the adhesion, activation, or migration of inflammatory cells, as well as platelet adhesion and aggregation. Additionally, the vascular endothelium influences the coagulation and fibrinolysis processes. Disruption of these processes underpins the mechanism of atherosclerosis of the blood vessels.

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The Adaptation-Maladaptation Framework of Aging

While a great deal is known about the ways in which old tissues differ from young tissues, there remains considerable room to theorize on how exactly aging is caused and progresses. Which manifestations are causative, and which downstream consequences, which mechanisms are important, which are side-effects or diversions. Theories of aging abound, alongside frameworks intended to steer thinking about aging. We stand in the opening years of a new era of medicine, in which the first rejuvenation therapies exist or are under development, senolytics that can clear senescent cells, alongside reprogramming strategies and potentially a few others. The growing attention only encourages more theorizing, but the practical development of therapies targeting specific mechanisms of aging will be the path to greater knowledge. Only by addressing a specific mechanism of aging and observing the results can we rapidly determine whether or not it is important.

The adaptation-maladaptation framework of aging posits that a cornerstone of aging is a decrease in the ratio of beneficial adaptation (Ab) to harmful adaptation (Ah) at several organizational levels of the organism, from cells to cell networks to the whole body. Decreases in Ab lead to lowered capacities in physiological adaptation functions such as learning and memory, immune system plasticity, and muscle anabolism, whereas increases in Ah promote dysfunctional metabolic remodeling, cancer, autoimmunity, and pathological cardiovascular remodeling, among others.

Certain adaptation mechanisms such as adaptive transcription can be involved in protection against aging as well as driving aging-related pathologies. Thus, aging-related decline might be inevitable but not necessarily due to random accumulation of damage over time but because adaptive mechanisms will, one way or the other, lead to progressive dysfunction (e.g., either through "directed" damage as part of adaptation or through maladaptation). Because aging is at least partly an active process, it might be possible to counteract it if we understand how biological goal states can be influenced and how adaptation mechanisms can be directed. To do so, we need to study the underlying molecular signaling dynamics in greater detail beyond mere upregulation or downregulation and beyond simple association studies.

Studying aging from the perspective of the adaptation-maladaptation dilemma with the central phenotype of a reduction in Ab/Ah opens up new experimental and theoretical approaches to study longevity mechanisms.

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