Fight Aging! Newsletter, August 15th 2022

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  • A Short Commentary on Why We Advocate for the Treatment of Aging
  • The Anti-Longevity Rhetoric that Characterizes Much of Aging Research
  • Cellular Senesence, a Key Target in the Treatment of Aging
  • Epigenetic Clocks Do Not Strongly Reflect Inflammatory Status?
  • Towards Lasting Engineering of the Gut Microbiome
  • Mechanisms Linking Red Meat Consumption and Cardiovascular Disease Risk
  • Building a Better Spermadine to Improve Mitophagy
  • SENS Research Foundation's Ending Aging Forum, September 2022
  • The Blood Microbiome Changes with Age
  • Hypoxia, Inflammation, and Cellular Senescence
  • Klotho in the Pathology of Aging
  • Heterochronic Parabiosis in Mice Fails to Extend Lifespan in the Older Animal
  • The Inflammatory Burden of Infection Accelerates Hematopoietic Aging
  • Inflammation and Cellular Senescence in the Aging Lung
  • Pace of Life and and the Longevity Resulting From Growth Hormone Deficiency in Mice

A Short Commentary on Why We Advocate for the Treatment of Aging

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.

The Anti-Longevity Rhetoric that Characterizes Much of Aging Research

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."

Cellular Senesence, a Key Target in the Treatment of Aging

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.

Epigenetic Clocks Do Not Strongly Reflect Inflammatory Status?

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.

Towards Lasting Engineering of the Gut Microbiome

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.

Mechanisms Linking Red Meat Consumption and Cardiovascular Disease Risk

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."

Building a Better Spermadine to Improve Mitophagy

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.

SENS Research Foundation's Ending Aging Forum, September 2022

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!

The Blood Microbiome Changes with Age

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.

Hypoxia, Inflammation, and Cellular Senescence

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.

Klotho in the Pathology of Aging

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).

Heterochronic Parabiosis in Mice Fails to Extend Lifespan in the Older Animal

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."

The Inflammatory Burden of Infection Accelerates Hematopoietic Aging

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."

Inflammation and Cellular Senescence in the Aging Lung

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.

Pace of Life and and the Longevity Resulting From Growth Hormone Deficiency in Mice

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.

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