Fight Aging!

Today's open access paper is a discussion of microRNA regulation of cell behavior in the context of age-related arterial stiffness. The stiffening of blood vessels with age is an important issue, as it produces hypertension via disruption of the feedback mechanisms that control blood pressure. The raised blood pressure of hypertension causes structural damage throughout the body, increasing mortality and accelerating progression of age-related disease.

Every distinct form of organ or tissue dysfunction in aging is made of up many layers. At the base are fundamental causes, forms of damage that arise from the normal operation of metabolism and have no deeper origin. In the case of arterial stiffness that includes loss of elastin and persistent cross-links in the extracellular matrix, both of which reduce the elasticity of blood vessel wall tissues. Some of us tend to put senescent cell accumulation in that layer as well, though the growing number of senescent cells with age is likely to be largely a result of immune system aging. The pro-inflammatory signaling of senescent cells is implicated in smooth muscle dysfunction in blood vessel walls.

These forms of damage feed into the next layer of tissue dysfunction, in which regulatory systems that control gene expression change in response to that damage. These include microRNAs, transcription factors, and other mechanisms involved in the control of the expression of networks of genes in the cell. Some responses are adaptive and some are maladaptive. Altered regulation then produces the uppermost layer of tissue dysfunction, consisting of broad and problematic changes in cell behavior and cell signaling, driven by alterations in protein abundance within the cell and changes in the environment of signals that pass between cells. The vast majority of research into aging and age-related disease focuses on these upper layers: gene expression and its regulation in the aged tissue environment. All too little work is focused on deeper causes.

Deciphering the Role of microRNAs in Large-Artery Stiffness Associated With Aging: Focus on miR-181b

Large artery stiffness (LAS) is a major, independent risk factor underlying cardiovascular disease that increases with aging. Arterial stiffness is determined by the composition and organization of the extracellular matrix, as well as the cytoskeletal properties of vascular smooth muscle cells. Therefore, investigators have concentrated on defining the biochemical and associated structural changes responsible for increased arterial stiffness, as well as the upstream regulatory pathways driving these changes. From this perspective, the microRNA system has emerged as a potential culprit, since this highly versatile signaling pathway can coordinate cellular adaptations in response to developmental and environmental signals and has been found to play key roles in vascular smooth muscle development and function. However, since each cell contains hundreds of distinct microRNAs, and these microRNA profiles differ across cell types, identifying candidate microRNAs involved in regulating arterial stiffness poses a difficult challenge.

Initial clues implicating dysregulation of specific microRNAs in LAS emerged from two approaches. As patients with LAS can be identified by measuring pulse wave velocity (PWV) using non-invasive techniques, investigators looked for alterations in microRNA signaling associated with elevated PWV. This approach yielded identification of two microRNAs linked to elevated PWV: miR-765 and miR-1185. The second approach was based on the epidemiological observation that the prevalence of LAS increases markedly with aging. Furthermore, mice also display aging-associated increases in PWV that model LAS. Thus, investigators checked for microRNAs that show altered expression with aging in blood samples from humans and in mouse aorta. This approach led to the identification of several candidate microRNAs that show altered expression with aging: mir-29, miR-34a, miR-92a, miR-137, miR-181b, miR-203, and miR-222. Mir-29, miR-34a, miR-137, miR-203, and miR-222 increase with aging in mouse aorta and miR-34a has been shown, very recently, to be associated, along with miR-34c, with aortic stiffening in human subjects. Conversely, miR-92a and miR-181b decrease in mouse aorta with aging and miR-92a is also decreased in human blood with aging.

Based on these initial observations, investigators examined whether mimicking these changes is sufficient to produce stiffening. Using a transfection-based approach in vivo, it was found that elevating miR-203 leads to arterial stiffening. Furthermore, administering an antagonist of miR-92a to mice increases PWV. To examine the effect of decreased miR-181b on aortic stiffness, researchers used mice carrying a deletion of the locus (miR-181a1/b1) that blocks expression of both miR-181a and miR-181b in aorta. These mice showed a premature onset of arterial stiffness as young adults. Thus, these findings indicate that aging-associated changes in expression of these candidate microRNAs play a causal role in eliciting arterial stiffness.

Although several studies have demonstrated that mimicking the alteration of a candidate microRNA is sufficient to elicit arterial stiffness, to our knowledge, miR-181b is the only candidate microRNA for which interventions have reduced arterial stiffness. Our strategy for normalizing miR-181b levels in aorta emerged from our observation that this microRNA is one of those elevated in a cell line that had been subjected to knockdown of the translin (TN)/trax (TX) microRNA-degrading enzyme, suggesting that it was targeted by this enzyme. We reasoned that if a decrease in miR-181b levels plays a key role in driving LAS, then TN knockout (KO) mice might be resistant to developing arterial stiffness. As C57BL6 mice display aging-associated arterial stiffening, they provide a suitable animal model of this disorder. However, since that would require waiting until the mice are close to 18 months old, we first tested this hypothesis in a paradigm that elicits increased aortic stiffness in just a few weeks. In this streamlined paradigm, mice are switched from regular water to high salt water (HSW; 4% w/v), and their PWV measured on a weekly basis. Remarkably, we found that TN KO mice are resistant to developing increased PWV induced by this paradigm. Furthermore, exposure to HSW decreases levels of miR-181b in WT mice, but not in TN KO mice, consistent with the view that TN deletion confers protection from increased stiffness by blocking degradation of miR-181b.

As inhibiting the activity of the TN/TX microRNA-degrading enzyme confers protection from the development of aging-associated arterial stiffening, inhibitors of this enzyme may have translational potential. However, since the observed protection occurred in mice with a constitutive inactivation of TN/TX, it will be important to check if inhibition of this enzyme after the initial onset of aging-associated arterial stiffening can prevent the progression or even reverse this process. In addition, as TN/TX inhibition may also elevate other microRNAs, it might be more advantageous to explore other strategies to increase miR-181b levels selectively. However, since extremely high elevations of miR-181b have been implicated in the development of atherosclerotic plaques, it may be important to identify strategies that reverse the age-associated decline in miR-181b levels without elevating them further into the range associated with pathological effects.

Excess visceral fat produces systemic dysfunction throughout the body through many different mechanisms. The most evident is an increase in chronic inflammation, disruptive of health and tissue function. This can occur through a greater burden of senescent cells, through signaling from fat cells that mimics that of infected cells, the presence of debris from dying fat cells, and further mechanisms. Researchers here look at one of these other signaling changes in fat tissue that provoke inflammation, as well as possible means to interfere in that detrimental signaling.

New research shows that fat cells control the systemic response to brain function, causing impairment in memory and cognition in mice. The activation of Na,K-ATPase oxidant amplification loop affects the expression of important protein markers in fat cells as well as in the hippocampus, which can worsen brain function and lead to neurodegeneration. Targeting the fat cells to antagonize Na,K-ATPase may improve these outcomes. "We have aimed to demonstrate that Na,K-ATPase signaling, specifically in adipocytes, play a central role in inducing alterations in specific regions of the brain, most notably in the hippocampus, which is critical to memory and cognitive function."

Researchers used a genetically-modified mouse model that released the peptide NaKtide specifically in adipocytes, or fat cells, to find that NaKtide inhibited the signaling function of Na,K-ATPase. The adipocyte-specific NaKtide expression improved the altered phenotype of adipocytes and improved function of the hippocampus, the part of the brain associated with memory and cognition. Inducing oxidative stress through western diet increased production of inflammatory cytokines confined to adipocytes as well as altered protein markers of memory and cognition in the hippocampus.

"Western diet induces oxidant stress and adipocyte alteration through Na,K-ATPase signaling which causes systemic inflammation and affects behavioral and brain biochemical changes. Our study showed that adipocyte-specific NaKtide expression in our murine model ameliorated these changes and improved neurodegenerative phenotype."

Link: https://jcesom.marshall.edu/news/musom-news/fat-cells-found-to-play-a-central-role-in-cognitive-decline-and-neurodegeneration/

The practice of calorie restriction produces a beneficial upregulation of cellular stress responses. In short-lived species such as mice this can produce a dramatic slowing of aging, improvement in health, and extension of life span. The same mechanisms produce similar short-term benefits to health, but not a significant lengthening of life, in species as long-lived a our own, however. Nonetheless, there is considerable interest in calorie restriction mimetics, compounds that can trigger at least some of the same regulatory mechanisms governing cellular stress responses, particularly the operation of autophagy.

Recent years have seen a growing interest in understanding how dietary interventions shape and interact with the most common cardiovascular risk factors, including hypertension, obesity, metabolic syndrome, and diabetes mellitus type 2. Substantial cardiometabolic improvements have been reported with fasting interventions such as reduction in blood pressure, body weight and fat mass, lower blood glucose, and improvement in insulin sensitivity, both in experimental and clinical studies. Although caloric restriction consistently improves several aspects of health, its application has been hampered by poor compliance and adverse side effects on bone health and immune response, especially in the elderly.

An interesting aspect that warrants further attention is the effect of caloric restriction mimetics or dietary interventions aimed at weight loss on the gut microbiome changes in obese patients with diabetes mellitus type 2 or metabolic syndrome. Although these interventions propose beneficial clinical outcomes, their effect on the gut microbiome is only beginning to unfold. Interestingly, a combination therapy of resveratrol and spermidine synergistically induces autophagy at doses which do not trigger effects of the same magnitude if administered alone. At present, however, it remains elusive what is the optimal dose for any of the caloric restriction mimetics that could provide health benefits or protect humans at risk of cardiovascular disease.

Unlike the current drug development approaches that focus on individual diseases in isolation and consider specificity as a desirable outcome in disease prevention and treatment, both caloric restriction mimetics and caloric restriction intercept multiple different targets. Such pleiotropic mode of action appears advantageous in targeting the complex process of aging as the greatest risk factor for cardiovascular diseases and associated comorbid conditions. Thus, dietary interventions should aim to maintain optimum health and prevent cardiovascular diseases by attenuating the molecular causes of biological aging directly.

Non-cell autonomous effects of caloric restriction mimetics and caloric restriction itself, such as the anti-inflammatory or immune modulatory functions, are increasingly viewed as relevant as cell autonomous mechanisms. Taking this into account, more research is needed to ascertain how different forms of fasting and caloric restriction mimetics can be the most favorable to further improve cardiometabolic markers in healthy adults and patients living with or at risk of developing cardiovascular disease. Based on the currently available data, harnessing caloric restriction mimetics or dietary interventions, such as intermittent fasting or the Mediterranean diet represent a promising preventive venue, which might reduce cardiovascular risk and the burden of cardiovascular disease.

Link: https://doi.org/10.3389/fnut.2021.758058

Larger institutions such as the NIH are now beginning to invest a great deal more into fundamental research connected to cellular senescence. Twenty years ago it was clear enough that senescent cells were important in aging for the Strategies for Engineered Negligible Senescence (SENS) pioneers to include it in their initial scientific paper, but the topic was largely ignored by the mainstream of aging research. It took a decade to get to the point of a compelling animal study of targeted senescent cell clearance that convinced the rest of the research community. Five years after that the first senolytic-focused biotech companies were established, working on therapies to selectively destroy senescent cells. A further five years after that we come to this present moment, at which large institutional funding programs get underway to expand the basic science.

Early senolytic therapies are impressive in terms of the results they produce in mice: rapid rejuvenation, extension of life span, reversal of many age-related conditions. These approaches appear to top out at removing about half of the burden of senescent cells in some of the aged tissues assessed. There is definitely room for improvement. The primary concern in the scientific community is not efficacy of therapies, however, but rather the question of how senescent cells might have meaningful differences from tissue to tissue, or by cause of senescence, or other factors. Additionally, are existing means of determining the burden of senescent cells in tissue actually measuring all senescent cells, and are they mistakenly identifying any populations of non-senescent cells that happen to employ some of the same biochemistry?

This work will likely have little influence over the course of the present senolytics industry, the fair number of startup biotechnology companies and established pharma entities attempting to bring the first rejuvenation therapies to the clinic. Some of those first generation senolytics look very promising, such as prodrug approaches to limiting chemotherapeutics to activate only in senescent cells. It will, however, inform the next generation of anti-senescence therapies, which we should expect to be somewhat more effective as as consequence.

NIH launches program to map a rare type of non-dividing cells implicated in human health and disease

The National Institutes of Health has launched a program to study a rare type of cells, called "senescent" cells, that play both positive and negative roles in biological processes. The NIH Common Fund's Cellular Senescence Network (SenNet) program will leverage recent advances in studying individual cells, or single-cell analysis, to comprehensively identify and characterize the differences in senescent cells across the body, across various states of human health, and across the lifespan. The rarity and diversity of these cells previously made them difficult to identify and study; therefore, a deeper understanding will help researchers develop therapies that encourage beneficial effects of senescent cells while suppressing their tissue-damaging effects.

NIH is funding $125 million to 16 grants over five years, pending available funds. NIH issued eight awards for the creation of SenNet Tissue Mapping Centers, seven awards for Technology Development and Application Projects, and one award for a Consortium Organization and Data Coordinating Center (CODCC). The Tissue Mapping Centers will identify biomarkers of senescent cells in humans and then construct high-resolution, detailed maps of cellular senescence across the lifespan and physiological states. The Technology Development and Application Projects will be critical in advancing promising tools, techniques, and methods for SenNet to study senescent cells. As the organizational hub, the CODCC will collect, store, and curate the Network's data, tools, and models. These projects will work together to create a publicly accessible and searchable Atlas of Cellular Senescence.

Cellular Senescence Network (SenNet)

One cell dividing into two is a hallmark of development in living beings. However, as we age the tissues in our body accumulate a small number of specialized cells that no longer divide. These cells are called senescent cells, and they play important roles in health and disease across the lifespan. Under certain circumstances, such as aging, senescent cells accumulate and release a collection of molecules that can cause damage to nearby tissue. Under other conditions, such as cancer or wound healing, senescent cells can protect health by preventing tumor growth or releasing molecules that promote the growth of new tissue. Biomedical researchers still have many unanswered questions about how, when, why, and where senescent cells form, but their rarity and diversity make them difficult to identify and characterize in the body. Despite this, senescence is an attractive target for new therapeutics, with some already in development. A deeper understanding of cellular senescence will help researchers to develop further therapies that encourage beneficial effects of senescent cells while suppressing their tissue-damaging effects.

The Common Fund's Cellular Senescence Network (SenNet) Program was established to comprehensively identify and characterize the differences in senescent cells across the body, across various states of human health, and across the lifespan. SenNet will provide publicly accessible atlases of senescent cells, the differences among them, and the molecules they secrete, using data collected from multiple human and model organism tissues. To identify and characterize these rare cells, SenNet will develop innovative tools and technologies that build upon previous advances in single cell analysis, such as those from the Common Fund's Human Biomolecular Atlas Program and Single Cell Analysis Program. Lastly, SenNet aims to unite cellular senescence researchers by developing common terms and classifications for senescent cells.

A fair number of researchers are investigating the molecular biology of species capable of proficient regeneration without scarring, such as salamanders and zebrafish. It is suspected that mammals retain much of the necessary biology to accomplish feats of regeneration such as regrowing limbs, mechanisms that are in some way blocked in adults, because this sort of regeneration can occur during embryonic development. Researchers here discuss a novel line of research based on the forces exerted on cells due to animal size, and how cells react to those forces. Proficient regeneration occurs in small species, and perhaps that is an important detail.

So what is the difference between animals that can regenerate tissue without scarring, and those that scar? The answer, it turned out, stemmed from something few if any scientists had previously focused on: animal size and the physical forces on their cells. In some small animals - think zebrafish and salamanders - you don't need strong bonds between cells to help them glom onto one another, but when animals grow as large as elephants or dinosaurs, the bonds between cells must be much stronger. Without such strong bonds, even tissues of medium-sized animals, like cats or dogs, would never hold together on the animals' skeleton. It would be like trying to pile pudding on a coat hanger.

"All the animals capable of scarless regeneration have very small bones and their tissues are almost gelatinous. We wondered if these allometric scaling forces might be part of the reason that zebrafish can regenerate tissues, but humans cannot. Allometric scaling forces are known to change bone size and muscle strength, but no one had looked into how they affect tissue regeneration."

To investigate the role of these forces in scarring, the researchers disrupted sensors that all cells have to detect mechanical stresses in their environment. The scientists blocked a molecule called focal adhesion kinase, the most evolutionarily conserved component of this sensing system, and observed how it affected the tissue healing process in pigs, which have the most similar skin to humans, through a very small lesion on anesthetized skin. "To our surprise, simply blocking this one component allowed burn injuries that normally result in scars to heal with completely normal skin architecture and morphology, just like a salamander would."

The researchers are now pursuing clinical trials to reduce scarring in burn patients or also use techniques described in the previously published research to reduce scarring after accidents or surgery. They are also hopeful that looking at these same mechanisms might be useful in helping other organs, such as the lungs, liver and heart, to heal without scarring after injury or disease.

Link https://scopeblog.stanford.edu/2021/10/15/when-it-comes-to-healing-without-scarring-it-pays-to-be-small/

Over the course of the past twenty years, researchers have established the techniques needed to grow small volumes of functional tissue for many organ types. Lacking blood vessel networks, these organoids are at most a few millimeters in size; any larger and nutrients cannot perfuse to the innermost cells. There will be a use for organoids grown from a patient's own cells or from universal cell lines in transplantation therapies, such as those developed by Lygenesis. As researchers note here, however, by far the greatest use at present is to produce models for research.

Patient-derived organoids are self-organized 3D tissue cultures that are derived from stem cells. Isolated patients' stem cells differentiate to form an organ-like tissue comprising multiple cell types. Organoids have self-renewal and self-organization capabilities and retain the characteristics of the physiological structure and function of their source. Recent culturing advances aim to create the right environment for the stem cells so they can follow their own genetic instructions to self-organize, forming organoid structures that resemble miniature organs composed of many cell types. This approach provides tractable in vitro models of human physiology and pathology, thereby enabling interventional studies that are difficult or impossible to conduct in human subjects.

The biology of aging is focused on the identification of novel pathways that regulate the underlying processes of aging to develop interventions aimed at delaying the onset and progression of chronic diseases to extend lifespan. However, the research on the aging field has been conducted mainly in animal models, yeast, Caenorhabditis elegans, and cell cultures. Thus, it is unclear to what extent this knowledge is transferable to humans since they might not reflect the complexity of aging in people.

Organoid culture technology is being used in the cancer field to predict the response of a patient-derived tumor to a certain drug or treatment serving as patient stratification and drug-guidance approaches. Modeling aging with patient-derived organoids has a tremendous potential as a preclinical model tool to discover new biomarkers of aging, to predict adverse outcomes during aging, and to design personalized approaches for the prevention and treatment of aging-related diseases and geriatric syndromes. This could represent a novel approach to study chronological and/or biological aging, paving the way to personalized interventions targeting the biology of aging.

Link: https://doi.org/10.3390/ijms221910547

Aging is built on feedback loops, interactions between damage and dysfunction in which both sides accelerate the other. This is a feature of all complex systems, not just biological ones. The existence of feedback loops in which damage accumulation causes dysfunction that accelerates damage accumulation is the fundamental reason as to why aging is an accelerating process. It starts slowly, and moves ever more rapidly with time. Aging in one's 30s is a very different beast to aging in one's 70s, and the downhill slide is much faster in later life.

The way to break this cycle is to repair the damage. This is true whether we are talking about a manufactured machine or a living being: repair is the only viable road to rejuvenation. All other options perform poorly. If you want to engage in a costly struggle, try to keep a damaged machine running without repairing the causes of its dysfunction. That is the story of most present day medicine for age-related disease, unfortunately. It is compensatory in nature and fails to address the causes of disease, the processes of aging itself.

Yet times are changing, and there is a far greater acceptance now for scientific and medical development initiatives that seek to address the damage that causes aging, such as the accumulation of senescent cells that actively disrupt tissue function and promote chronic inflammation. To the degree that these initiatives succeed, we will all have the opportunity to live significantly longer, better lives, spending a greater number of years in vigorous, youthful health.

The metabolic roots of senescence: mechanisms and opportunities for intervention

The senescence response can be beneficial or deleterious, depending on the physiological context. This dualism is consistent with the evolutionary theory of antagonistic pleiotropy. Antagonistic pleiotropy postulates that traits selected to ensure the survival of young organisms in natural environments, in which life spans are short, can become deleterious in modern protected environments, in which life spans are significantly longer. Thus, aging is likely a consequence of the declining force of natural selection with age.

With regard to the beneficial effects of cellular senescence, the senescence growth arrest protects young organisms from developing cancer. In addition, senescence-associated secretory phenotype (SASP) factors can optimize the morphogenesis of certain structures in the embryo, and initiate parturition in the placenta. Finally, senescent cells occur transiently at sites of tissue damage where they contribute to wound healing, tissue repair and regeneration, most likely through specific SASP factors.

In contrast, senescent cells increase with age in most mammalian tissues, where they appear to persist. Whether this increase is due to increased production or decreased clearance, for example by the immune system, is unclear. More importantly, experiments using human cells and tissues, transgenic mouse models, and pharmacological interventions in cells and mice strongly implicate senescent cells in a large number of age-related pathologies, ranging from neurodegeneration to, ironically, age-related cancer. Most of the detrimental effects of senescent cells can be attributed to the SASP, which is rich in pro-inflammatory molecules.

A growing body of literature indicates that both senescence and the SASP are sensitive to cellular and organismal metabolic states, which in turn can drive phenotypes associated with metabolic dysfunction. Here, we review the current literature linking senescence and metabolism, with an eye toward findings at the cellular level, including both metabolic inducers of senescence and alterations in cellular metabolism associated with senescence.

There are three types of interventions that target senescent cells and their degenerative pathologies. First, we can slow the formation of senescent cells, as observed during dietary restriction and similar interventions. Second, we can allow senescent cells to accumulate, but prevent them from causing harm, as observed during metformin-mediated SASP suppression or after CD38 inhibition. Finally, we can use senolysis to remove senescent cells. Unlike the first two interventions, senolysis can be used intermittently - allowing for a 'hit and run' approach that might be easier to implement in humans - whereas dietary and suppressive drug regimens require regular adherence to maintain benefits. We conclude that the most effective interventions will likely break a degenerative feedback cycle by which cellular senescence promotes metabolic diseases, which in turn promote senescence.

The implementation of journalistic balance is a self-parodying genre of writing. In the case in which the scientific community is working towards saving countless lives, by implementing therapies targeting the underlying mechanisms of aging, the paint-by-numbers journalist and editor duo will dutifully find a curmudgeonly figure who thinks that everyone should just get on and die, and put in a few quotes in order to balance the article. The piece here is an example of exactly this phenomenon; it is left as an exercise for the reader to identify the other popular media checkboxes lazily checked in the course of its few pages. And one can still use this to say that the quality of articles on the development of therapies for aging is much better than it used to be! A low bar, but slowly rising. Still, it is hard to take the output of what passes for journalism these days at all seriously. Sadly all too many people do just that for every topic with which they have little familiarity.

The quest for eternal youth may not be new, but it is now bankrolled by some of the wealthiest individuals and corporations on Earth. Anti-ageing science works at the level of gene therapy, cell hacking and reconstituting human blood; the medical treatments at its heart are based on "bleeding edge" science and aimed at the mass market. Some focus on biological reprogramming: adding proteins known as Yamanaka factors to cells, causing them to revert to a previous state. Others look at genomic instability or the way DNA damage that accumulates over time might be repaired.

The entrepreneurs in this fledgling field are determined that the end of ageing will come via therapies approved by the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA). The elixir of youth won't be a single drug, but a regimen of treatments that knock out different hallmarks of ageing and allow us to get older without losing our bodies and minds. We will still die: there will be accidents as well as diseases unrelated to age (children still get fatal cancers, after all). But death will become increasingly remote, and no longer preceded by years of inevitable decline. Its advocates argue that, once ageing is cured, the financial, medical, societal, and emotional burden of taking care of the elderly will disappear. But have these entrepreneurs thought about what a post-ageing world would look like? And if they have, would anyone want to live there?

Paul Root Wolpe, 64, director of the centre for ethics at Emory University (and a former senior bioethicist at NASA), told me that a world without ageing would be "an economic disaster". The argument some advocates make for its enormous social benefits is "a misdirection", he said. "I find their arguments extremely naive, sociologically unsupportable, and most importantly, deeply narcissistic. I've never heard a single plausible argument of how radical life extension would benefit society - only an egocentric desire not to die. The truth is, they want to stop ageing. They want to live healthily to 150."

In Wolpe's view, anti-ageing scientists and entrepreneurs minimise or ignore the profound implications of significantly increasing the human lifespan. "The International Monetary Fund has stated that an ageing population in Japan has led to a vanishing labour force, higher demands for social services, a shrinking tax pool, greater wealth disparities - and that's just from living what is currently our lifespan. If we increase it, all of those things would increase exponentially." But in the future envisaged by the biotech start-ups, we would work into our hundreds: an elderly population would still be a labour force. Wolpe had little patience for this idea. "That is a profoundly elite perspective."

Link: https://www.newstatesman.com/long-reads/2021/10/who-wants-to-live-forever-big-tech-and-the-quest-for-eternal-youth

There is an ongoing debate over whether or not persistent viral infection plays an important role in the development of Alzheimer's disease. That is largely focused on the function of the immune system, given the demonstrated relevance of chronic inflammation and microglial dysfunction to the progression of neurodegenerative conditions. Here, however, researchers provide in vitro evidence to support the hypothesis that viral infection can promote the spread of misfolded proteins between cells in the brain. Aggregates of misfolded or otherwise harmfully modified proteins such as amyloid-β, α-synuclein, and tau are involved in many neurodegenerative conditions. Exactly how these proteins spread as the condition progresses is an area of considerable interest in the research community.

Transmission of aggregates could involve direct cell-to-cell contact, the release of "naked" aggregates into extracellular space or packaging in vesicles, which are tiny bubbles surrounded by a lipid envelope that are secreted for communication between cells. "The precise mechanisms of transmission are unknown. However, it is an obvious guess, that aggregate exchange by both direct cell contact and via vesicles depends on ligand-receptor interactions. This is because in both scenarios, membranes need to make contact and fuse. This is facilitated when ligands are present that bind to receptors on the cell surface and then cause the two membranes to fuse."

Researchers investigated the intercellular transfer of either prions or aggregates of tau proteins, as they occur in similar form in prion diseases or Alzheimer's disease and other "tauopathies". Mimicking what happens as a result of viral infection, the researchers induced cells to produce viral proteins that mediate target cell binding and membrane fusion. Two proteins were chosen as prime examples: SARS-CoV-2 spike protein S, which stems from the virus causing COVID-19, and vesicular stomatitis virus glycoprotein VSV-G, which occurs in a pathogen that infects cattle and other animals. Moreover, cells expressed receptors for these viral proteins, namely the LDL receptor family, which act as docking ports for VSV-G, and human ACE2, the receptor for the spike protein.

"We could show that the viral proteins are incorporated both into the cellular membrane and into the extracellular vesicles. Their presence increased protein aggregate spreading between cells, both by direct cell contact or by extracellular vesicles. The viral ligands mediated an effective transfer of aggregates into recipient cells, where they induced new aggregates. The ligands act like keys that unlock the recipient cells and thus sneak in the dangerous cargo. Certainly, our cellular models do not replicate the many aspects of the brain with its very specialized cell types. However, independent of the tested cell type producing the pathologic aggregates, the presence of viral ligands clearly increased the spreading of misfolded proteins to other cells. All in all, our data suggests that viral ligand-receptor interactions can in principle affect transmission of pathologic proteins."

"The brains of patients suffering from neurodegenerative diseases sometimes contain certain viruses. They are suspected to cause inflammation or to have a toxic effect, thus accelerating neurodegeneration. However, viral proteins could also act differently: They could increase intercellular spreading of protein aggregates already ongoing in neurodegenerative diseases like Alzheimer's. Of course, this needs further studies with neurotropic viruses. Clearly, the impact of viral infections on neurodegenerative diseases deserves in-depth investigation."

Link: https://www.dzne.de/en/news/press-releases/press/viral-infections-could-promote-neurodegeneration/

Every cell in the body contains hundreds of mitochondria, the evolved descendants of ancient symbiotic bacteria. Their primary purpose is to produce adenosine triphosphate (ATP), an energy store molecule used to power cellular operations. They are also involved in a great many other aspects of cell function, however. Mitochondria are dynamic organelles, capable of fusing together, passing component parts between one another, and replicating like bacteria. A cell regulates mitochondrial function in part through mitophagy, an autophagy process that breaks down and recycles mitochondria when they become worn and damaged.

Mitochondrial function is understandably vital to cell function. With age, however, mitochondria change and falter. Their dynamics alter, making it harder for mitophagy to function correctly, and components of the broader autophagic process themselves exhibit dysfunction. The result is an accumulation of broken, malfunctioning mitochondria. An alternative, less common path is the generation of mutations in mitochondrial DNA that both cause dysfunction and protect the broken mitochondria from mitophagy, allowing them to take over a cell via replication.

Cells containing dysfunctional mitochondria behave poorly. Organ function suffers as a consequence. This is one of the noteworthy contributing causes of degenerative aging, though it is likely that most mitochondrial dysfunction is downstream of underlying issues that cause alterations in the expression of proteins necessary to mitophagy or mitochondrial dynamics. The brain is an interesting mix of mitochondrial issues, as it is both energy-hungry, and thus sensitive to disruption of mitochondrial function, and contains a great many long-lived cells, in which the progressive age-related failure of mitophagy likely has a different balance of causes in comparison to to those of short-lived cells.

What can an individual do about the challenge of mitochondrial dysfunction in aging? Presently not a great deal. The only available approaches to improved mitophagy, such as NAD upregulation, tend to replicate a thin slice of the benefits produced by exercise. Calorie restriction slows the progression of all aspects of aging, mitochondrial function included, but only to a modest degree in humans. More promising classes of therapy that may be capable of producing meaningful degrees of rejuvenation, such as gene therapies to copy mitochondrial genes into the cell nucleus, or transplantation of functional mitochondria in large numbers, are being worked on, but clinical availability remains years in the future.

Impaired Mitophagy in Neurons and Glial Cells during Aging and Age-Related Disorders

Aging is accompanied by a decline in cognitive function in a significant part of the population and is a major risk factor for the development of most neurodegenerative diseases, including Alzheimer's disease (AD) and Parkinson's disease (PD). Mechanisms of brain aging remain poorly understood, and studies aimed at the development of targeted therapy for neurodegenerative diseases are an important task for modern medicine.

Over the past few decades, it has been shown that aging processes in the brain are closely associated with mitochondrial dysfunction, resulting in oxidative stress and bioenergetic deficiency in various cells of the nervous tissue, which are extremely sensitive to energy deprivation. Mitochondrial dysfunction is also a key pathological marker for neurodegenerative diseases. For example, it is a central player in sporadic and familial forms of PD, since dopaminergic neurons of the substantia nigra are especially vulnerable to energy deficiency due to their ability for autonomous activity, constant recirculation of synaptic vesicles, and developed axonal network. Therefore, maintaining adequate energy levels through a functional pool of mitochondria is critical for neuron survival and function.

The main mechanism that prevents the development of mitochondrial dysfunction is mitophagy. Mitophagy is a complex multicomponent process that ensures control of the quality and quantity of mitochondria by eliminating damaged forms of these organelles via autophagy. The importance of mitophagy for neurons may be explained by the significant role of the cytoplasmic renewal system for postmitotic cell populations. Maintaining the basal level of mitophagy is critical for ensuring the correct functioning of neurites since the bulk of mitochondria are localized in the distal parts of neuronal processes. Mitophagy restricts the production of reactive oxygen species, prevents the accumulation of mitochondrial DNA (mtDNA) mutations and the decrease in ATP production, and blocks apoptotic signaling and the activation of inflammasomes. It is the progressive decline in this type of selective macroautophagy throughout life that appears to lead to mitochondrial dysfunction and aging.

Many neurodegenerative diseases are characterized by the accumulation of neurotoxic protein aggregates resulting from mutations in the genes encoding for proteins that trigger mitophagy: PTEN-induced kinase 1 (PINK1), parkin, and protein deglycase DJ-1, among others. Therefore, determination of the relationships between mitophagy markers and various parameters of neurodegenerative processes in PD, AD, and other age-related disorders seems to be highly promising from both a clinical and fundamental point of view.

In conclusion, mitophagy pathways play an important role in maintaining physiological homeostasis, are involved in the mechanisms of aging and neurodegenerative disorders, and represent promising targets for the development of potential therapeutic agents aimed at regulating mitochondria quality control in neurons and glial cells. A significant number of molecules that induce or inhibit mitophagy are currently under consideration, which may be useful for testing hypotheses or developing drugs for the treatment of neurodegenerative diseases. The validation of promising drugs in animal and cell models, including neurons and glial cells derived from human iPSCs as well as the elucidation of mitophagy regulation mechanisms in human samples, requires reliable biomarkers.

Currently, specific biomarkers that reflect the activity of mitophagy include ubiquitin phosphorylated at serine 65, phosphorylated PINK1 and parkin, the expression and phosphorylation of several proteins of the outer mitochondrial membrane, in addition to general biomarkers of oxidative stress and neuroinflammation. At the same time, given the variety of the regulatory pathways of mitophagy, there is no doubt that this list will be expanded, eventually including indicators that reflect the state of mitophagy in certain types of cells of the nervous tissue.

Both calorie restriction and intermittent fasting can extend life in short-lived species such as mice, the former producing a larger benefit. Both appear to produce benefits to health in humans, though nowhere near the same effects on life span. Mice in past calorie restriction studies tended to be fed at intervals, such as daily, that were in practice imposing periods of fasting as well as a lowered calorie intake. How much of the observed benefits are due to the metabolic changes imposed by reduced calorie intake versus the metabolic changes imposed by time spent fasting? A growing interest in intermittent fasting in the research community has led to the discovery that both reduced calorie intake during a fast and then the restoration of a higher calorie intake at the end of a fast appear to produce distinct benefits. Researchers here report on their efforts to split apart the effects of reduced calorie intake from duration of fasting in mice. The results are interesting.

Researchers began to realize that previous studies had unintentionally combined calorie restrictions with long fasts by providing animals with food just once a day. It was difficult, then, to distinguish the effects of one from the other. "This overlap of treatment - both reducing calories and imposing a fast - was something that everybody saw, but it wasn't always obvious that it had biological significance. It's only been in the past few years that people started getting interested in this issue."

Researchers designed four different diets for mice to follow. One group ate as much as they wanted whenever they wanted. Another group ate a full amount, but in a short period of time - this gave them a long daily fast without reducing calories. The other two groups were given about 30% fewer calories either once a day or dispersed over the entire day. That meant that some mice had a long daily fast while others ate the same reduced-calorie diet but never fasted, which differed from most previous studies of calorie restriction.

It turned out that many of the benefits originally ascribed to calorie restriction alone - better blood sugar control, healthier use of fat for energy, protection from frailty in old age and longer lifespans - all required fasting as well. Mice who ate fewer calories without fasting didn't see these positive changes. Fasting on its own, without reducing the amount of food eaten, was just as powerful as calorie restriction with fasting. Fasting alone was enough to improve insulin sensitivity and to reprogram metabolism to focus more on using fats as a source of energy. The livers of fasting mice also showed the hallmarks of healthier metabolism.

The researchers did not study the effect of fasting alone on lifespan or frailty as mice aged, but other studies have suggested that fasting can provide these benefits as well. While the mice that ate fewer calories without ever fasting did show some improved blood sugar control, they also died younger. Compared with mice who both ate less and fasted, these mice that only ate less died about 8 months earlier on average. "That was quite surprising. In addition to their shorter lifespans, these mice were worse in certain aspects of frailty, but better in others. So, on balance their frailty didn't change much, but they didn't look as healthy."

Link: https://news.wisc.edu/fasting-is-required-to-see-the-full-benefit-of-calorie-restriction-in-mice/

High levels of physical activity in individuals with the greatest risk of cardiovascular disease may well be worse than moderate physical activity when it comes to mortality. We might theorize that this is the outcome of putting an excessive level of stress on a weakened, damaged system. The study noted here is supportive of other similar studies that suggest that physical activity at the high end of the range is detrimental over the long term, in comparison to more moderate levels. Though in this context, "moderate" is probably twice the present recommendation of 150 minutes per week, which is itself more moderate exercise than most of the population undertakes.

The beneficial effect of moderate physical activity (PA) on morbidity and mortality has been observed in the general population. However, the ideal intensity of PA for improving cardiovascular longevity in Japanese general population is uncertain. The aim of this study was to investigate the relationship between the PA and cardiovascular mortality in the general population. This longitudinal cohort study included 1,826 apparently healthy subjects who participated in a community-based health checkup.

There were 31 cardiovascular deaths during 10-year follow-up. Subjects were divided into 4 groups based on the quartiles of PA (low, mild, moderate and high). Kaplan-Meier analysis and multivariate Cox proportional hazard analysis demonstrated that the most favorable cardiovascular prognosis was observed in subjects with moderate PA followed by those with mild PA. High PA as well as low PA were associated with higher cardiovascular mortality compared with mild and moderate PA. Noteworthy, in subjects with high PA, Cox hazard analysis revealed that previous cardiovascular disease, smoking, brain natriuretic peptide levels, and Framingham risk score were associated with cardiovascular mortality.

The results suggest a U-shaped association between cardiovascular mortality and PA. Mild to moderate PA was associated with favorable cardiovascular outcomes in the Japanese general population. High PA might be associated with poor cardiovascular outcomes in subjects with a history of heart disease and high coronary risk factors.

Link: https://doi.org/10.17179/excli2021-3818

A major gap exists in the present spectrum of efforts to develop the means to treat aging, rejuvenate the old, and turn back age-related conditions. An the one hand, a small number of promising potential therapies to treat the mechanisms of aging can at present be applied by physicians off-label, or otherwise without the need for a great deal of interaction with the FDA. On the other hand, there are a good hundred or more clinical indications, specific age-related conditions recognized by regulatory authorities, that might be improved by these therapies. Several hundred small, informal trials could be run, starting now, given approaches that presently exist, in order to determine whether or not these forms of therapy are in fact effective.

Let us only consider the senolytic combination of dasatinib and quercetin, for example, a low-cost treatment that can be given off-label and that has been demonstrated to clear senescent cells in human patients. Clearance of senescent cells in mice produces profound and rapid rejuvenation. Senolytics as a class of therapy are at present in human trials for only a few indications: osteoarthritis, idiopathic pulmonary fibrosis, COVID-19, chronic kidney disease, and recently Alzheimer's disease. The whole senolytic industry, and associated academic trial groups, after nearly ten years of development, has done no more than initiate a few formal human trials, at great expense, and which are very slow to answer the question of whether this actually works well. Senescent cells are involved in some way in near every age-related condition, disrupting tissue function throughout the body, provoking chronic inflammation. Effects on the full panoply of age-related conditions could be assessed. This is not being done.

If considering small informal trials, let us say that one aims for 100 to 200 people per trial, more than enough to produce meaningful evidence for efficacy when the effect size is significant. With volunteer efforts, cheap off-label treatments and low-cost assays for suitable endpoints, this sort of informal trial can be conducted for $200,000 - which is exactly what Lifespan.io is doing for their PEARL trial of mTOR inhibition. The model works. Even if the cost were $500,000 or $1,000,000, then that would still be vastly cheaper than the full, formal FDA IND process. A single non-profit with significant funding could run many such trials in a year, generating human evidence at a much greater rate than the scientific community and biotech industry combined are managing at the moment.

That evidence is much needed. There is an enormous amount of funding sitting on the sidelines. Funding that could be supporting the deployment of senolytic drugs to the population, or could be running large-scale formal clinical trials to validate the use of senolytics. The organizations capable of deploying that funding are very conservative. They will only start in on such project after there is already proof, after the debate is already won. Which is why we need the results of many low-cost trials - in order demonstrate that dasatinib and quercetin is a meaningful and useful approach to the treatment of aging.

Everything said above about the dasatinib and quercetin senolytic combination also applies to, say: fecal microbiota transplantation; or periodic blood plasma dilution; or the Khavinson peptides for thymic regrowth; or the Intervene Immune approach to thymic regrowth; or CASIN for CDC42 inhibition and restored immune function; or injection of stem cell derived exosomes; and forth into a growing list of approaches that may well be capable of achieving good results in old people. Many of these are already being used by self-experimenters, but that will never generate the sort of data that is convincing to the powers that be. There is tremendous potential to demonstrate benefits in older individuals via addressing one or more of the underlying mechanisms of aging, and the world is instead largely squandering time as the clock keeps on ticking on all of our lives.

Extracellular vesicles carry the bulk of communication between cells. The use of extracellular vesicles to adjust cell function and spur regeneration in aged tissues is a logical step beyond stem cell therapies. Much of the benefit of first generation stem cell therapies is mediated by the release of vesicles by transplanted cells, in the short time before those cells fail to engraft and consequently die. Harvesting, storing, and injecting these vesicles is a logistically easier prospect than working with cells; even now, exosomes from stem cell populations can be purchased at a fraction of the cost of stem cell therapies. This is, however, an enormously complex area of biology. As is the case for stem cell therapies, work towards exosome therapies is a way to bypass the lack of a full understanding of the relevant biochemistry by using known beneficial cell populations as a source of signaling to adjust cell behavior in the body. A great deal of work still lies ahead in the continued development of this form of therapy.

The once mythological idea that young blood may confer antiaging benefits has had legitimate scientific support for more than 60 years. Despite the intrigue of these early parabiosis experiments, potential mechanisms for how young blood may be exerting rejuvenating effects remained elusive until much more recently. Historically characterized as "platelet dust" with a role in thrombin formation, or simply as a cellular waste disposal system, the involvement of extracellular vesicles (EVs) in a wide array of biological processes, including aging, is becoming increasingly appreciated. There is an already substantial and quickly growing body of evidence attesting to the importance of EVs in the regulation of systemic aging as well as in a number of age-related detriments including inflammaging, cellular senescence, metabolic dysfunction, cardiovascular disease, cancer, and neurodegeneration.

Additionally, the utilization of age-related changes in EVs as easily accessible aging biomarkers is an attractive strategy. However, the small size of EVs, the insufficiency of current methodologies, and the heterogeneity of EV producers, recipients, and affected biological processes have created extraordinary complexity in the EV field. Significant efforts have been put forth to standardize EV collection methods, characterization, and use to increase reproducibility. While these standardized recommendations offer a reasonable foundation, much work is needed to unravel the physiological significance of EVs in different biological paradigms.

Aging is characterized by a number of complex pathophysiological alterations, some of which are also intensive research topics in the field of EV biology. The intersection of these two fields offers considerable promise, constituting a new and exciting research arena. Recent work in this arena suggests that characterization and manipulation of age-related changes in EVs has the potential to provide a unique window through which to view, and perhaps one-day treat, the systemic deterioration that accompanies aging.

Link: https://doi.org/10.1096/fba.2021-00077

Very old flies cease to age, at least under the definition of aging as the rise of mortality rate with age. Very old flies have a high mortality rate, but that rate plateaus. There has been some back and forth over the years as to whether such a late life plateau in mortality rates can be observed in humans. Presently the consensus is that it is not apparent. It is, however, challenging to draw any robust conclusions on human mortality past the age of 110, as there are so very few survivors to that late stage of life. All of this is fascinating from a scientific point of view, but something of a sideshow when it comes to the treatment of aging as a medical condition. Earnest therapies for aging are needed at half the age of interest here, and given good approaches to repair the underlying damage of aging, it becomes somewhat irrelevant as to what happens when those therapies are not used.

The validity of conclusions about mortality at extreme age depends crucially on the quality of the data on which they are based, as age misrepresentation for the very old is common even in countries with otherwise reliable statistical data. Motivated by this, demographic researchers from 13 countries contribute to the International Database on Longevity (IDL), the third (August 2021) release of which contained 1119 individually validated life lengths of supercentenarians, i.e. those reaching age 110 or more; the data, which cover different time periods for different countries, can be obtained from www.supercentenarians.org. For some countries, the IDL now also includes data on semi-supercentenarians, i.e. people living to an age of at least 105. Since October 2019, IDL has contained French data on 9571 semi-supercentenarians and 241 supercentenarians who died between 1 January 1987 and 31 December 2016. We call these the France 2019 data; all these supercentenarians but only some of the semi-supercentenarians were validated.

We use a combination of extreme value statistics, survival analysis, and computer-intensive methods to analyse the mortality of Italian and French semi-supercentenarians. After accounting for the effects of the sampling frame, extreme-value modelling leads to the conclusion that constant force of mortality beyond 108 years describes the data well and there is no evidence of differences between countries and cohorts. These findings are consistent with use of a Gompertz model and with previous analysis of the International Database on Longevity and suggest that any physical upper bound for the human lifespan is so large that it is unlikely to be approached. Power calculations make it implausible that there is an upper bound below 130 years. There is no evidence of differences in survival between women and men after age 108 in the Italian data and the International Database on Longevity, but survival is lower for men in the French data.

Link: https://doi.org/10.1098/rsos.202097

A growing body of evidence suggests that microglia in the brain are important in the progression of neurodegenerative conditions such as Alzheimer's disease. Like the similar macrophages outside the brain, microglia can adopt packages of behavior known as polarizations. M1 is an aggressive, inflammatory polarization suited to hunting pathogens, while M2 is an anti-inflammatory, pro-regenerative polarization suited to the maintenance and repair of tissue. This taxonomy is an oversimplification of a more complex reality, but it is a useful model when thinking about how and why microglia may contribute to neurodegeneration.

Chronic inflammation in brain tissue is a feature of neurodegenerative conditions, and activated M1 microglia help to sustain that inflammatory state. This contribution to chronic inflammation is particularly the case when microglia become senescent, and studies in animal models have shown benefits to result from the use of senolytic therapies that selectively destroy senescent cells in the brain. Further, if more of the microglial population is M1, then it is likely that fewer microglia are undertaking necessary M2 activities. With that in mind, today's open access paper provides supporting evidence for the loss of M2 macrophage activities in neurodegenerative disease.

What can be done about this? One possible approach is to clear the entire microglial cell population in the brain, and let it reconstitute. That replacement happens quite rapidly, and the new microglia are less problematic than the originals, at least for a time. Researchers have used CSF1R inhibitors to achieve clearance of microglia in mice, and shown that it helps in models of Alzheimer's disease. It remains to be seen as to whether and when this will be attempted in human patients.

Microglial gene signature reveals loss of homeostatic microglia associated with neurodegeneration of Alzheimer's disease

Microglia are the resident innate immune cells of the central nervous system (CNS), and are key players to mediate neuroinflammation, playing critical roles in the recognition and clearance of Aβ in Alzheimer's disease (AD). The activation phenotype of microglia was previously classified by the expression pattern of cytokines in analogy of activated macrophages: the proinflammatory "classical" activation phenotype (M1) and the anti-inflammatory "alternative" activated phenotype (M2). However, this simplistic view of microglial phenotypes does not adequately reflect the complex physiology of microglia.

The progression of neurodegenerative disease induces the loss of microglial homeostatic molecules and functions, leading to chronically progressive neuroinflammation. In addition, recent studies demonstrated that a common disease-associated microglia (DAM) or "neurodegenerative" phenotype, defined by a small set of upregulated genes, was observed in neurodegenerative diseases including AD, amyotrophic lateral sclerosis (ALS), and frontotemporal dementia, and aging. However, it remains unclear whether the loss of homeostatic function in microglia or the DAM phenotype is correlated with the degree of neuronal cell loss, and whether DAM is beneficial or detrimental to neurodegenerative diseases.

In this study, we performed RNA sequencing of microglia isolated from three representative neurodegenerative mouse models, AppNL-G-F/NL-G-F with amyloid pathology, rTg4510 with tauopathy, and SOD1G93A with motor neuron disease. In parallel, gene expression patterns of the human precuneus with early Alzheimer's change (n = 11) and control brain (n = 14) were also analyzed by RNA sequencing.

We found that a substantial reduction of homeostatic microglial genes in rTg4510 and SOD1G93A microglia, whereas DAM genes were uniformly upregulated in all mouse models. The reduction of homeostatic microglial genes was correlated with the degree of neuronal cell loss. In human precuneus with early AD pathology, reduced expression of genes related to microglia- and oligodendrocyte-specific markers was observed, although the expression of DAM genes was not upregulated. Our results implicate a loss of homeostatic microglial function in the progression of AD and other neurodegenerative diseases. Moreover, analyses of human precuneus also suggest loss of microglia and oligodendrocyte functions induced by early amyloid pathology in human.

It costs a great deal to run a reasonably sized clinical trial within the formal system of regulatory governance. If the goal is to make a compelling demonstration of effectiveness, then at the very least a larger-than-usual phase 2 trial is required. The cost of getting to that point is upwards of $15-20 million in industry, and still a substantial fraction of that for academic institutions that have much of the supporting infrastructure already in place. Yet groups like Lifespan.io can put together a less formally administered trial, one that will teach us almost as much about whether or not a given approach is efficacious, for less than $250,000.

Not enough of this sort of work is taking place. There are too few low-cost assessments carried out with the aim of generating good data that may otherwise never arise. Even just looking at senolytics, there are scores of age-related conditions that may be beneficially effected by the low-cost dasatinib and quercetin combination. Academia and industry have yet to even start on the assessment of senolytic treaments for more than three of four of those indications. Time is ticking. The world needs more organizations and collaborative projects like Lifespan.io and the RLE Group noted here, working to responsibly gather data to show whether the present range of promising approaches to the treatment of aging work or not.

Our another achievement is the plasmapheresis trial, which is pretty well-known in the community. We didn't expect to observe dramatic improvements in biomarkers that we would treat as promising, we just wanted to understand the logistics of the whole plasmapheresis process. Because you need to replace half of your plasma with the saline + albumin solution and this is not a simple and standard procedure. But we managed to calculate how many plasma you need to donate with each visit to the doctor and how many albumin you need to replace and we did this and surprisingly we have found some pretty interesting changes in the biomarkers of this gentleman. We have found, for instance and contrary to our expectations, that cholesterol goes both directions - bad LDL goes down and good HDL goes up, which is pretty interesting. Of course we have only two data points, so we cannot draw too many conclusions from that, but we have started a clinical trial aiming to compare plasmapheresis with albumin and without albumin, because the role of albumin of the whole procedure is an interesting question.

A few smaller things our group has achieved. We have tried various senolytics in our volunteers. Created a lentiviral vector for APO-A1 Milano gene delivery. And also a microbiome replacement experiment, because we have access to samples from soviet cosmonauts (who are usually considered exceptionally healthy, so our hypothesis is that transferring the microbiome could yield interesting health improvements).

Here are several things we are planning to deliver in the upcoming years. We are intrigued by the study showing muscular aging through 15-PGDH, and we want to reproduce it on ourselves. Another target is epigenetic rejuvenation of hematopoietic stem cell function via targeting Cdc42. This type of cell is very reluctant to different approaches in reversing aging (even our extracellular matrix one), so we plan to rejuvenate them and investigate how to maintain the useful environment for these rejuvenated cells. The third thing is targeting elastogenesis. Elastin is now considered to be one of the longest living proteins in our body, elastogenesis is limited to early infancy and then the old synthesized elastin remains in our body, accumulates calcium, is degraded by enzymes and so on, therefore we lose elastin which leads to progressive deterioration of various tissues - blood vessels, skin, lungs, ligaments, muscles, ... All tissues lose their elasticity and that is crucial not only for appearance but also functional health. We can try - and already have some methods - to increase elastin production in vivo.

Link: https://foresight.org/salon/alexander-fedintsev-biohacking-a-necessary-component-of-a-strategy-for-radical-life-extension/

Old age brings with it a much reduced capacity for healing of skin injuries. Researchers here delve into the details, identifying factors that negatively influence the ability of keratinocyte stem cells to migrate. This offers the potential to override the reaction of these stem cells to age-related changes in the signaling environment. This sort of compensatory approach does nothing to address the underlying damage of aging that causes such changes in signaling. As a class of approach, compensation will never be as good as repair of damage, but compensatory signaling can in some cases still be beneficial enough to be worth pursuing as a basis for therapy.

With advanced age, a reduced skin wound healing ability is associated with the development of so-called chronic nonhealing disorders, such as diabetic ulcers and pressure sores. Skin stem cells, also called keratinocyte stem cells, are responsible for skin regeneration and wound closure through a process called re-epithelialization. "Live-imaging and computer simulation experiments showed that human skin stem cells motility is coupled with their proliferative and regenerative capacity and old stem skin cells have a significantly reduced motility."

To understand the mechanisms behind this reduced motility in old stem cells, researchers compared the wound healing and proliferative ability of skin stem cells derived from young mice (12 weeks old) and aged mice (19-25 months old). The experiments showed that a specific molecule, called EGFR (Epidermal Growth Factor Receptor), drives skin stem cell motility and that EGFR signalling is reduced in old stem cells. EGFR acts by preventing the degradation of a specific type of collagen, COL17A1, which is necessary to hold the layers of the skin together.

Interestingly, COL17A1 coordinates the movement of skin stem cells towards the injury by regulating actin and keratin filament networks in the cells. The researchers found that with age, a decrease in EGFR signalling occurs, leading to lower levels of COL17A1 and skin stem cells with reduced mobility that are less able to re-epithelialize the skin. "Although further investigations are still required, stabilizing COL17A1 by regulating its proteolysis is a promising therapeutic approach for improving the decline in skin regeneration observed with age."

Link: https://www.tmd.ac.jp/english/press-release/20210922-1/

Before the advent of the first senolytic drugs capable of selectively destroying senescent cells, it was thought by many that progress towards producing rejuvenation in the old via the safe elimination of senescent cells from the body would require the identification of surface markers that are distinctive to the state of senescence. Given a surface marker that clearly and distinctively identifies a cell population, a broad range of strategies become available for the development of targeted therapies. As it turned out,, however, the first senolytics took advantage of the peculiarities of the internal state of senescent cells. These cells are primed to undergo the self-destruction of apoptosis, and as a consequence it was discovered that interference in anti-apoptosis mechanisms will kill senescent cells without harming normal cells. The question of surface markers was largely put aside, with only a few groups, such as SIWA Therapeutics, pursuing approaches of that nature.

Given that, it is interesting to take a look at today's open access paper, in which researchers report a distinctive surface marker for senescent cells. It remains the case that any such marker can enable many novel approaches to senolytic therapy, not just the one used as a proof of concept by the authors of this paper. It has to be said that the senolytics field is already well stocked with a diversity of innovative approaches at various stages of development - but more can't hurt! Ultimately, multiple senolytic therapies that are based on very different strategies may be needed in order to obtain an optimal coverage of tissues and high level of senescent cell destruction in older people. Even without considering that point, a marketplace that will ultimately consider everyone much over the age of 40 an occasional customer has plenty of room for products and providers.

Targeted clearance of senescent cells using an antibody-drug conjugate against a specific membrane marker

Senescence is an irreversible proliferation arrest and a key restriction mechanism to prevent the propagation of damaged cells. However, the progressive accumulation of senescent cells with time has been associated with loss of tissue homeostasis, and is known to contribute to the functional impairment of different organs typically seen in ageing. Recently, it has been shown that it also plays an important role in fibrosis and tumour progression, and that it may be involved in cataracts, obesity, diabetes, Alzheimer's and Parkinson's diseases, arthritis, atherosclerosis and many other age-related conditions. This supports the hypothesis that senescence is an antagonistically pleiotropic process, with beneficial effects in the early decades of life of the organism (in development, tissue repair, and as a tumour suppressor mechanism) but detrimental to fitness and survival at later stages, after the percentage of senescent cells in tissues reaches a critical threshold.

Consistent with this view, it has been reported that clearing senescent cells from tissues has a protective effect against cancer and the onset of age-related pathologies. Because of this, great interest has been placed in a recently discovered group of drugs that can preferentially kill senescent cells, collectively known as senolytics, which have been shown to increase healthspan and lifespan of mice with attenuation of age-related dysfunctions like emphysema, hepatic steatosis, lung fibrosis, osteoporosis, osteoarthritis, cardiac regeneration dysfunctions, cognitive memory impairments or Alzheimer disease in different in vivo models. Recently, senolytics, were shown to also decrease the number of senescent cells in humans and alleviate the symptoms of idiopathic pulmonary fibrosis.

In this context, targeted senolytics are emerging as a promising alternative. For instance, it has recently been shown that toxic nanoparticles activated by the presence of β-galactosidase can eliminate senescent cells in vitro and in vivo, confirming the feasibility of the approach. We propose that the senescent surfaceome, the specific profile of membrane proteins differentially upregulated in senescent cells, could be used to this end even more effectively. Using mass spectrometry, we identified a number of markers highly expressed in the plasma membranes of senescent cells in response to the activation of one of the two main pathways of induction of the phenotype (p53/p21 or p16).

We show that an antibody-drug conjugate (ADC) against the marker B2M clears senescent cells by releasing duocarmycin into them, while an isotype control ADC was not toxic for these cells. This effect was dependent on p53 expression and therefore more evident in stress-induced senescence. Non-senescent cells were not affected by either antibody, confirming the specificity of the treatment. Our results provide a proof-of-principle assessment of a novel approach for the specific elimination of senescent cells using a second generation targeted senolytic against proteins of their surfaceome, which could have clinical applications in pathological ageing and associated diseases.

Microglia are innate immune cells of the central nervous system, involved in maintaining neural function as well as in chasing down pathogens and clearing molecular waste. Here, researchers show that some microglia play an important part in maintaining the microvasculature of the brain. Of note, capillary networks throughout the body decline in density with age, reducing the supply of nutrients and oxygen. This is particularly consequential in energy-hungry tissues such as muscles and the brain. It is known that microglia become increasingly inflammatory and senescent with advancing age; it is interesting to speculate on the degree to which this may contribute directly to the decline in vascular function in the brain.

Scientists have known that microglia play many important roles in the brain. For example, the cells police the natural blood-brain barrier that protects the organ from harmful germs in the bloodstream. Microglia also facilitate the formation of the brain's complex network of blood vessels during development. And they are known to be important in many diseases. In Alzheimer's disease, for example, recent work suggests that the loss of the immune cells is thought to increase harmful plaque buildup in the brain.

Scientists have been unsure, however, what role microglia play in maintaining blood vessels in a normal, healthy brain. The new research reveals that the cells are critical support staff, tending the vessels and even regulating blood flow. The researchers identified microglia associating with the brain's capillaries, determined what the immune cells do there and revealed what controls those interactions. Among the cells' important responsibilities is helping to regulate the diameter of the capillaries and possibly restricting or increasing blood flow as needed.

"We are currently expanding this research into an Alzheimer's disease context in rodents to investigate whether the novel phenomenon is altered in mouse models of the disease and determine whether we could target the mechanisms we uncovered to improve known deficits in blood flow in such a mouse model of Alzheimer's. Our hope is that these findings in the lab could translate into new therapies in the clinic that would improve outcomes for patients."

Link: https://news.virginia.edu/content/discovery-new-role-brains-immune-cells-could-have-alzheimers-implications

Osteoporosis is the name given to the characteristic loss of bone mass and strength that takes place with age. Bone is constantly remodeled, and this condition is the consequence of a growing imbalance between the activity of osteoclasts, responsible for breaking down bone, and osteoblasts, responsible for building bone. Researchers here make the observation that osteoclasts perform functions related to bone construction even as they break down bone, meaning that therapies intended to limit osteoclast populations may not work as well as hoped. Instead, specifically dialing back only the breakdown of bone tissue by altering regulatory proteins in osteoclasts, without dialing back their other activities, may be a better approach.

Scientists are eager to understand what causes the bone loss of osteoporosis, and to develop new ways to treat and prevent it. Researchers have found an important contributor, a cellular protein called ELMO1. This protein, they found, promotes the activity of the bone-removing osteoclasts. While osteoclasts may seem like 'bad guys' because they remove bone, they are critical for bone health, as they normally remove just enough to stimulate new bone growth. The problem arises when the osteoclasts become too aggressive and remove more bone than the body makes. Then bone density suffers and bones grow weaker.

This excessive bone degradation is likely influenced by genetic factors. They note that many of the genes and proteins linked to ELMO1 have been previously associated with bone disorders and osteoclast function. Encouragingly, the researchers were able to prevent bone loss in lab mice by blocking ELMO1, including in two different models of rheumatoid arthritis (RA). That suggests clinicians may be able to target the protein in people as a way to treat or prevent bone loss caused by osteoporosis and RA.

They note that prior efforts to treat osteoporosis by targeting osteoclasts have had only mixed success, and they offer a potential explanation for why: Osteoclasts not only remove bone but play a role in calling in other cells to do bone replacement. As such, targeting ELMO1 may offer a better option than simply waging war on the osteoclasts. "We used a peptide to target ELMO1 activity and were able to inhibit degradation of the bone matrix in cultured osteoclasts without affecting their numbers. We hope that these new osteoclast regulators identified in our study can be developed into future treatments for conditions of excessive bone loss such as osteoporosis and arthritis."

Link: https://www.eurekalert.org/news-releases/931365

The gut microbiome consists of a broad range of microbial populations locked into in a constant, dynamic state of competitive population growth and decline. The balance of benign versus harmful microbial species is important to health and the progression of aging. Benign species produce useful metabolites, while harmful microbes provoke systemic chronic inflammation, an important contribution to many of the dysfunctions of aging and age-related disease. There is a bidirectional relationship between the immune system and the gut microbiome. The immune system gardens the microbiome by destroying selected cells, particularly those capable of producing inflammation, while the microbiome can influence the immune system into inflammatory behavior.

With age, the immune system declines in effectiveness, and the balance of populations in the gut microbiome shifts. Beneficial populations decline while harmful, inflammatory populations increase in number. Some of these shifts occur surprisingly early in adult life, in the mid-30s. Restoring a youthful gut microbiome via fecal microbiota transplantation from young animals to old animals has been shown to improve health, reduce inflammation, and extend life span. Other approaches shown to improve the microbiome may be similarly beneficial to long-term health, to various degrees, such as icariin supplementation or flagellin innoculation. It remains to be assessed as to how much of an effect on late life health and mortality these interventions can produce in humans.

Immune system keeps the intestinal flora in balance

The bacteria living in the intestine consist of some 500 to 1000 different species. They make up what is known as the intestinal flora, which plays a key role in digestion and prevents infections. Unlike pathogens that invade from the outside, they are harmless and tolerated by the immune system. The way in which the human immune system manages to maintain this delicate balance in the intestine largely remains unknown. It is known that type A immunoglobulins, referred to as IgA antibodies, play an important role. These natural defense substances are part of the immune system, and recognize an exogenous pathogen very specifically.

A group of researchers have recently been able to show in a mouse model that IgA antibodies specifically limit the fitness of benign bacteria at several levels. This enables the immune system to fine-tune the microbial balance in the intestine. The researchers succeeded in tracking the in-vitro and in-vivo effect in the intestines of germ-free mice with pinpoint accuracy. The antibodies were found to affect the fitness of the bacteria in several ways. The mobility of bacteria was restricted, for example, or they hindered the uptake of sugar building blocks for the metabolism of the bacteria. The effect depended on the surface component that was specifically recognized. "This means that the immune system is apparently able to influence the benign intestinal bacteria through different approaches on a simultaneous basis. Understanding exactly how and where antibodies recognize microorganisms in the intestine will also allow us to develop vaccines against pathogenic organisms on a more targeted basis."

Parallelism of intestinal secretory IgA shapes functional microbial fitness

Dimeric IgA secreted across mucous membranes in response to nonpathogenic taxa of the microbiota accounts for most antibody production in mammals. Diverse binding specificities can be detected within the polyclonal mucosal IgA antibody response, but limited monoclonal hybridomas have been studied to relate antigen specificity or polyreactive binding to functional effects on microbial physiology in vivo. Here we use recombinant dimeric monoclonal IgAs (mIgAs) to finely map the intestinal plasma cell response to microbial colonization with a single microorganism in mice. We identify a range of antigen-specific mIgA molecules targeting defined surface and nonsurface membrane antigens.

Secretion of individual dimeric mIgAs targeting different antigens in vivo showed distinct alterations in the function and metabolism of intestinal bacteria, largely through specific binding. Even in cases in which the same microbial antigen is targeted, microbial metabolic alterations differed depending on IgA epitope specificity. By contrast, bacterial surface coating generally reduced motility and limited bile acid toxicity. The overall intestinal IgA response to a single microbe therefore contains parallel components with distinct effects on microbial carbon-source uptake, bacteriophage susceptibility, motility, and membrane integrity.

Researchers here discuss the distinguishing features of senescent cells and known ways to target those features in order to selectively destroy these cells. Senescent cells accumulate with age throughout the body, likely the consequence of an accelerated pace of creation and a slower pace of destruction by the immune system. These errant cells cease replication and secrete a potent mix of signals that provoke chronic inflammation and disrupt normal tissue structure and function. Removal of as little as a third of the senescent cells present in old mice produces quite impressive reversals of aging and age-related disease.

As senescent cells are highly heterogeneous in both their molecular biology and their physiological function, targeted strategies are needed that ideally preserve senescent cells in beneficial contexts while eliminating effects that are detrimental. Broadly, these therapies can be broken down into the major categories of senomorphic and senolytic drugs, although this classification might be arbitrary as agents with senomorphic effects in one cell type or context may be senolytic in another and vice versa. Senomorphic compounds target pathologic SASP signaling, while senolytics eliminate the underlying senescent cells that release damaging SASP factors. Senomorphics are discussed elsewhere, but in brief senomorphics prevent the production of, antagonize or neutralize SASP components, and usually require continuous administration. We will instead focus on emerging senolytic strategies that address a root cause of senescence pathology, senescent cells, yielding pleiotropic benefits with intermittent administration.

While the first senolytics were developed using a bioinformatically informed approach aimed at disrupting senescent cell anti-apoptotic pathways (SCAPs) and other pro-survival networks, the class has expanded to take advantage of additional senescence features and enhance immune-mediated clearance. Broadly, first-generation agents act by transiently disabling SCAPs, causing those senescent cells with a tissue-damaging SASP to kill themselves. Importantly, while all senolytic strategies may elicit off-target effects or interfere with beneficial populations, these can often be limited as most therapeutics are amenable to intermittent 'hit-and-run' dosing strategies that do not require daily, or even weekly, administration.

Characterization of senescent cells has revealed unique markers that serve as senescence-associated self-antigens. These can be co-opted for immune system-mediated senolytic activity and clearance. A recent study took advantage of this using chimeric antigen receptor (CAR) T cells targeted against the urokinase-type plasminogen activator receptor (uPAR) in a mouse model. uPAR is associated with extracellular matrix remodeling that is upregulated at the cell surface of senescent cells during replicative, oncogene-induced and toxicity-induced senescence. Cytotoxic CAR T cells were able to selectively clear uPAR-expressing senescent cells in vitro and in vivo.

Prototypic senolytic drugs were developed to target SCAP networks. In contrast to a one-drug, one-target approach, SCAP inhibition may interface with several pro-survival signals at once. As a result, these early senolytics typically possess several pharmacologic mechanisms of action that interact synergistically. Prime examples of this are the flavonoid fisetin as well as dasatinib and quecertin (D + Q), which have been utilized and reviewed thoroughly. In brief, although the precise mechanism of action is unknown (as is the case for most agents), the D + Q combination exerts broad spectrum senolytic activity through interference with several pro-survival networks.

Additional aspects of senescent cells are advantageous for directed senolysis. One such feature is their increased lysosomal enzyme activity. This can be leveraged with the use of prodrugs that are cleaved and activated by the lysosomal enzyme SA-β-gal or by loading cytotoxic chemicals into galacto-polymer-coated nanoparticles that can be preferentially released into senescent cells. Further, outside its role as a cellular recycling system, autophagy can lead to activation of cell death pathways when highly activated under persistent stress. Autophagy is inhibited within senescent cells, but senescent cells are primed for cell death following an autophagic push. This is demonstrated by autophagy induction and subsequent senolysis.

Link: https://doi.org/10.1038/s43587-021-00121-8

Would that the popular media produced more popular science articles about the longevity industry like this one. It is not just a profile of someone trying to make a difference in the world by advancing the state of medicine, but also a look at some of the companies and ventures involved in that process. And all that while being a sober consideration of the potential to bring aging under medical control, and thereby end some of the largest causes of suffering and death in late life.

Michael Greve thought to himself: It would be stupid to kick the bucket now. He started to look into nutrition, gave up coke, pizza, and red wine, lost 20 kilos, gave up smoking, gained the 20 kilos back, and lost them again. After a total of three years, his body was ready for a life that wouldn't have to be boring for decades. Greve thought to himself: to kick the bucket now would be even stupider. Then he made the decision that changed his life, and may soon change yours: To not end up as the richest man in the graveyard. Michael Greve decided to take such a serious approach to health that he began to study the field of longevity, the science of extending the healthy human lifespan. He plowed through studies and began to get involved, as actively as only a person with a nine or ten-figure bank account can.

Five years ago, he donated the first ten million to the SENS Research Foundation, an authority on longevity research. In the same year, 2016, Greve founded the Forever Healthy Foundation. Forever Healthy has long been globally active, the language of the foundation is English, and the most recently hired employees are based in Istanbul and New York. From Karlsruhe, Greve and a small team currently manage 14 startups that have emerged from particularly promising research projects. In collaboration with the SENS Research Foundation, he organizes an annual conference, Undoing Aging, at which the industry's renowned scientists and opinion leaders meet.

With his own team, he produces scientific papers that can be thought of as a screenshot of current world knowledge on a topic - each paper based on about 2000 abstracts and 150 studies. He publishes them in a database on his website, freely accessible to anyone at any time, comprehensibly transformed into practical advice, for example things like fisetin and EDTA. He has turned himself into the leading global figure of a new approach to longevity: he talks about rejuvenation, the preservation and restoration of youth. He talks about viewing the process of aging as a treatable disease, not an inescapable fate. All this not with the goal of eternal life, but of prolonging the healthy life span as much as possible. To give you an idea of the avalanche Greve has unleashed in the past five years: One of his 14 startups has reached the point where it can dissolve tumors by injection. Another one can repair broken arteries.

Worldwide around 150,000 people die every day: 50,000 from accidents, violence, wars, things like that. 100,000 from diseases like diabetes, cancer, Alzheimer's, and heart attacks. You could simplify it and say: 100,000 people die every day from the worst disease in the world, namely aging. We humans have lived with this for a few million years, we humans have died with this for a few million years. We have become accustomed to that. But does it have to stay that way? "What we're doing now is getting to the bottom of the whole thing. Where does cancer start, where does Alzheimer's start? Where is the root? And more importantly, what can we do about it? I'm only interested in research that results in action. So in working with our startups and at our conference, we don't talk about model organisms and regulatory stuff. We're not talking about someday. We're talking about human treatments, we're talking about therapy, and we're talking about now."

Link: https://www.redbull.com/int-en/theredbulletin/michael-greve-biohacking-longevity

Revel Pharmaceuticals is the result of work funded in large part by the SENS Research Foundation, with the support of its many philanthropic donors. That part of the history of the underlying research isn't covered in today's short article on the company, so it seems worth mentioning here. Cross-links are chemical bonds formed between molecules in the extracellular matrix. Some are necessary to structure and function, but other unwanted cross-links are added over the years, creating stiffness in flexible tissues such as blood vessel walls and skin. In the case of blood vessels, stiffness causes hypertension, and eventual mortality. Revel is aiming to remove cross-links based on glucosepane, which appear to be the dominant type of persistent pathological cross-linking in human tissues.

The field of glucosepane cross-link research is an excellent example of the way in which philanthropy is required to make progress. There was compelling evidence that such cross-links are likely important in the aging process, and yet next to no-one chose to work on the problem. This was a bootstrapping problem: because no-one had spent a good deal of time on glucosepane, the tools to work with it didn't exist. Worse, glucosepane isn't a factor in short-lived mammals, their important pathological cross-links are chemically different from those in humans, so animal models of such cross-linking were a distant prospect at best. Thus scientists, funding sources, and others all turned their attention to other projects in other fields, because those other projects promised a more rapid path to what the world at large considers useful outcomes. Next to no-one funded or worked in the field of glucosepane cross-linking precisely because next to no-one funded or worked in the field of glucosepane cross-linking research.

How was this problem resolved? The SENS Research Foundation, a non-profit, stepped in and used funds provided by donors to fund the work to produce the necessary tools for glucosepane cross-linking research, as well as projects that identified bacterial enzymes capable of breaking down glucosepane. That work was licensed out to Revel Pharmaceuticals, and one of the researchers involved is now heading the company in an effort to turn those enzymes into therapies. The point here is that philanthropy works. This is one of any number of similar efforts to unblock research and development undertaken by the SENS Research Foundation and Methuselah Foundation over the past twenty years. The outcome will hopefully lead to a proof of concept to demonstrate that glucosepane cross-linking is an important aspect of aging, and that in turn will shortly thereafter become an industry with as much promise as the present senolytics industry when it comes to human rejuvenation.

A new approach to reversing tissue aging

The formation of Revel Pharmaceuticals is a reimagination and expansion of targeting AGE crosslinks using enzymes rather than small molecules as the therapeutic. "Enzymes are biologics, so we can be very precise as we make modifications to repair damaged proteins and break up crosslinks."

"We're quite unique right now, in the aging space - not many companies are focused on the structural, protein side of aging. If you look at the literature and clinical data, it's very clear that damage and crosslinking of collagen and other proteins is a significant contributor to aging. As the structure of the extracellular matrix surrounding cells becomes crosslinked and degraded, proteins begin to aggregate and lose functionality, tissues become stiffer, and the immune system becomes activated leading to low level inflammation. We're looking at the same targets that have been of interest for a long time, but no one's had a good way to correct or repair them. We started out looking at glucosepane, the predominant crosslink in aging human tissue, but there are many other important aging crosslinks and damage products to which we've expanded our scope."

"Our work has led us to five or six interesting targets, which also serves to de-risk our pipeline, so all of our eggs aren't in one basket. What we have now is a suite of enzymes targeting a suite of different damage products." Revel is preparing to move therapeutic enzymes into pilot studies in animal models and human cadaver tissue from biobanks. "If we have 80 year old tissue that comes from a biobank, then the gold standard is really to show that, when we add our enzymes to that very old tissue, we can repair these modifications and correct the damage. Once that critical milestone is met for each enzyme, we will immediately push into animal studies and eventually clinical testing."

Consumer devices that can measure useful age-related cardiovascular metrics such as pulse wave velocity and heart rate variability are not that great in comparison to the much more expensive lines of medical devices. The most important difference lies in whether measuring these parameters in the periphery (arm, wrist, finger) or in the body itself (neck, torso). There is a lot more noise in the periphery, and these are already noisy metrics by their nature, prone to a lot of moment to moment and circumstantial variance. If pulse wave velocity is 6.3 m/s on day one and 8.5 m/s on day two, an entirely likely outcome, what exactly is one supposed to do with that information, other than resign oneself to a two to three week process of twice daily measurements in order to obtain a meaningful average? Still, more options are better, and researchers here suggest a metric that appears to correlate decently with cardiovascular aging, and which could in principle be added to any existing device via a suitable software update.

As age increases, the elasticity of arterial vessels decreases, and the inner diameter widens due to changes in the mechanical properties of blood vessels and the cardiovascular system. A decrease in elasticity leads to the stiffness of arterial vessels increasing and the reflected wave returning quickly, and abnormalities in proximal aortic diameter are responsible for the abnormal aortic pressure-flow relationship. This phenomenon increases arterial pressure, which elevates the risk of cardiovascular disease (CVD), including hypertension. Therefore, examining these age-related changes in arterial stiffness and appropriate indicators reflecting the stiffness caused by cardiovascular aging are important to prevent risk factors for CVD.

The pulse wave velocity (PWV), one of the representative indicators of arterial stiffness, is the speed at which a blood pressure pulse wave propagates through the arterial system. There is a distance measurement error caused by assuming a straight arterial segment, and in the most frequently used carotid-femoral PWV, the carotid and femoral pulse waves traveling in opposite directions cause overestimation of the PWV. Another measure of arterial stiffness is the augmentation index (AIx), which is the ratio of the height of the peak above the shoulder of the wave to the pulse pressure. The AIx is easier to measure and less time consuming than the PWV; additionally, the AIx enables observation of the reflective properties of the arteries. The AIx increases with age and blood pressure, which has been explained by the fact that wave reflection increases with age.

The sharpness of the pulse wave is a representative characteristic in pulse waveform analysis. Because it is well known that blunter waveforms are generally found in older people, whereas sharper pulse waveforms are found in younger people, pulse sharpness could reflect age-related characteristics, such as vascular aging or arterial stiffness, as well as the AIx. In addition, as the average pulse morphology variability near the peak point of the percussive wave was less than only 2% in a previous study, pulse sharpness could be an index with low variability. However, despite these intuitive considerations of pulse sharpness, few studies have been explored the availability of sharpness as an indicator of vascular aging or arterial stiffness, unlike the AIx. In addition, a formally accepted algorithm for detecting sharpness has not been reported.

The aim of this study was to develop a robust algorithm to quantify pulse sharpness that can complement the limitations of radial augmentation index (rAIx) and explore the role of this quantitative sharpness index in reflecting vascular aging or arterial stiffness. The pulse sharpness index (PSI) was developed by combining the end point angle and virtual height, and 528 radial pulses were analyzed.

Significant sex differences were identified in the rAIx and PSI, and significant age-dependent decreases in the PSI were observed. In addition, the PSI and age were correlated (r = - 0.550) at least as strongly as the rAIx and age (r = 0.532), and the PSI had a significant negative correlation with arterial stiffness (r = - 0.700). Furthermore, the multiple linear regression model for arterial stiffness using the PSI, age, sex and heart rate showed the excellent performance, and the PSI was found to have the greatest influence on arterial stiffness. This study confirmed that the PSI could be a quantitative index of vascular aging and has potential for use in inferring arterial stiffness with an advantage over the rAIx.

Link: https://doi.org/10.1038/s41598-021-99315-8

Data on hypertension and its effects on health and mortality has in recent years indicated that even modest increases above optimal blood pressure, increases that are not considered hypertension, and even fall within what is thought of as the normal healthy range for blood pressure, nonetheless cause an accelerated pace of damage and dysfunction over the course of later life. Raised blood pressure leads to pressure damage to sensitive tissues in the body and brain, as well as accelerating the progression of atherosclerosis. It appears that there is no sudden threshold above which these problems arise, but it is instead the case that the harms scale by the degree to which blood pressure is raised above the optimal level.

People with elevated blood pressure that falls within the normal recommended range are at risk of accelerated brain ageing, according to new research. If we maintain optimal blood pressure our brains will remain younger and healthier as we age. "It's important we introduce lifestyle and diet changes early on in life to prevent our blood pressure from rising too much, rather than waiting for it to become a problem. Compared to a person with a high blood pressure of 135/85, someone with an optimal reading of 110/70 was found to have a brain age that appears more than six months younger by the time they reach middle age."

Researchers examined more than 2,000 brain scans of 686 healthy individuals aged 44 to 76. The blood pressure of the participants was measured up to four times across a 12-year period. The brain scan and blood pressure data was used to determine a person's brain age, which is a measure of brain health. The findings highlight a particular concern for young people aged in their 20s and 30s because it takes time for the effects of increased blood pressure to impact the brain. "By detecting the impact of increased blood pressure on the brain health of people in their 40s and older, we have to assume the effects of elevated blood pressure must build up over many years and could start in their 20s. This means that a young person's brain is already vulnerable."

The research findings show the need for everyone, including young people, to check their blood pressure regularly. "Adults should take the opportunity to check their blood pressure at least once a year, with an aim to ensure that their target blood pressure is closer to 110/70, particularly in younger and middle age groups. If your blood pressure levels are elevated, you should take the opportunity to speak with your GP about ways to reduce your blood pressure, including the modification of lifestyle factors such as diet and physical activity."

Link: https://www.anu.edu.au/news/all-news/optimal-blood-pressure-helps-our-brains-age-slower

Many of the interventions demonstrated to produce interesting effects on the pace or state of aging are challenging to learn from. This is the case because these interventions change so much of the operation of metabolism as to make it hard to pick apart what is most relevant to the progression of aging versus what is a side-effect. Calorie restriction is the canonical example - it alters the entire laundry list of cellular processes thought relevant to aging, and a good many others besides. Similar issues arise when looking at heterochronic parabiosis, as linking the circulatory systems of a young animal and an old animal changes the signaling environment profoundly.

This makes it all too easy to pull together an argument for a specific area of metabolism to be important in aging. In the case of iron metabolism, the subject of today's open access paper, there is a reasonable case to be made. The challenge, as is the case for just about every other argument for process A or process B to be important in aging,is how does one prove the hypothesis? That iron metabolism is altered in calorie restriction is only mild support at best, for the reasons given above.

Proof of relevance in aging requires targeted interventions that address only the one specific causative mechanism. On the rejuvenation, damage repair side of the house, senolytic drugs to destroy senescent cells are a recent example. Animal studies using senolytics have proven that the accumulation of senescent cells causes a sizable fraction of age-related pathology. But one might also look at the compensatory therapy of antihypertensive medication, and see it as a way to prove that raised blood pressure is an important intermediary mechanism in aging, caused by underlying molecular damage, and capable of itself causing a meaningful amount of downstream structural damage. In the case of iron metabolism, I'm not sure that any of the example interventions given in today's paper rise to the level of being sufficiently narrow and targeted to prove the point.

Iron: an underrated factor in aging

All life forms require the element iron as a constituent of their biochemical systems, iron being used in producing ATP in mitochondria, in cytochromes and hemoglobin, and in many other uses. Iron is essential for organismal growth and maintenance, so all life, from bacteria and algae to mammals, have developed the means to collect and store iron from their environments; this centrality of iron for all life suggests that iron may be involved in aging. Most organisms, including humans, have no systematic means of ridding themselves of excess iron. Whether this lack of ways to dispose of excess iron came about due to a relative scarcity of iron, or because the detrimental results from excess iron were relatively rare in an environment in which few organisms died from natural aging, is a question that remains to be answered. Whatever the answer to that may be, most organisms accumulate iron as they age.

A problem that organisms face in the use of iron in biological systems is protecting cells from iron damage. The very property of iron that makes it useful, its ability to accept or donate electrons, also gives it the ability to damage molecules and organelles via the Fenton reaction, in which iron reacts with hydrogen peroxide, leading to the formation of the highly reactive and toxic free radical, hydroxyl.

Most iron in cells is bound to proteins and other molecules that safely store it and prevent it from interacting with other macromolecules. In mammals, ferritin and transferrin are such proteins; hemoglobin is, however, the quantitatively most important iron depot in mammals. In theory, these storage proteins should be enough to protect organelles and macromolecules from iron's reactivity, but in practice another process becomes perhaps more important, and that is iron dysregulation. Storage proteins such as ferritin can themselves be damaged, leading to "leakage" of free iron, which can then react with and damage cellular structures, which in turn can lead to organ damage and the deterioration associated with aging. Whether this damage associated with aging is in fact a cause or consequence of aging of course remains to be determined, but as we shall see, there are several other reasons to think that iron is a driver of aging.

The practice of calorie restriction, eating fewer calories while still obtaining sufficient micronutrients, is well demonstrated to reduce cancer risk in animal models, and also appears to improve outcomes in the case of an established cancer. This is similarly the case for practices such as intermittent fasting or fasting mimicking diets, the latter having undergone trials as an adjuvant therapy in human cancer patients. Researchers here review this topic through the lens of nutrient sensing and growth signaling in the body, such as the well studied pathways involving growth hormone and IGF-1. More growth means more DNA damage, and thus a greater risk of developing cancer. Greater growth signaling also aids an established cancer in all of the obvious ways.

Many dietary patterns, including the Western diet, are associated with reduced lifespan and health span and appear to affect cancer incidence by two major hormonal axes/pathways: (1) the growth hormone-IGF-1; (2) the insulin signaling. Higher protein intake increases the release of growth hormone releasing hormone, and consequently growth hormone release from the pituitary gland and IGF-1 release primarily from the liver. High IGF-1 has been associated with elevated incidence of a number of cancers.

Studies in simple organisms and mice, demonstrate the link between nutrients and particularly protein intake, growth factors, DNA damage, and cancer. The effect of growth factors on DNA damage and cancer is mediated, at least in part, by oxidative stress and damage, but in part also by the inhibition of apoptosis. The reduced activity of growth factors and the lowering of oxidation and DNA damage not only decreases cancer but also extends longevity, since aging is the most important factor promoting cancer. Calorie restriction (CR) is a powerful anti-aging intervention, but it also forces the organism into an extremely low nourishment state, which may not constitute malnourishment in the short-term but which may do so long-term.

Interventions such as intermittent fasting (IF) and periodic fasting (PF) are emerging as alternatives to CR, with some of them being able to minimize side effects and burden while maximizing efficacy. Studies on PF have also pointed to 2 key processes absent or low in CR and IF: (a) a pronounced breakdown process both at the intracellular (autophagy etc) and cellular (apoptosis) levels requiring 2 or more days and associated with a high ketogenic state, (b) a rebuilding/regeneration process involving stem cells and progenitor cells in multiple system and associated with the return from PF to normal feeding (re-feeding).

The fasting mimicking diet (FMD) developed and studied by our laboratories is emerging as a viable and effective intervention in the longevity and cancer prevention fields, since it does not require chronic treatment, it does not cause malnourishment or loss of muscle mass and may be effective when performed only a few times a year for 5 days. In the future years it will be important to continue to test different nutritional interventions with the potential to extend the health span and prevent cancer, with a focus on those that are safe and feasible for long-term use in humans.

Link: https://doi.org/10.3390/cancers13184587

An enormous amount of data can be derived from analysis of the cells and molecules found in a blood sample. Researchers will be kept busy for decades yet, ever more fficiently gathering and mining this data, in search of ways to assess the progression of aging and specific age-related diseases. The work here is interesting for finding a correlation between the abundance of a small number of microRNA molecules and age-related cognitive decline. Many microRNAs are promiscuously involved in the regulation of important cellular pathways, altering the expression levels of proteins that are themselves important the regulation of cell activities. Evolution finds new uses for existing molecules, and the microRNA layer of gene expression is a good example of this principle.

The establishment of effective therapies for age-associated neurodegenerative diseases such as Alzheimer's disease (AD) is still challenging because pathology accumulates long before there are any clinical signs of disease. Thus, patients are often only diagnosed at an already advanced state of molecular pathology, when causative therapies fail. Therefore, there is an urgent need for molecular biomarkers that are (i) minimally invasive, (ii) can inform about individual disease risk, and (iii) ideally indicate the presence of multiple pathologies. Such biomarkers should eventually be applicable in the context of routine screening approaches with the aim to detect individuals at risk for developing AD that could then be subjected to further diagnostics via more invasive and time-consuming examinations.

We use a novel experimental approach combining the analysis of young and healthy humans with already diagnosed patients as well as animal and cellular disease models to eventually identify a 3-microRNA signature (miR-181a-5p, miR-146a-5p, and miR-148a-3p) that can inform about the risk of cognitive decline when measured in blood. The 3-microRNA signature also informs about relevant patho-mechanisms in the brain, and targeting this signature via RNA therapeutics can ameliorate AD disease phenotypes in animal models.

We suggest that the analysis of this microRNA signature could be used as point-of-care screening approach to detect individuals at risk for developing AD that can then undergo further diagnostics to allow for early and effective intervention. In addition, our data highlight the potential of stratified RNA therapies to treat Alzheimer's disease.

Link: https://doi.org/10.15252/emmm.202013659

The thymus is vital to a sustained and functional immune system. Thymocytes generated in the bone marrow migrate to the thymus, where a complex process of maturation and selection takes place, turning the thymocytes into T cells of the adaptive immune system. T cells must be capable of recognizing and reacting to pathogens and cancerous cells, without mistakenly attacking any of the normal systems of the body and its diverse cell population. That risk of self-immunity is the price of an adaptive immune system. The wide range of autoimmune conditions observed in the human population demonstrates that evolution does not produce infallible mechanisms.

The thymus atrophies with age, the active tissue replaced with fat. This reduces the supply of T cells, and in the absence of reinforcements the adaptive immune system relies increasingly on replication of peripheral immune cells to maintain its population. This leads to an aged immune system consisting of ever more harmful, senescent, exhausted, or otherwise problematic T cells. It is a sizable contribution to the age-related decline of immune function into chronic inflammation and incapacity.

There are many possible approaches to regeneration of the thymus, all of which have their issues. The thymus is a small, deep organ, which makes it hard to deliver therapies in a high enough dose without direct injection, and direct injection of that nature is probably too risky for widespread use. Mortality rates for similar procedures are around 0.1 to 0.2%. Several genes (e.g. FOXN1), recombinant proteins (e.g. growth hormone, KGF), and inhibitors (of androgens) would probably work very well to regrow the human thymus if the therapy could be delivered only to the thymus. Of these, only growth hormone can be used systemically at a reasonable cost-benefit calculation, as in the Intervene Immune protocol, but even then growth hormone isn't a treatment to be taken lightly.

Cell therapies and implantation of tissue engineered thymus organoids are presently the only obvious ways to work around the delivery issues. Several types of cell naturally home to the thymus, and researchers have demonstrated thymic regrowth in mice via delivery of such cells. It is plausible to consider the manufacture of universal cell lines that can be cost-effectively used in any patient; work on universal cells has yet to reach clinical approval, but it is quite advanced, undertaken by a number of large companies in the biotech industry. On the tissue engineering side of the fence, the company Lygenesis is built on research showing that thymus organoids can be implanted into lymph nodes, where they function in the same way a a normal thymus does. Building such organoids is presently an expensive process requiring donor tissue, however, and surgery, even minor surgery, is never cheap.

Several research groups are in search of a small molecule approach to spurring thymic regrowth, and have been for some years now. Small molecules have a different set of issues in comparison to the potential therapies noted above, in that what is known of the regulatory systems governing thymic growth does not yet present good, distinct targets. The thymus is an epithelial tissue, like the lining of the throat and intestines. As work on KGF demonstrates, there are unpleasant side-effects that attend the systemic delivery of signals to tell all epithelial tissue to grow. The path to a small molecule drug for thymus growth, if such a thing can be made, is to first search for a layer of regulation that is unique to the thymus. That is the goal of the research group responsible for today's materials.

New study identifies molecular players in 'dead man's switch' that triggers key immune organ's regeneration after damage

Prior to the current study, researchers had sketched the rough outlines of the thymus' renewal processes. This included identifying molecules that orchestrated two separate regenerative pathways (one triggered by a molecule called IL-22, and another by Bmp-4), and showing that it is the damage itself that triggers the thymus to renew. They'd also discovered that damage to the thymus sparks its regeneration by temporarily destroying a normal thymic developmental process.

T cells developing in the thymus undergo a rigorous "education" process that ensures that we aren't stuck with a lot of mature T cells that either can't recognize any signs of disease, or are primed to attack our healthy tissue instead of infected cells. Most T cells don't make the cut and get weeded out, dying by the thousands. Prior work suggested that dead and dying T cells acted as a brake on regeneration. When damage to the thymus wipes out T cells - surviving and dying alike - this brake is removed, and renewal mechanisms roar in to fill the void. Though researchers knew that dying T cells somehow acted as a brake to keep IL-22 and Bmp-4 - and thymic regeneration - suppressed, they didn't know how. Outlining the molecules that made up this sensor and suppressor system would reveal potential targets they could manipulate to promote regeneration.

The cells that help the thymus refill itself with T cells aren't T cells themselves, but accessory cells that support young T cells as they clear - or miss - their developmental hurdles. Researchers found that it's these accessory cells that sense dying T cells. They then outlined the molecular relays that lead from thymic damage to Bmp-4 and IL-22 (which activate thymus regeneration), identifying several key molecules along the way. Then, the researchers tested whether they could intervene. Researchers assessed whether blocking one of the players, called Rac1, (thereby boosting IL-22 and Bmp-4) helps improve thymic function after damage. They treated mice with an experimental Rac1 inhibitor after exposing them to radiation (similar to the thymus-blasting regimen that patients receive before bone marrow transplant). Mice treated with the Rac1 inhibitor produced more T cells than either untreated mice or treated mice that lacked a molecule in the T cell-death sensing pathway.

Perhaps the biggest hurdle right now is the lack of a Rac1 inhibitor available for clinical use. But researchers are hopeful; molecules related to Rac1, collectively called Rho GTPases, have been implicated in many diseases, and are an active area of investigation by pharmaceutical companies. "To move it forward, it's really going to require a drug itself. And that's where we're at, at the moment, trying to develop compounds that could be used clinically."

Senolytic treatments are those that selectively destroy senescent cells, a form of intervention that has produced rejuvenation in older animals. A high dose of the flavonol fisetin is not yet proven to be usefully senolytic in humans, but has shown a surprising degree of efficacy in mice. The only senolytic therapy demonstrated to clear senescent cells in old humans is the dasatinib and quercetin combination. Quercetin itself, though similar to fisetin, does not appear to be usefully senolytic on its own. The paper here notes a clinical trial of fisetin for older COVID-19 patients. It is thought that the larger number of senescent cells present in older individuals contribute meaningfully to a greater susceptibility to the severe inflammatory events that are the cause of death in COVID-19. This is one of a number of trials of fisetin as a senolytic; we might hope that at least one of these studies reports on whether or not senescent cell burden is actually reduced in these patients, as was done in one of the dasatinib and quercetin trials.

The burden of senescent cells (SnCs), which do not divide but are metabolically active and resistant to death by apoptosis, is increased in older adults and those with chronic diseases. These individuals are also at the greatest risk for morbidity and mortality from SARS-CoV-2 infection. SARS-CoV-2 complications include cytokine storm and multiorgan failure mediated by the same factors as often produced by SnCs through their senescence-associated secretory phenotype (SASP). The SASP can be amplified by infection-related pathogen-associated molecular profile factors.

Senolytic agents, such as Fisetin, selectively eliminate SnCs and delay, prevent, or alleviate multiple disorders in aged experimental animals and animal models of human chronic diseases, including obesity, diabetes, and respiratory diseases. Senolytics are now in clinical trials for multiple conditions linked to SnCs, including frailty; obesity/diabetes; osteoporosis; and cardiovascular, kidney, and lung diseases, which are also risk factors for SARS-CoV-2 morbidity and mortality.

A clinical trial is underway to test if senolytics decrease SARS-CoV-2 progression and morbidity in hospitalized older adults. We describe here a National Institutes of Health-funded, multicenter, placebo-controlled clinical trial of Fisetin for older adult skilled nursing facility residents who have been, or become, SARS-CoV-2 rtPCR-positive, including the rationale for targeting fundamental aging mechanisms in such patients.

Link: https://doi.org/10.1111/jgs.17416

Senescent cell accumulation is a feature of aging, a growing imbalance between the rate of creation and rate of destruction. Senescent cells perform a number of useful tasks in the short-term, but when present for the long-term, their inflammatory secretions disrupt tissue function and contribute meaningfully to the onset and progression of age-related disease. A great many research groups are working towards the basis for therapies that can selectively destroy senescent cells (senolytics). Others are working on ways to prevent cells from becoming senescent, or suppress the worst of the bad behavior of existing senescent cells (senomorphics). The open access paper here is a representative example of the latter development process.

The senescence-associated secretory phenotype (SASP) is a striking characteristic of senescence. Accumulation of SASP factors causes a pro-inflammatory response linked to chronic disease. Suppressing senescence and SASP represents a strategy to prevent or control senescence-associated diseases. Here, we identified a small molecule SR9009, a specific agonist of NR1D1/NR1D2, as a potent SASP suppressor in therapy-induced senescence (TIS) and oncogene-induced senescence (OIS). The mechanism studies revealed that SR9009 inhibits the SASP and full DNA damage response (DDR) activation through the activation of the NRF2 pathway, thereby decreasing the ROS level by regulating the expression of antioxidant enzymes.

We further identified that SR9009 effectively prevents cellular senescence and suppresses the SASP in the livers of both radiation-induced and oncogene-induced senescence mouse models, leading to alleviation of immune cell infiltration. Taken together, our findings suggested that SR9009 prevents cellular senescence via the NRF2 pathway in vitro and in vivo, and activation of NRF2 may be a novel therapeutic strategy for preventing cellular senescence.

Link: https://doi.org/10.1111/acel.13483

Senolytic therapies selectively destroy senescent cells, an important cause of inflammation and tissue dysfunction in older individuals. Removal of senescent cells via pharmacological means produces impressive demonstrations of rejuvenation in old mice, reversing the progression of many different age-related conditions. An intermittent or one-time high dose of fisetin has been tested as a senolytic in mice, and showed surprisingly good results. Why surprising? Because the similar compound quercetin does not appear to be meaningfully senolytic on its own. Quercetin improves the ability of the senolytic dasatinib to kill senescent cells; the combination of dasatinib and quercetin was the first pharmacological approach to senolytics tested in mice. The surprise is that fisetin on its own does just as well as dasatinib and quercetin at destroying senescent cells in mice, if the one study showing that outcome is to be taken at face value.

Fisetin is not a widely used supplement, relatively speaking, but it has been used for a good number of years, at doses 30-fold lower than the senolytic dose. What are the odds that an ability to produce sizable gains in human health in late life via an existing supplement was overlooked because a much higher dose was needed? We can debate the possible answers to that question, but it is better to wait for the results of an ongoing clinical trial of fisetin at these higher doses. One might also take a look at the Forever Healthy Foundation report that summarizes what is known of fisetin as a senolytic.

The supplement industry, of course, never waits on clinical trials. It is also an industry well practiced in the matter of lying by omission, distorting scientific findings, and selling hope and fraud rather than factual data. As might be expected given that history, one can presently find any number of groups selling "senolytic" supplements bearing small amounts of fisetin. Similarly for quercetin.

I'm going to point out Elysium Health as a particularly egregious example of this sort of thing, as it was founded by noted scientists in the aging research field, and continues to be associated with the Mayo Clinic, an institution presently carrying out clinical trials of senolytic therapies. If one looks at the latest marketing effort from Elysium that capitalizes on the efforts of researchers, in order to extract money from the credulous and the hopeful, you will find that they do not even say how much fisetin is included in their new product. They tout its link to clinical trials while deliberately obscuring the information needed to validate that the protocol offered is the same. Everyone involved in Elysium Health and its relationship with the research community should be ashamed of themselves.

This is a pointed example of the way in which the supplement industry is corrosive of integrity. I am all in favor of more of the safe senolytics being made more accessible to more people, with guidance on how to follow existing clinical trial programs. Even in advance of confirming human data, if a part of the supplement rollout is to produce equivalent data from a population of supplement users. The formal trial process is too slow, and good data can be obtained at less cost and more rapidly via other means. But there is a right way and a wrong way to go about this, and supplement industry companies near always choose the wrong way. This latest Elysium product adds little, and obscures much.

Elysium Health Announces the Launch of FORMAT Advanced Immune Support

Elysium Health, a leading life sciences company developing clinically validated health products based on advancements in aging research, today announced the launch of FORMAT, the first and only immune product to uniquely pair a daily immunomodulatory supplement with an intermittent senolytic complex to combat the effects of immune aging and provide complete immune support. The Senolytic Complex contains a powerful blend of quercetin and fisetin to help the body manage senescent cells, which supports healthy immune function and combats immunosenescence.

Format

We now have access to substances called senolytics that, when administered on an intermittent basis, help to clear these problematic cells, supporting healthy immune function and helping the body respond to immunosenescence. Format incorporates micronutrients - necessary for baseline immune function - and pairs them with powerful senolytic compounds to keep your immune system functioning optimally. The formulation of Format's Senolytic Complex is based on research led by James Kirkland, M.D., Ph.D., Elysium Scientific Advisory Board member and director of the Robert and Arlene Kogod Center on Aging at Mayo Clinic. This research has shown that senolytics are effective when administered intermittently.

I recently noted the Astera Institute's Rejuvenome project. The work will be conducted in collaboration with the Buck Institute. It is a sizable proposal, to conduct large and rigorous mouse studies with the ultimate goal of testing combined interventions, a necessary activity that the research community and industry alike largely fail to carry out. This is a big problem in the field of aging, as aging is the outcome of a range of distinct processes of damage accumulation. Sizable degrees of rejuvenation or slowing of aging can in the long run only emerge from combinations of approaches, repairing or working around multiple forms of damage. Given this large gap in research and development, one that will never be filled by existing institutions, philanthropic efforts must step in to fill the gap.

Research on aging is at a critical inflection point, with breakthroughs in basic science and multiple compounds being tested in clinical trials. While the field is starting to have tools and treatments that target the biology of aging and improve health, a deep and fundamental understanding of how they work, and the models used to validate such findings, is still lacking. Further, because of vision, funding constraints, infrastructure limitations and other impediments, smaller projects are conducted independently of each other and there is little to no research into combination therapies, even though this will likely be the only avenue to achieving meaningful results.

"The Rejuvenome Project was launched to target these bottlenecks. We hope to do that by characterizing treatments and regimens, both established and newly invented, for which we have reason to believe improve health and longevity. The breadth and depth of this project centered around an unprecedentedly extensive and deep whole-body functional and multi-omic assay panel has the potential to redefine scientific understanding of how to best intervene in the aging process."

The Rejuvenome Project is expected to take approximately seven years to complete. All wet lab operations will be centered at the Buck while the dry lab computational aspects of the project will reside at the Astera Institute in Berkeley. "The Rejuvenome is the quintessential moonshot project in longevity. If we are successful it will provide the most complete picture ever of how best to intervene in aging and will produce powerful new avenues for drug development."

Link: https://www.buckinstitute.org/news/astera-institute-and-buck-institute-announce-70-million-collaboration-to-redefine-the-field-of-research-on-aging/

Regeneration might be thought of as a complex and highly coordinated interaction between stem cells, somatic cells, and senescent cells. Some small fraction of cells in the injured tissue become senescent, cease replication, and secrete pro-growth, pro-inflammatory factors. They are then removed by the immune system once their task is done, to prevent long-term disruption of tissue function by those same secretions. The problem of senescent cells in aging is entirely that this signaling for growth and inflammation, beneficial in the short term, becomes very harmful and disruptive to normal tissue function when present for the long term.

It was thought that senescent cells assist in wound healing throughout the body, based on evidence gathered largely from skin injuries. Here, however, researchers present evidence to show that senescent cells actually hinder fracture healing, and thus senolytic therapies to selectively destroy senescent cells may be beneficially applied to this sort of injury. This suggests that senescent cells may actively impede regeneration in other tissues as well.

Senescent cells have detrimental effects across tissues with aging but may have beneficial effects on tissue repair, specifically on skin wound healing. However, the potential role of senescent cells in fracture healing has not been defined. Here, we performed an in silico analysis of public mRNAseq data and found that senescence and senescence-associated secretory phenotype (SASP) markers increased during fracture healing. We next directly established that the expression of senescence biomarkers increased markedly during murine fracture healing. We also identified cells in the fracture callus that displayed hallmarks of senescence, including distension of satellite heterochromatin and telomeric DNA damage; the specific identity of these cells, however, requires further characterization.

Then, using a genetic mouse model containing a Cdkn2aInk4a-driven luciferase reporter, we demonstrated transient in vivo senescent cell accumulation during callus formation. Finally, we intermittently treated young adult mice following fracture with drugs that selectively eliminate senescent cells ('senolytics', Dasatinib plus Quercetin), and showed that this regimen both decreased senescence and SASP markers in the fracture callus and significantly accelerated the time course of fracture healing. Our findings thus demonstrate that senescent cells accumulate transiently in the murine fracture callus and, in contrast to the skin, their clearance does not impair but rather improves fracture healing.

Link: https://doi.org/10.7554/eLife.69958

Given a suitable delivery system, one that localizes to the desired target tissues to a far greater degree than to all other undesirable off-target tissues, the big advantage of a gene therapy is it precisely achieves the manipulation desired. It dials up or dials down expression for selected genes, alters the amount of proteins produced from those genes, and thereby changes cell behavior as a consequence - and that is all it does. One doesn't have the endless concern about off-target effects that characterize small molecule drug development.

There are, of course, different challenges. Setting aside some adventurous technologies that won't be deployed in therapies any time soon, manipulating a few genes at a time is the present practical upper limit on gene therapy. Further, there is no viable delivery system for most target tissues in the body, if the goal is to maximize expression in a limited set of locations. Yes, a great many interesting technologies exist for use in animal studies, but the bounds of the possible are more limited when it comes to what is permitted in the clinic. Injecting a gene therapy vector into the bloodstream means that most of it will end up in the liver, lungs, and heart, and very little in lesser, smaller organs. Injecting a vector directly into tissue is prohibitively risky for most internal organs except in cases of very serious disease.

Another pressing issue is that there is no proven gene therapy vector that can produce months of expression. Too long an expression is as much of a problem as too short an expression when it comes to treating disease. The only options on the table are (a) permanent changes via integration into the genome, (b) non-integrating viral vectors such as AAV that produce expression that can last for years, (c) very short term expression changes via RNA therapies that might last a few days. In principle, plasmid delivery can produce expression that lasts for months, but no-one has yet robustly solved the very poor expression characteristics of plasmids once delivered into a cell. They just don't want to localize to the nucleus where they need to be in order to express.

Yet another problem: viral vectors are the most effective, but a given vector can be used once in a given individual. Thereafter the immune system will clear further doses before they can take effect. For some of the older vectors, a fraction of the population is already reactive to some variants, and must be screened out. In general, the immune system is the dose-limiting concern for most gene therapies. If it takes too much notice of a therapeutic, serious side-effects can result due to an inflammatory response. There are groups working towards ways to cloak vectors, but none are yet clinically approved, robust, and ready to be used for arbitrary therapies.

In summary, most of the challenges inherent in developing gene therapies revolve around delivery. The other hurdles are much less of a problem, and there are many groups working on solutions at various stages of development. What the industry is waiting for is a good delivery system that overcomes the issues noted above. That would enable a sudden blossoming of gene therapies.

A last point to made about gene therapies is that yes, they are the future of medicine when it comes to manipulating cellular pathways, in principle much more precise and capable than small molecules. Bigger effects are possible, with fewer side-effects. But if gene therapies are only used to adjust the operation of an aged metabolism, forcing a restoration of the expression of important regulatory and signaling genes to youthful levels, without addressing the underlying causes of those age-related changes in gene expression, then they are still only a compensatory therapy. The same limits apply here as for small molecule compensatory therapies: change one consequence of damage, and all the other consequences are still there. In a complex, interacting system, the benefits of such a strategy are necessarily limited.

Gene therapies and small molecule therapies can be rejuvenation therapies, repairing damage. They can be used to target deeper causes of aging. Senolytics, for example, are largely small molecule drugs that achieve the goal of selectively destroying senescent cells. The important thing is not the methodology but the goal, removal of a form of damage that is as close to the root causes of aging as possible, with many downstream consequences alleviated as a result. As today's short article notes, that is not what Rejuvenate Bio is doing. They are producing compensatory gene therapies, aiming at targets that allow a clear demonstration of superiority over small molecule strategies. But the upside remains limited by the underlying damage of aging, still there, still causing all of the other harms it is capable of.

Rejuvenate Bio is Reversing Age-Related Diseases to Increase Healthspan

"Today we think about aging as a dysregulation of genes and proteins that lead to age-related diseases, such as heart disease, obesity, diabetes, etc. When we talk about reversing aging - or, more accurately, the disease states associated with aging - we're talking about reregulating genes back to the healthy state people had when they were younger." Unlike most companies addressing the diseases associated with aging, Rejuvenate Bio tackles multiple cardiac, metabolic, and renal issues at once. "Based on the data we've seen from mice and dogs, we can reverse obesity, diabetes and heart disease."

Rejuvenate Bio has two therapies in its pipeline, RJB-01 and RJB-02, targeting the cardiac, metabolic and renal space. Both are delivered via adeno-associated viruses (AAV). The company expects RJB-01 to enter the clinic for humans in 2023, and also to be commercialized for animals that same year. RJB-01 targets overexpression of FGF21 and downregulation of TGFß1 via expression of sTGFßR2. Rejuvenate is developing it for heart failure. Research conducted by other companies shows that targeting these genes is also effective and safe for weight loss, diabetes, and tumor inhibition. The second therapy, RJB-02, is designed to treat osteoarthritis. It targets two genes - downregulation of TGFß1 via expression of sTGFßR2, and overexpression of αKlotho. The latter is associated with improving cognitive performance as well as protecting the heart and kidneys, and increasing insulin sensitivity.

Notably, the researchers combined two therapies into one to treat four age-related conditions. The results in mice showed "a 58% increase in heart function in ascending aortic constriction ensuing heart failure, a 38% reduction in α-smooth muscle actin (αSMA) expression, and a 75% reduction in renal medullary atrophy in mice subjected to unilateral ureteral obstruction, as well as a complete reversal of obesity and diabetes phenotypes in mice fed a constant high-fat diet. What's particularly exciting is that in mice, we showed we could halt progression of heart disease in its tracks despite the surgical tightening of the aorta." Similar results were seen in dogs, too.

The relationship between lithium intake and health is a topic of minor interest, in that no-one is going to be building a rejuvenation therapy on the basis of the mechanisms by which lithium may very modestly slow aging in short-lived species. There is some evidence for greater human life expectancy to occur in areas in which there is more lithium in the water supply, but this sort of geographical epidemiology is fraught with confounding factors relating to wealth, preferences, culture, and migration. As researchers note here, lithium has both a narrow therapeutic window and only small effects on healthspan in mice.

The anti-depressant and mood stabilizing effects of lithium were discovered the mid 20th century, and administration of lithium salts is still the first-line therapy for bipolar disorders. Lithium can also ameliorate pathology in animal models of neurodegeneration, through multiple molecular mechanisms, and has been proposed as a therapy for Alzheimer's disease. Suggesting that it may have a broader therapeutic range, lithium can also extend lifespan in fission yeast, C. elegans, and Drosophila, in the last by inhibition of GSK-3 and activation of the transcription factor NRF2. Human survival across 18 Japanese municipalities correlated with increased lithium level in drinking water. These findings suggest that conserved molecular responses to lithium treatment could improve health during ageing in mammals. In this study, we therefore analysed the influence of lithium treatment on lifespan and parameters of health during ageing in mice.

To determine the concentration of lithium suitable to be administered in a longitudinal ageing study, we first tested the effects of lithium chloride (LiCl) in doses from 0.01 to 2.79 g LiCl per kg chow. C57Bl/6J mice fed with 1.05-2.79 g/kg LiCL in the diet showed lithium plasma levels between 0.4 and 0.8 mM/l. While plasma levels to 0.4 and 0.8 mM/l are well tolerated by human patients, at doses above 1.44 g LiCl/kg, we observed an obvious dose-dependent polydipsia combined with a distinct polyuria, pointing towards a significant degree of kidney toxicity.

We therefore carried out life-long lithium treatment in the range from 0.02 to 1.05 g/kg diet. Administration to both sexes at doses of 0.02 and 0.05 g/kg starting at 3 months or 18 months of age did not affect lifespan. In an additional group, treatment of females with 0.1 g/kg starting at 19 months of age also had no significant effect. Treatment of male and female mice from an age of 3 months with 0.02 and 0.05 g/kg LiCl, and then switching late in life at 22 months to 0.5 and 1.05 g/kg, respectively, had no effect on male survival and reduced maximum lifespan of females (survival of last 20% of animals to die).

We assessed the effects of lithium on other age-related phenotypes of the mice. Decreased fat mass despite unaffected food consumption indicates an effect of lithium on lipid metabolism. Mice on the low doses of 0.02 and 0.05 g/kg LiCl administered from 3 months of age showed delayed age-related loss of glucose tolerance. In addition, male mice that were switched to 0.5 and 1.05 g/kg at 22 months, after being treated with 0.02 and 0.05 g/kg from an age of 18 months, respectively, showed significantly increased tolerance to glucose at ages over 26 months. Neither treatment improved glucose tolerance in females.

There was a dose-dependent increase in motor function on the rotarod in old males under LiCl treatment, possibly related to their lower body weight. Additionally, in 24-month-old Li2CO3-treated mice, both motor function on the rotarod and endurance on the treadmill were significantly increased in males, with no effect in females. Histopathological analysis of 2-year-old, Li2CO3-treated, C3B6F1 mice showed reduced age-related pathologies in the kidneys, with significantly decreased kidney inflammation (leukocyte infiltration) in both sexes, which in males coincided strongly with a reduction of glomerulopathy.

Considering the use of a broad range of well-tolerated lithium concentrations, different lithium salts and different mouse strains, we conclude that, in contrast to the findings in yeast, worms, and flies, lithium does not seem to be a promising candidate for geroprotection in humans. Although it caused mild improvements in body weight and composition, glucose tolerance and motor performance, these were largely confined to males and were not accompanied in either sex by increased lifespan.

Link: https://doi.org/10.1111/acel.13479

Engineered T cells are the dominant form of cell therapy for cancer at the present time, an approach that has achieved considerable success, and remains actively under further development. T cells can attack cancer cells directly, given the right tools to recognize those cells and overcome the various immunosuppressive mechanisms deployed by cancerous tissue. There are other approaches to rousing the immune system to action, however, such as focusing on B cells. B cells carry out a variety of roles that are important in the coordination of the immune response, in providing targets for other cells to attack, and rousing those cells to action. Thus it should be possible to engineer B cells to be much more effective in the context of cancer, improving the overall immune response.

Nowadays, cancers still represent a significant health burden, accounting for around 10 million deaths per year, due to ageing populations and inefficient treatments for some refractory cancers. Immunotherapy strategies that modulate the patient's immune system have emerged as good treatment options. Among them, the adoptive transfer of B cells selected ex vivo showed promising results, with a reduction in tumor growth in several cancer mouse models, often associated with antitumoral immune responses. Aside from the benefits of their intrinsic properties, including antigen presentation, antibody secretion, homing, and long-term persistence, B cells can be modified prior to reinfusion to increase their therapeutic role.

For instance, B cells have been modified mainly to boost their immuno-stimulatory activation potential by forcing the expression of costimulatory ligands using defined culture conditions or gene insertion. Moreover, tumor-specific antigen presentation by infused B cells has been increased by ex vivo antigen loading (peptides, RNA, DNA, virus) or by the sorting/ engineering of B cells with a B cell receptor specific to tumor antigens. Editing of the B cell receptor also rewires B cell specificity toward tumor antigens, and may trigger, upon antigen recognition, the secretion of antitumor antibodies by differentiated plasma cells that can then be recognized by other immune components or cells involved in tumor clearance by antibody-dependent cell cytotoxicity or complement-dependent cytotoxicity for example.

With the expansion of gene editing methodologies, new strategies to reprogram immune cells with whole synthetic circuits are being explored: modified B cells can sense disease-specific biomarkers and, in response, trigger the expression of therapeutic molecules, such as molecules that counteract the tumoral immunosuppressive microenvironment. Such strategies remain in their infancy for implementation in B cells, but are likely to expand in the coming years.

Link: https://doi.org/10.3390/ijms22189991

Mitochondria are the power plants of the cell, generating the chemical energy store molecule adenosine triphosphate (ATP). Throughout the body, mitochondrial function declines with age, leading to corresponding declines in tissue and organ function. This universal malaise appears to be a downstream consequence of the underlying causes of aging. Those causes in some way lead to changes in gene expression that alter mitochondrial dynamics in ways that reduce the efficacy of the quality control mechanism of mitophagy. When not regularly destroyed, worn and dysfunctional mitochondria accumulate, and ATP production suffers.

It is possible to achieve benefits by introducing replacement mitochondria? Won't they just succumb to the same problem due to the aged environment? Eventually, yes, most likely. But studies to date suggest that the benefits of mitochondrial transplantation can large enough and long-lasting enough to be worth pursuing, even if the benefits fade over time.

Cells will readily take up whole mitochondria from their environment, and thus the immediate hurdles are largely a matter of logistics: being able to reliably generate and characterize mitochondria in the vast numbers needed to make a difference to cell function throughout the body. Once that is possible, then a range of further questions can be explored: duration, safety, long-term effects, whether transplanted mitochondrial DNA must match the recipient, or whether it can be improved upon, and so forth. A number of biotech companies, such as cellVie and Mitrix, are working to develop mitochondrial transplantation as a basis for therapies, so the next few years will be an interesting time in this part of the field.

Mitochondrial Dysfunction in Diseases, Longevity, and Treatment Resistance: Tuning Mitochondria Function as a Therapeutic Strategy

It has been shown that mitochondria can be transferred both artificially and under normal physiological state. We can transfer mitochondria as a "cybrid" or treated isolated mitochondria directly into the cells or tissues. We can also transfer mitochondria by co-culture cells as a normal physiological state. Mitochondria transfer from one cell to another cell occurs especially when the mitochondria are injured. Therefore, the mitochondrial transplantation from healthy cells to abnormal cells is thought to be a novel and attractive therapeutic concept. It has been reported that mitochondria and/or organelles transfer between cells through tunneling nanotubes.

Replacement of damaged mitochondria with healthy mitochondria has been developed in order to overcome mitochondrial diseases and mitochondria dysfunctions. It has been shown that mitochondrial transplantation (mtTP) rescues ischemia reperfusion-induced damage and protects the brain from apoptosis. Current clinical and preclinical studies utilizing mtTP have been conducted or are in progress for the treatment of heart ischemia, brain ischemia, sepsis, cancer, acute kidney injury, and theoretically for any disorders in which mitochondria are damaged and disrupted.

We have demonstrated that mitochondria from a non-cancer cell line can be transplanted into cancer cell lines that lack mtDNA (ρ0 cells). This mitochondrial transplantation has been checked using MitoTracker, which can stain mitochondria, and confirmed that the healthy stained mitochondria from fibroblast cells have certainly transplanted into ρ0 cells. Recently, in a clinical trial, it has been shown that mtTP leads to cardio protection. It has been reported that mtTP ρ0 cells have decreased intracellular Fe2+ levels and downregulation of aquaporins. Since aquaporins regulate H2O2 permeability, these cells exhibit H2O2 resistance compared with the non-mtTP ρ0 cells. Thus, mtTP may enhance mitochondrial function that will allow for the rescue of cells and restoration of normal function.

Taken together, these results indicate that mtTP may be an upcoming effective therapeutic option. Therefore, mtTP is a very promising technique, which may be applicable for the treatment of many diseases including cancer. However, mtTP is only in the beginning stages of development, so further investigation will be needed to address various technical and ethical issues.

The hundreds of mitochondria present in every cell are critical to cell function. As the descendants of ancient symbiotic bacteria, mitochondria have their own remnant DNA, separate from the chromosomal genomic DNA present in the cell nucleus. Both sorts of DNA suffer similar forms of mutational damage and are attended by broadly similar repair mechanisms, but nuclear DNA is by far the better protected and maintained of the two. Some forms of mitochondrial DNA mutation, particularly the deletion of genes important to the electron transport chain, are thought to confer both dysfunction and competitive advantages to mitochondria, leading to a cell overtaken by broken mitochondria, exporting toxic reactive molecules into surrounding tissue. This may be important in aging, and in support of that proposition, researchers here find that longer lived mammalian species have a greater capacity for some forms of mitochondrial DNA repair.

Is the DNA repair of endogenous damage higher in long-lived animals? When base excision repair (BER) of genomic DNA was measured in four organs including heart and brain it was found not significantly changed or even decreased (instead of increased) in longer-lived caloric restricted mice. Moreover, comparative studies in brain and liver of 15 mammalian and avian species have shown that repair of genomic DNA endogenous oxidative damage by BER in nuclear fractions does not correlate with longevity or, more frequently, is lower (instead of higher) in tissues of long-lived mammals when compared to short-lived ones.

BER plays an important role in repairing oxidative damage to DNA, but these results might indicate that genomic (almost all nuclear) BER does not play a key role in longevity extension. The negative correlation of genomic DNA BER with longevity is analogous to what was previously found for the endogenous total cellular antioxidant enzymes CuZn SOD, catalase, glutathione peroxidase, and glutathione reductase, as well as reduced glutathione, which most generally negatively correlate, and in some cases do not significantly correlate with longevity in mammals and vertebrates.

The likely evolutionary explanation for this is that the mitochondrial ROS production rate (mitROSp) is also lower in long-lived than in short-lived animals. Since the mitochondria of long-lived animal species produce less H2O2 to the cytosol, they would also need less total cell endogenous antioxidants and less nuclear DNA repair systems. Endogenous total cell antioxidants and DNA repair enzymes are transitorily induced, when needed, to come back again to low levels when episodic increases in oxidative stress have been overcome. In this way, cells save much energy, which otherwise would be invested in the protein synthesis needed to continuously maintain high levels of cellular antioxidants and nuclear DNA repair enzymes when they are not needed at such high levels.

That is the situation concerning BER in nuclear DNA, but what occurs in the case of mitochondrial BER (mitBER)? MitBER had never been measured in species with different longevities, and we hypothesized that mitochondrial, instead of nuclear, BER is higher in long-lived than in short-lived mammals. We have thus recently measured activities and/or protein levels of various mitBER enzymes including DNA glycosylases, NTHL1 and NEIL2, and APE endonuclease in mitochondrial liver and heart fractions from eight mammalian species differing by 13-fold in longevity. Our results show, for the first time, a positive correlation between mitBER and mammalian longevity. This suggests that the low steady-state oxidative damage in mitDNA of long-lived species, not observed for nuclear DNA, can be due to the combination of a low rate of damage generation (low mitROSp) and a high level of mitDNA repair (by mitBER) in these slowly aging animals.

Link: https://doi.org/10.18632/aging.203595

Cancer patients who exercise tend to do better than those who do not. While one cannot escape an established cancer via physical activity, one can modestly slow it down, it appears. Researchers here explore some of the mechanisms by which exercise can achieve this goal, focusing on muscle tissue signaling that both slows cancer cell growth and provokes greater immune system activity. The usual path forward for this sort of research, given a large enough effect size to be interesting, is to try to find a way to deliver additional signal proteins as a form of treatment. This might be achieved directly using recombinant protein therapy, or via some form of small molecule drug that upregulates signal protein expression. In either case, that is a road of some years from present understanding to eventual therapy, and it isn't at all clear that the size of the effect justifies that effort.

Exercise causes muscles to secrete proteins called myokines. Researchers have learned these myokines can suppress tumour growth and even help actively fight cancerous cells. A clinical trial saw obese prostate cancer patients undergo regular exercise training for 12 weeks, giving blood samples before and after the exercise program. Researchers then took the samples and applied them directly onto living prostate cancer cells.

"The patients' levels of anti-cancer myokines increased in the three months. When we took their pre-exercise blood and their post-exercise blood and placed it over living prostate cancer cells, we saw a significant suppression of the growth of those cells from the post-training blood. That's quite substantial indicating chronic exercise creates a cancer suppressive environment in the body."

while myokines could signal cancer cells to grow slower - or stop completely - they were unable to kill the cells by themselves. However, myokines can team up with other cells in the blood to actively fight cancer. "Myokines in and of themselves don't signal the cells to die. But they do signal our immune cells - T-cells - to attack and kill the cancer cells."

Link: https://www.ecu.edu.au/newsroom/articles/research/cancer-breakthrough-exercise-may-stop-disease-in-its-tracks

Inflammation is a necessary part of the immune response to injury and infection, required in order to defend and rebuild. Normally, inflammation is a cycle of signaling that changes cell behaviors, response followed by resolution. When resolution fails, serious consequences can result. Conditions such as sepsis and severe COVID-19 cases are examples of a runaway inflammatory response leading to a high mortality. Both of these examples are age-related, in the sense that old people are far more susceptible to undergoing such a breakdown of the normal inflammatory feedback loops. The age-related dysfunction of the immune system predisposes it to overactivation and inflammation, just as it also makes the immune response less effective.

Senescent cells accumulate with age. These cells are constantly created and cleared in the body, and when present for only a short time play an important role in cancer suppression and wound healing. With age, however, the pace of creation accelerates and pace of clearance by the immune system slows. A constant presence of senescent cells allows their inflammatory, pro-growth senescence-associated secretory phenotype (SASP) to grow to pathological levels, encouraging a rising level of chronic inflammation throughout the body. It is hypothesized that this is an important cause of age-related susceptibility to runaway inflammation in response to circumstances that the regulatory mechanisms of young individual would successfully cope with.

Senescence-associated hyper-activation to inflammatory stimuli in vitro

Advancing age is associated with a multitude of physical and physiological deteriorations that leave the elderly susceptible to a wide variety of pathological conditions. Consequently, there is a steep decline in the health-related quality of life for the elderly. Amongst a wide variety of conditions, increased susceptibility to severe infections (such as COVID-19) and inflammatory conditions (such as sepsis) is one such age-related phenomenon. Despite representing under 25% of the population, people older than 60 account for more than 75% of sepsis related death. With respect to COVID-19, people over 60 are three times more likely to die from a severe infection than people under 60. The severity of disease progression in these population upon infection is partially attributed to the higher prevalence of severe cytokine storm in the elderly. Though there are many theories as to what makes the elderly susceptible to severe cytokine storm, there is no commonly accepted explanation to this phenomenon.

Cellular senescence is a phenomenon by virtue of which stressed or damaged cells undergo a permanent cell cycle arrest. In healthy individuals, senescent cells (SnCs) are cleared rapidly by the immune system. This clearance mechanism has been shown to become impaired with advancing age, leading to the accumulation of SnCs. In turn, the accumulation of SnCs has been implicated in many age-related pathologies and diseases. The detrimental effects of SnCs are partly a consequence of their expression of the senescence-associated secretory phenotype (SASP). The SASP includes an extensive list of factors such as inflammatory cytokines, chemokines, and matrix metalloproteases (MMPs), which are detrimental to the normal functioning of neighboring cells.

Hence, we hypothesized that SnCs contribute to the increased severity of infectious diseases and infection-mediated cytokine storm in the elderly through the expression of the SASP. To test this hypothesis, we examined whether SnCs exhibit hyper-activation to LPS, IL1β, and TNFα stimulation. Our results show that SnCs indeed have a greater proclivity to become hyper-activated in response to inflammatory insults, resulting in the increased production of a variety of inflammatory cytokines and chemokines when compared to their non-senescent counterparts, which we term senescence-associated hyper-activation. Senescence-associated hyper-activation may be attributable to a higher basal activation of the p38 mitogen activated protein kinase (p38) and NF-κB pathways. These findings lay a foundation to elucidate the important role of SnCs in the age-related increased susceptibility to severe infections and inflammatory conditions.

The increased blood pressure of hypertension causes structural damage to delicate tissues throughout the body, particularly in the brain. Beyond the matter of an increased pace of rupture of capillaries, killing tiny volumes of brain tissue, the blood-brain barrier is disrupted by pressure damage, allowing unwanted molecules and cells into the brain to provoke chronic inflammation and disruption of function. Blood pressure is so influential on health that lowering blood pressure via antihypertensive medication, an approach that does not in any way address the underlying causes of the problem, produces a reduction in mortality that is in the same ballpark as that resulting from exercise programs.

Individuals who are diagnosed with high blood pressure at ages 35-44 had smaller brain size and were more likely to develop dementia compared to people who had normal blood pressure, according to new research. Hypertension is very common in middle-aged people (45-64 years), and early onset high blood pressure is becoming more common. Although the association among hypertension, brain health, and dementia in later life has been well-established, it was unknown how age at onset of hypertension may affect this association. If this is proven, it would provide some important evidence to suggest earlier intervention to delay the onset of hypertension, which may, in turn, be beneficial in preventing dementia.

The researchers analyzed data from participants in the UK Biobank, a large database containing detailed anonymous health information of about half a million volunteer participants in the United Kingdom. To determine brain changes, they compared magnetic resonance imaging (MRI) measurements of brain volume between two large groups of adults in the database: 11,399 people with high blood pressure diagnosed at different ages (younger than age 35; 35-44 years; and 45-54 years), and 11,399 participants who did not have high blood pressure, matched for age and multiple health-related variables. Participants entered the databank between 2006 and 2010, and they had MRI brain scans between 2014 and 2019.

In each diagnostic age category (from 35 to 54), the total brain volume was smaller in people diagnosed with high blood pressure, and the brain volume of several regions were also smaller compared to the participants who did not have high blood pressure. Hypertension diagnosed before age 35 was associated with the largest reductions in brain volume compared with controls. Among people with normal blood pressure readings at the time of their MRI scans, those who were previously diagnosed with hypertension at ages younger than 35 years old had smaller total brain volume compared to people with normal blood pressure who had never been diagnosed with hypertension.

The risk of dementia from any cause was significantly higher (61%) in people diagnosed with high blood pressure between the ages of 35 and 44 compared to participants who did not have high blood pressure. The risk of vascular dementia (a common form of dementia resulting from impaired blood flow to parts of the brain, as might happen after one or more small strokes) was 45% higher in the adults diagnosed with hypertension between ages 45-54 and 69% higher in those diagnosed between ages 35-44, compared to participants of the same age without high blood pressure.

Link: https://newsroom.heart.org/news/earlier-onset-of-high-blood-pressure-affects-brain-structure-may-increase-dementia-risk

Naked mole-rats show little decline of function until late life, are highly resistant to cancer, and live nine times longer than similarly sized rodent species. An important aspect of immune system aging in mammals is the atrophy of the thymus. Thymocytes created in the bone marrow migrate to the thymus where they mature into T cells of the adaptive immune system. As active thymic tissue is replaced with fat, in the process of thymic involution, this supply of T cells declines. Absent reinforcements, the T cell population of the body becomes ever more damaged, malfunctioning, exhausted, and senescent. Researchers here show that not only do naked mole-rats have much delayed thymic involution, but they also exhibit the presence of multiple thymi.

Here, we provide the first characterization of the naked mole rat (NMR) thymus. We discovered that naked mole rats have an additional pair of cervical thymi. This is an unexpected finding as mammals, including humans and mice, as a rule, have only one bilateral thymus. Cervical thymi can occasionally be detected in mice, but their frequency is rare and they have unilateral appearance. Similarly, rare ectopic cervical human thymi had been reported in children. In contrast, cervical thymi are a principal component of NMR ontogenesis. Interestingly, among vertebrates, chickens have seven, sharks five, and amphibians three thymi. It is tempting to speculate that the presence of additional thymi in the naked mole rat may contribute to prolonged maintenance of immune function during their lifespan.

We provide evidence for a delay of thymic involution in naked mole rats beyond the 1st decade of their lifespan. Age-associated marker expression and thymic cell composition remained at the level of neonates. The absence of thymic involution up to midlife is unprecedented in mammals. This would translate into similar or even slightly heightened thymic weights and cell counts for humans in their 30s.

Thymic involution decreases output of naive T cells and reduces the ability to mount protective responses against new antigens. In naked mole rats, we did not see thymic involution in animals older than 10 years old, while markers for thymic function and development, AIRE and FOXN1, were maintained at neonatal levels. Furthermore, the reduction of early T-cell progenitors accompanying age-related lymphoid decline did not manifest in naked mole rats, arguing that their intrinsic myeloid bias in the marrow does not predispose hematopoiesis toward less lymphoid commitment. However, naked mole rats are not immortal and do show frailty in old age. Therefore, an eventual decline in thymic cellularity and immune function is to be anticipated, albeit delayed as opposed to the lifelong steady decline in humans and mice.

Link: https://doi.org/10.1111/acel.13477

In today's open access paper, researchers report on an improved mapping of changes in microbial populations in the gut with advancing age. Past studies have shown that significant changes start comparatively early, in the mid-30s, for reasons yet to be clearly understood. Age-related changes in diet (generally worse) and exercise (generally lessened) clearly play a role, but at the high level, the most important changes are thought to be the result of a bidirectional interaction between the immune system and the microbiome. Growing numbers of inflammatory microbes contribute to the harmful chronic inflammation of aging, expanding their populations at the expense of beneficial microbes that generate useful metabolites. Meanwhile, the age-related decline of immune function, partially caused by chronic inflammation, means that harmful microbes are less effectively suppressed, enabling their expansion in the intestinal tract.

The novel results in this work include a link between medication status in later life and changes in the gut microbiome. Most older people take one or more medications for chronic conditions. This is quite interesting and a topic that has gone largely untouched to date in investigations of how the microbiome interacts with health in later life. Given the influence of the gut microbiome on systemic inflammation, and noting that inflammation is of great importance in aging and age-related disease, this sounds like one more good reason to push for the widespread clinical use of fecal microbiota transplantation and other approaches shown to improve the quality of the aged gut microbiome.

This study examines how the duodenal microbiome changes with chronological age and with the process of aging. In this article, we have used the term aging to include chronological age, the number of concomitant diseases, and the number of medications used. Our results indicate that the duodenal microbiome changes progressively and significantly in older subjects, including a decrease in microbial diversity that was driven not only by chronological age but also by increases in the number of medications used and the number of concomitant diseases. Furthermore, this decrease in diversity is associated with increases in coliform levels. Representatives from phylum Firmicutes demonstrate stability and predictability over time, but other components of the common core duodenal microbiome change significantly with chronological age. This was driven by increases in phylum Proteobacteria, which increases to the second most abundant phylum in the duodenum in adults aged 36-50 years and remains in this position throughout adulthood. In contrast, phylum Bacteroidetes progressively decreases in RA with increasing age. The increase in RA of phylum Proteobacteria results from increases in the family Enterobacteriaceae, and specifically the genera Escherichia and Klebsiella. These changes are most pronounced when comparing young adults in their 20s and 30s to adults in their 70s and beyond, and correlated with changes in predicted microbial metabolic pathways, including the ubiquinone biosynthesis pathway, which is an antioxidant pathway whose expression is increased under stress conditions, including in anoxic environments for Escherichia coli.

We identified a significant decrease in duodenal microbial diversity in older subjects, which is consistent with previous data demonstrating reductions in microbial diversity in the stool microbiome with age, coupled with shifts in the dominant species and declines in beneficial microorganisms. However, advancing chronological age is accompanied by multiple factors that complicate microbial analysis. For example, the process of aging is associated with increases in the number of concomitant diseases present in older subjects and the number of medications used, factors that were not explored in previous studies. Through multivariate analyses controlling for these factors, we found that the decrease in duodenal microbial diversity was driven by a combination of chronological age, increases in the number of concomitant diseases, and increases in the number of medications used by older subjects, rather than solely by age alone. Our culture findings indicate that this decrease in microbial diversity in the duodenum is also associated with increased levels of coliform bacteria in the duodenum. This included increased relative abundance of the genera Klebsiella and Escherichia, a finding that is also consistent with previous findings in studies using stool, but here we show that Escherichia is associated with chronological age rather than the aging process, and that Klebsiella is associated with the number of medications used.

Previous studies have shown that the stool microbiome is dominated by bacteria from the phyla Firmicutes and Bacteroidetes. We found that the common core microbiome in the duodenum is also dominated by phylum Firmicutes, including the genera Streptococcus and Veillonella which are part of the core of the duodenal microbiome, but the relative abundance of the other major phyla differ with increasing age, including decreased relative abundance of Bacteroidetes, which is consistent with recent findings from the stool microbiome. These changes appear to be driven by increases in phylum Proteobacteria, which significantly and negatively affects the relative abundance of the phyla Firmicutes and TM7. Within phylum Proteobacteria, changes in the family Enterobacteriaceae also significantly and negatively impact the duodenal microbiome, affecting both the relative abundance of other microbial families and overall microbial diversity. These increases in Enterobacteriaceae were driven by the genera Escherichia and Klebsiella, both of which are coliforms, again supporting a link between increases in duodenal coliforms and decreased microbial diversity in older adults.

Further comparisons between the youngest and oldest groups of adults (ages 18-35 and 66-80 years, respectively) revealed that the changes in some genera were solely associated with chronological age (e.g., Escherichia, family Enterobacteriaceae), whereas others were in fact associated with the number of medications used (e.g., Klebsiella, family Enterobacteriaceae) or with the number of concomitant diseases (e.g., Clostridium, family Clostridiaceae). Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis of predicted microbial metabolic pathways based on 16S data suggested enrichment of microbial genes associated with the ubiquinone biosynthesis pathway in the duodenal microbiome of older adults. Ubiquinone constitutes the first line of defense in oxidative stress and plays an essential role in respiration in E. coli, so it is not surprising that this pathway could be enriched in older subjects.

In conclusion, this study examined how age and the process of aging are associated with changes in the microbiome of the small intestine, using validated sampling and processing techniques. The most significant differences are higher relative abundance of the phylum Proteobacteria and decreased relative abundance of Bacteroidetes in older subjects when compared to the youngest group. The higher relative abundance of Proteobacteria appeared to affect other duodenal microbial taxa, leading to decreased microbial diversity and increased relative abundance of coliforms and of anaerobic bacteria. The small intestine is vital to digestion, nutrient absorption, and incretin regulation, and consequently has a critical effect on host metabolism. The small intestine microbial changes reported here may play a clinically relevant role in human health and disease throughout the aging process. Further studies are needed to understand the causes and implications of these microbial changes with advancing age.

Link: https://doi.org/10.1016/j.celrep.2021.109765

You might recall that researchers have been working on the direct conversion of glial cells in the scars produced following ischemic injury to the brain. Overexpression of NeuroD1 via gene therapy appears an effective approach to achieve this goal, at least in the controlled scenario of an animal model. In mice this intervention gives rise to neurons that integrate into existing neural circuits, leading to some degree of functional recovery.

We demonstrated that NeuroD1-mediated in vivo direct reprogramming of astrocytes into neurons promoted their neural circuit integration and led to the visual functional recovery after ischemic injury. Our work bridged the knowledge gap between individual cellular response recovery and animal behavioral recovery, where we characterized the functional synapses formed from specific projections and assessed neuronal response to stimuli in awake mice, which are critical functional characterization at the intermediate neural circuit level. The mouse primary visual cortex is a unique model system providing an opportunity to quantify projection specific functional connectivity and the direct visual responsiveness of the reprogrammed cells. Furthermore, the ability to record responses to different visual features such as orientation and direction provides a unique ability to quantify how well the cells mature and whether the synapses they receive are functional.

In our model system, the visual responses were drastically reduced following ischemic injury, yet they recovered following the NeuroD1 delivery. The putative excitatory neurons started to regain their visual responses 3 weeks after reprogramming, while the putative inhibitory neurons progressively integrated circuit inputs and refined their activity over a longer period of time. This delayed recovery of inhibition after reprogramming is similar to the absence of matured inhibition at an early age. Furthermore, these visual responses became more specific with time, based on our two-photon calcium imaging and extracellular recording results. The NeuroD1 converted cells gradually developed to be selective to the orientations and directions of visual stimuli, which is a typical feature of the mature visual cortical neurons. Interestingly, the reprogrammed cells at 6 weeks post-infection demonstrated higher selectivity compared to the healthy controls, which could be potentially explained by the more functionally developed synaptic inputs received by the reprogrammed cells compared to the healthy controls.

Compared to other studies, the functional recovery achieved by NeuroD1-mediated astrocyte-to-neuron conversion in vivo was similarly efficient. The local functional circuit and visual response recovery were also similar to embryonic neuronal transplantation results. Direct in vivo conversion of astrocytes into neurons removes the possibility of graft rejection and provides a viable solution for this problem, however. Our findings suggest that the NeuroD1-based in vivo direct reprogramming technology may be a promising gene therapy treatment of brain injury by replenishing the lost neurons and successfully integrating them into the existing neural circuit.

Link: https://doi.org/10.3389/fcell.2021.720078

Given the failure of a locally injected senolytic drug to make a meaningful impact in osteoarthritis, the present consensus at the senolytics end of the longevity industry appears to be that systemic inflammatory signalling from senescent cells elsewhere in the body outweighs the contribution of local senescent cells in osteoarthritic joints. But perhaps the senolytic drug used in the failed trial was not a good candidate for humans; it remains to be seen as to whether better outcomes can be produced by systemic senolytic approaches in clinical trials for osteoarthritis. Meanwhile, researchers here suggest that there is in fact a meaningful contribution to harmful inflammation arising from senescent cells in osteoarthritic cartilage, and propose that the nature of the senescent cell population may explain some of the apparently contradictory past results.

Although osteoathritis (OA) was considered as a non-inflammatory disease, an ever-increasing body of evidence suggests that chronic degeneration of the joint is associated with persistent long-term low-grade inflammation in the joint. The source of inflammation in OA is unknown, although it has been shown to associate with high-fat diet, mechanical injury, and aging. We have shown here that one of the sources of joint inflammation is mesenchymal stromal cells (OA-MSC) within cartilage itself. OA-MSC synthesizes pro-inflammatory cytokines and chemokines that have been implicated in OA pathogenesis. We demonstrated that the induction of such pro-inflammatory molecules occurs at both mRNA and protein levels. We have also shown that the induction of inflammation in OA cartilage occurs during the transition from normal cartilage stromal cell (NCSC) in the young to the OA-MSC in the old during aging.

In recent years, cell senescence has been shown to be closely associated with OA pathogenesis. Injection of senescent cells into the joint space led to joint degeneration. Conversely, local clearance of p16INK4a-positive senescent cells from the joint attenuated injury and aging induced OA. Although the role of senescent cells in causing joint degeneration has been established, the molecular mechanism by which a chondrocyte reaches senescence has not been well understood. The expression levels of the cell senescence marker p16INK4a and senescence-associated secretory phenotype (SASP) were elevated in the serial passages of human chondrocyte culture in vitro and in aged human and mouse cartilage in vivo. However, inactivation of p16INK4a in chondrocytes of adult mice failed to attenuate joint degeneration during aging or injury. This observation raised an important question whether senescent chondrocytes were involved in cartilage degeneration.

We have shown here for the first time that OA-MSC, but not OA chondrocytes (OAC), has elevated levels of p16INK4a and SASP. Therefore, OA-MSC, but not OAC, are the senescent cells that become a source of inflammation in the joint. Our study also provided a plausible molecular explanation to the observation that joint degeneration was not affected when the p16INK4a gene was deleted in chondrocytes. Since p16 is expressed at very low levels in the OAC, targeting OAC for p16 knockout might not affect the real source of cell senescence in OA cartilage. Our data predict that joint degeneration would be attenuated if p16 were knocked out in OA-MSC, since it would abolish the source of SASP in OA cartilage. Although this prediction remains to be tested, OA-MSC should be considered as potential target cells of senolytics and anti-inflammation therapy for OA intervention in future studies.

Link: https://doi.org/10.3389/fcell.2021.725071

Why do women tend to live longer than men? There are a good many possible explanations for this well characterized observation. Gender differences in the pace of aging appears to be a robust outcome of the intersection of natural selection with a given mating strategy, but that doesn't say much about the specific mechanisms involved. Sex hormones are the obvious starting point for any investigation of the relevant molecular biology. In humans, estrogen provides numerous physiological benefits in addition to being a sex hormone, and so a higher estrogen level in women is a possible candidate mechanism.

The tudy reported in today's open access paper is an interesting examination of some of the outcomes on metabolism in women who undergo induced menopause followed by estrogen replacement therapy. The effects of these changes are so sweeping that it is hard to separate those relevant to aging: evidence tends to be more suggestive than conclusive in this sort of investigation. No one study will be compelling on its own. The weight of literature does lean in the direction of a sizable role for estrogen in determining a slower pace of aging in women versus men, however.

Estrogen Replacement Therapy Induces Antioxidant and Longevity-Related Genes in Women after Medically Induced Menopause

The great increase in average life expectancy during the 20th century emerges as one of society's greatest achievements. As a matter of fact, in the last two decades, life expectancy at birth has increased by 5-10 years. Regardless of the cultural or socioeconomic context, women have lived longer than men in different countries and in every era. Nowadays, 75% and 90% of people older than 100 years and 110 years (respectively) are women, and the longest living centenarian person (122 years old) was a woman. This phenomenon occurs not only in humans, but in many species, like all Old-World monkeys, apes, short-finned pilot whales, African lions, red deer, and Wistar rats, in which female life expectancy exceeds male life expectancy by 16%.

One plausible explanation for this protection against aging is that females are endowed with higher levels of estrogens than males. Estrogens are known to have many beneficial effects: cardioprotection, skeletal homeostasis maintenance, brain function, and hematopoietic stem cell division enhancement, among others. Moreover, intramuscular estrogen levels have been recently associated with skeletal muscle strength and power. Furthermore, they act as antioxidants in vitro and also have beneficial effects against oxidative stress in vivo. Indeed, a few years ago, we reported that estrogens were able to induce antioxidant and longevity-related genes, such as glutathione peroxidase (GPx) and manganese superoxide dismutase (Mn-SOD) in rats, through a mechanism involving the ERK1-2/NFκB pathway. We thus suggested that this finding could explain why females suffer less oxidative stress than males in many species, including humans.

However, all these estrogen beneficial effects may be lost in menopause. Indeed, we observed that when mimicking postmenopausal loss of estrogens by ovariectomizing Wistar rats, their peroxide production rose, and their glutathione levels decreased. They were restored after estrogen replacement therapy. This confirmed the impact of estrogen as a causative agent for this effect and made us hypothesize that this finding could be extrapolated to humans, that is, that estrogen replacement therapy (ERT) may be useful to restore estrogen levels and thus the estrogen-related beneficial effects.

Thus, the aim of this study was to confirm the ability of estrogens to upregulate antioxidant and longevity-related genes in humans, particularly in women, after a medically induced menopause. As expected, we found that medically induced menopause significantly decreased sexual hormone (estrogens and progesterone) levels. It also lowered glutathione peroxidase (GPx), 16S rRNA, P21, and TERF2 mRNA expression and blood glutathione levels. Estrogen replacement therapy significantly restored estrogen levels and induced mRNA expression of Mn-SOD, GPx, 16S rRNA, P53, P21, and TERF2 and restored blood gluthatione levels. Progesterone replacement therapy induced a significant increase in MnSOD, P53, sestrin 2, and TERF2 mRNA expression when compared to basal conditions. These findings provide evidence for estrogen beneficial effects in upregulating antioxidant and longevity-related genes in women.

A number of companies and research groups are performing drug discovery by using effects on frailty in mice as a readout. To what degree is frailty an adequate measure of the harms done by aging? One way to answer that question is to assess mortality in a human study population against a measure of frailty, with and without factoring in chronological age. Researchers here show that frailty is a fair marker for age-related mortality, but it is not a reflection of every degenerative, harmful process taking place under the hood. Frailty and age combined provide a better correlation with mortality than frailty alone, indicating that there are aspects of age-related decline that contribute meaningfully to mortality without producing evident frailty.

As populations get older, the association between chronological age and health status becomes increasingly heterogeneous. To describe this heterogeneity in health status as we age, the concepts of biological age or frailty versus fitness spectrum have been proposed. The frailty index (FI) methodology was introduced to quantify the accumulation of people's health 'deficits' (i.e., symptoms, clinical signs, medical conditions and disabilities) at a given chronological age. This method has allowed for the establishment of potentially useful population norms and the study of influences of wider determinants of health on the variation in health status within people of a similar chronological age.

Since FI deficits increase with age, the FI has a statistically significant association with chronological age. However, on the account of population heterogeneity, the effect size of this association has been found to be small. It has been suggested that given the age-related nature of its constituent deficits, the FI should be interpreted jointly with age. Our aim was to utilize data from 8,174 wave 1 participants in The Irish Longitudinal Study on Ageing (TILDA) to conduct, separately by sex, supervised machine learning analyses of the ability of the individual items of an FI to predict 8-year mortality. To gain insights as to the importance of age in this prediction, we repeated the analyses including age as a feature.

By wave 5, 559 men and 492 women had died. In the absence of age, the FI was an acceptable predictor of mortality with area under the curve (AUCs) of 0.7. When age was included, AUCs improved to 0.8 in men and 0.9 in women. After age, deficits related to physical function and self-rated health tended to have higher importance scores. Not all FI variables seemed equally relevant to predict mortality, and age was by far the most relevant feature. Chronological age should remain an important consideration when interpreting the prognostic significance of an FI.

Link: https://doi.org/10.3390/geriatrics6030084

The inaugural press release from the Longevity Science Foundation touts their commitment to put $1 billion over the next ten years into research aimed at extending the healthy human lifespan, but is light on details as to where the funding is coming from. It is unclear as to how aspirational versus actual the proposal is. That said, the people involved are serious and successful scientist and entrepreneurs in the field, so we shall see. It is certainly the case that more sizable initiatives are needed, as well as more initiatives devoted to projects focused on the biotechnologies of rejuvenation, and not merely efforts to reproduce the effect of exercise or calorie restriction. Given the vast ongoing toll of suffering and death caused by aging, there is room for far more research and development funding than is presently devoted to this cause.

A consortium of biotech founders, clinicians, and leading longevity research institutions announced today the launch of the Longevity Science Foundation. The new Swiss foundation has committed to distributing more than $1 billion over the next ten years to research, institutions and projects advancing healthy human longevity and extending the healthy human lifespan to more than 120 years. The Longevity Science Foundation will provide funding to promising longevity research institutions and groups around the world. The focus of the Foundation will be to select support projects in four major areas of healthy longevity medicine and tech - therapeutics, personalised medicine, AI, and predictive diagnostics. The Foundation is seeking to fund projects that can make a significant difference in people's lives as soon as possible - even within five years.

One of the main focuses of the Foundation is in driving longevity medicine from theoretical concepts to real-world applications. The Foundation's donations will support the transformation of scientific findings and deep technological advances into treatments and solutions that can be used in the clinic today. By identifying and funding the most promising and cutting-edge advances, the Foundation seeks to address one of the most pressing issues in the science and applicability of longevity medicine - radical inequality in accessing and understanding longevity-focused treatment. Significant funding gaps remain an obstacle to bringing longevity medicine out of the laboratory and into the real world.

Link: https://longevity.foundation/tpost/g9kst7iaf1-longevity-science-foundation-pursuing-12

My encounters with the hyperfunction theory of aging have at times left me confused, and I suspect that not all of those arguing for it are working from exactly the same picture in their heads. The version presented in today's editorial is somewhat more clear, possibly because the primary intent of the paper is to clarify. It is worth noting up front that the author is very much a proponent of the centrality of mTOR and related signaling pathways in aging, in the sense that aging and age-related degeneration is a program of regulatory change that produces damage. The opposing mainstream viewpoint in the research community is that aging is an accumulation of molecular damage, and regulatory change in signaling pathways is a consequence of that damage.

Hyperfunction is (roughly) the inappropriate continuation of developmental programs past their allotted time, leading to harm to the organism. The author of the editorial below would suggest too much mTOR signaling in later life as a case in point. On the other side of the fence, accumulation of damage is, roughly, the side effect of a metabolism optimized for early life success, lacking long-term repair capabilities, such as the ability to break down persistent cross-links that accumulate only very slowly, or lacking the structural capacity for indefinite function, as is the case for the adaptive immune system, which requires ever more resources devoted to memory.

Both the hyperfunction and damage accumulation views of aging are examples of antagonistic pleiotropy, meaning a given mechanism or system that operates beneficially in youth, and then harmfully in later life. This is the guiding view of the evolution of aging because early reproduction is favored by natural selection. Early reproduction wins the evolutionary niche, up to a point, and therefore there is a race to the lower bound of success, producing organisms optimized to win the competition for early reproduction at the cost of later health. There are counterbalances to the primacy of early reproduction, such as the grandmother effect: our capacity for culture (relative to other primates) has extended human life span (relative to other primates) because grandparents can contribute to the reproductive success of their grandchildren. But on the whole, natural selection favors early reproduction, and builds systems that fall apart once that critical period is done with.

On the topic of the primacy of mTOR and related signaling: I can't say as I think that a central role for mTOR signaling as a rate-limiting cause of aging is a defensible hypothesis given the evidence. It is also not defensible to say that the outcome of the targeted removal of cell and tissue damage in mice suggests that this damage is not life-limiting. Life span in short-lived mammals is very plastic in response to regulatory changes related to the central mechanisms covering cell replication, nutrient sensing, and cell maintenance processes upregulated in response to stresses, such as autophagy. This is not the case in long-lived mammals, as illustrated by the sizable difference in the life extension produced by calorie restriction in mice (as much as 40%) versus humans (a few years at best). While mTOR inhibition has slowed aging to a similar degree to clearance of senescent cells in mice, it hasn't achieved results anywhere near as impressive as clearance of senescent cells when it comes to reversal of specific age-related conditions, such as cardiac hypertrophy. Damage accumulation and repair as rejuvenation after the SENS view of aging looks much more compelling.

The hyperfunction theory of aging: three common misconceptions

The first misconception is that hyperfunction is always an increase of function. Correctly, hyperfunction is often an unchanged function, that is still higher than optimal for longevity. Hyperfunction is a function that was not switched off upon its completion. In some cases, age-related alterations are indeed an absolute increase: hyper-secretory phenotype, pro-inflammation, hypertension, hyperlipidemia, hyperglycemia, hyperinsulinemia, hyperplasia, and hypertrophy of cells and organs (e.g., heart and prostate). In typical cases, hyperfunction is relative. It may even be a decrease of function that is still higher than optimal for longevity in the aging organism.

Using an analogy, consider a car driving 65 miles per hour (mph) on the highway with a 65 mph speed limit. This is the normal and optimal speed on this highway, or optimal functioning early in life. Early in life, during organism growth, all cellular and systemic functions are optimal for growth (not for longevity). However, if the car exits the highway to enter low-speed streets without decreasing speed (stuck accelerator) and continues at the same speed, 65 mph becomes over-speeding, or hyperfunction. The car is bound to crash on your driveway and is destroyed by over-speeding. It has no chance to be destroyed on a molecular level by rusting.

The second misconception is that the hyperfunction theory of aging denies a harmful accumulation of molecular damage. To clarify, molecular damage does accumulate. Furthermore, molecular damage would eventually kill the organism, unless the organism dies from hyperfunctional aging or, even more specifically, from mTOR-driven aging. Aging due to molecular damage and due to cellular hyperfunctions occur in parallel, but the latter is a life-limiting process, which progresses faster. How do we know that hyperfunctional aging is life-limiting and accumulation of molecular damage is not? In several dozen studies, rapamycin (mTORC1 inhibitor) prolonged lifespan in animals. Then mTOR-driven aging is life-limiting almost by definition.

The third misconception is that hyperfunction theory is primarily based on an evolutionary theory. Correctly, the hyperfunction theory is principally based on a cellular model of geroconversion. The hyperfunction theory is not just an evolutionary theory, even though it is completely in agreement with the latter and develops the notion of Antagonistic Pleiotropy (AP) further. Evolutionary perspectives in the hyperfunction theory are needed mostly to explain why hyperfunctional (quasi-programmed) aging is life-limiting and why accumulation of molecular damage is not. Otherwise, the hyperfunction theory is a mechanistic theory: an analogy of the cellular model of geroconversion in vitro. When cells proliferate, mTOR and other growth-promoting signaling pathways drive cellular mass growth, which is balanced by cell division. However, if the cell cycle is blocked by p21 or p16, then the same mTOR pathway drives "pathological growth" (geroconversion) from reversible arrest to irreversible senescence. Geroconversion is a continuation of growth - a quasi-program of growth.

The hyperfunction theory is a translation of the rules of geroconversion to the organism. Organismal aging and geroconversion can be described in similar terms, and similar signaling pathways drive geroconversion and organismal aging. It does not necessarily mean that a few senescent cells cause organismal aging. Fully senescent cells may contribute to aging, but are not required. Instead, most cells are becoming at least relatively hyperfunctional, gerogenic, producing age-related diseases.

The Leucadia Therapeutics staff has been working for a few years now to prove the founder's hypothesis on the cause of Alzheimer's disease. In this view, the primary problem is impaired drainage of cerebrospinal fluid. As the drainage path through the cribriform plate is blocked by slow ossification of channels, metabolic waste builds up in the olfactory bulb, the closest region of the brain. This is where Alzheimer's pathology initially starts, before spreading. The team has gathered an imposing amount of human anatomical data, and their eventual goal is to unblock the drainage path via an implant placed in the cribriform plate.

Cerebrospinal fluid (CSF) clears the brain's interstitial spaces, and disruptions in CSF flow or egress impact homeostasis, contributing to various neurological conditions. Here, we recast the human cribriform plate from innocuous bony structure to complex regulator of CSF egress with an apical role in Alzheimer's disease etiology. It includes the pathological evaluation of 70 post-mortem samples using high-resolution contrast-enhanced micro-CT and cutting-edge machine learning, a novel ferret model of neurodegeneration, and a clinical study with 560 volunteers, to provide conclusive evidence of a relationship between cribriform plate aging/pathology and cognitive impairment.

Interstitial spaces within the medial temporal lobe and basal forebrain are cleared by CSF flow that drains through olfactory structures to the olfactory bulb, directly above the cribriform plate. We characterized CSF flow channels from subarachnoid spaces under the olfactory bulb to the nasal mucosa through subarachnoid evaginations that subdivide into tiny tubules that connect to an elaborate conduit system within the cribriform plate. These conduits form an internal watershed that runs from the crista galli's vault to a bony manifold within the olfactory fossa's back wall, connecting with large apertures in between.

We found that the cross-sectional area of apertures limits CSF flux through the cribriform plate, which declines with increasing age. Subjects with a confirmed post-mortem diagnosis of Alzheimer's disease had the smallest CSF flux capacity, which reduces CSF-mediated clearance in upstream areas and leads to the accumulation of toxic macromolecules that seed AD pathology.

We surgically occluded apertures in adult ferrets and found that this manipulation induced progressive deficits in spatiotemporal memory and significant atrophy of the temporal lobe, olfactory bulbs, and lateral olfactory stria. Finally, we explored human cribriform plate aging/pathology and cognition in a clinical study with 560 participants (20-95 years old). We evaluated cribriform plate morphology with CT and Deep Learning, assessed memory with a novel touch screen platform, tested olfactory discrimination, and asked questions about family history and relevant life events, like broken noses. Deep learning algorithms effectively parsed subjects and established the feasibility of predicting Alzheimer's disease years before a clinical presentation of cognitive impairment.

Link: https://doi.org/10.1101/2021.10.04.21264049

The gut microbiome is important in health and aging. Populations of microbes change with age, favoring harmful inflammatory populations at the expense of populations that generate beneficial metabolites. Restoration of a youthful microbiome via fecal microbiota transplantation has been demonstrated to be beneficial in animal studies. The research community is also evaluating other approaches to at least partially rejuvenate the aged gut microbiome, such as flagellin immunization to provoke the immune system into removing more of the harmful gut microbes. Researchers here provide evidence for treatment with icariin, a plant-derived flavonoid, to favorably adjust the balance of intestinal microbial populations in mice, though it is unclear as to the mechanism of action.

We previously reported the neuroprotective effects of icariin in rat cortical neurons. Here, we present a study on icariin's anti-aging effect in 24-month aged mice by treating them with a single daily dose of 100 mg/kg of icariin for 15 consecutive days. Icariin treatment improved motor coordination and learning skills while lowered oxidative stress biomarkers in the serum, brain, kidney, and liver of the aged mice. In addition, icariin improved the intestinal integrity of the aged mice by upregulating tight junction adhesion molecules and the Paneth cells and goblet cells, along with the reduction of iNOS and pro-inflammatory cytokines (IL-1β, TNF-α, IL-2 and IL-6, and IL-12). Icariin treatments also significantly upregulated aging-related signaling molecules, Sirt 1, Sirt 3 and Sirt 6, Pot1α, BUB1b, FOXO1, Ep300, ANXA3, Calb1, SNAP25, and BDNF in old mice.

Through gut microbiota (GM) analysis, we observed icariin-associated improvements in GM composition of aged mice by reinstating bacteria found in the young mice, while suppressing some bacteria found in the untreated old mice. To clarify whether icariin's anti-aging effect is rooted in the GM, we performed fecal microbiota transfer (FMT) from icariin-treated old mice to the old mice. FMT-recipients exhibited similar improvements in the rotarod score and age-related biomarkers as observed in the icariin-treated old mice. Equal or better improvement on the youth-like features was noticed when aged mice were FMT with feces from young mice. Our study shows that both direct treatments with icariin and fecal transplant from the icariin-treated aged mice produce similar anti-aging phenotypes in the aged mice. We prove that GM plays a pivotal role in the healing abilities of icariin. Icariin has the potentials to be developed as a medicine for the wellness of the aged adults.

Link: https://doi.org/10.1016/j.phrs.2021.105587

Theory and modeling dominates the study of the evolution of aging, as is the case in any field in which one is presented with a snapshot of a very complex environment and no ability to conduct directly relevant experiments on that environment. Beyond the state of the natural world here on earth, astrophysics is another good example: a zoo of diverse phenomenon out there in the universe and a great deal of highly mathematical back and forth here on Earth over exactly why the night sky looks the way it does.

Given the nature of the field, any discussion of the fine details of the evolution of aging should be taken as speculative. Evolution as a whole is well supported by the evidence, and a demonstrably useful concept that has informed and accelerated progress in the life sciences. But many of the specific hypotheses and mathematical models that foam and compete under the surface of the bigger picture are likely incorrect in some or all of their details.

The commentary on the evolution of aging in today's open access paper might be taken as the polar opposite of programmed aging hypotheses. Here, aging is envisaged as an inevitable byproduct of the way that natural selection operates, stronger in its effects on early life. Early reproduction is an effective strategy across near all niches, since the occupants of near all niches are affected by predation, disease, and other forms of mortality. Thus mechanisms and systems that aid in early life success at the cost of late life health are selected, despite reducing the hypothetical overall number of offspring that could be produced over a lifetime absent predation, disease, and other extrinsic causes of mortality. Evolution as a process produces imperfect machines, good enough at the outset, but which fall apart thereafter.

Evolution, Chance, and Aging

Evolutionary theory allows for various types of byproduct effects that can affect late life, both negatively and positively. If pleiotropy is viewed mechanistically, molecule-based and network-based pleiotropy make late life effects likely. Research on model systems has already shown that there are a large number of mechanisms by which single mutations can affect late life, supporting the possibility that populations accumulate diverse positive and negative late life effects. It is likely that late life is subject to little selection due to rapidly decreasing population size and lack of late life reproduction in most species, making it unlikely that aging is under simple regulatory control. Instead, it could potentially be an emergent property of the many byproduct effects that affect late life (both selection-based and neutrality-based) and the accumulation of mutations primarily affecting late life. Each species will have its own constellation of byproduct effects and late acting mutations.

This will translate into a large and complex mixture of genetic variation that will distribute across the individuals in populations. Some of the mutations affecting aging may be shared between species, due to conservation of molecules or networks, while others will be species specific. Characteristic lifespans for different species would be another emergent property. Superimposed upon this pattern of aging would be physiological responses to environmental insults common to aging animals, such as stress and infection. Such responses could contribute to the aging pattern. These responses would also consist of both conserved and species-specific components. While it is unclear how age-related tissue dysfunction connects to organism mortality, tissue specific changes with age would be expected to contribute to the species-specific pattern.

One of the most prominent theories accounting for aging and age-dependent mortality rates postulates cumulative damage leading to stochastic failure of tissues and the organism. Specific mechanisms included in this theory are oxidative damage or somatic mutation. The disposability model states that repair capacities are limited by evolutionary constraints, leading to this cumulative damage. At the present time these theories cannot account for the full range of aging patterns in all species. Perhaps aging can be viewed as the net result of hundreds of byproduct effects combined with the accumulation of late-acting mutations, encompassing both positive and negative effects upon mortality and vigor.

Aging is correlated with a large number of species, tissue, and cell type specific changes at the molecular level. It is possible that aging is an emergent property of hundreds of effects, some conserved, some fixed at the species level, and some that are variable at the population level. According to this view, it would only be a modest exaggeration to say aging is all trees and no forest.

How much of the benefit of a healthier diet arises from the effects of natural calorie restriction mimetic compounds? That question is an interesting one from a scientific perspective, but the answers are probably not all that valuable in a practical sense. We have a fairly good idea as to the size of the benefits to long-term health obtained via a better diet, and separately by eating less of that diet, the practice of calorie restriction while still obtaining sufficient micronutrients. Calorie restriction mimetic compounds trigger some of the same beneficial cellular stress response mechanisms as does a low calorie diet, though in lesser and more piecemeal ways. Knowing more about how and why a better diet is a better diet isn't the path to large improvements in human longevity, but it is a fascinating subject, nonetheless.

In addition to genetic, environmental and lifestyle factors, nutrition plays a vital role in shaping health throughout human aging. Recently, health was defined as the sum of several hallmarks, including, the ability to react to environmental and cellular stress, integrity of barriers and maintenance of cellular and organismal homeostasis, of which many cross-talk with dietary factors. While a moderate consensus has been reached on what defines an unhealthy diet, the constitution of a healthy diet remains debated and subject to different beliefs. In principle, healthy diets should have positive effects on diverse health parameters, while not evoking negative effects. Different concepts of healthy dietary plans have been developed. These indices estimate and rate the intake of 8-12 components (for instance whole grain, nuts, legumes, fruit, vegetable, alcohol, etc.) and good scores are linked to lower cardiovascular disease (CVD) incidence and cancer mortality.

Accumulating evidence suggests that caloric restriction (CR) and various forms of fasting (intermittent fasting, time restricted eating, periodic fasting), avoiding malnutrition and including an adequate intake of macro- and micronutrients, present yet additional possibilities to promote the health status by reducing CVDs and cancer, among other beneficial effects. Recently, the concept of caloric restriction mimetics (CRMs) was developed to describe pharmacologically active substances that mimic some of CR's myriads of effects. At the core of the CRM definition, we and others argue that potential CR-mimicking compounds should in principle increase life- and/or healthspan and ameliorate age-associated diseases in model organisms, thus often the simultaneous use of the term "anti-aging substances." Additionally, CRMs should be capable of inducing autophagy, a homeostasis-regulating cellular recycling mechanisms that degrades obsolete, damaged or otherwise unneeded proteins, cellular structures or organelles.

Natural CRM candidates are widely present in foods and, in most cases, inevitably consumed by humans. Given their prominent occurrence in plant-based foods (especially polyphenols and polyamines), it is conceivable that these compounds contribute to the beneficial effects of healthy diets. Nevertheless, to date, specific dietary recommendations must be read with caution as too many uncertainties remain regarding bioavailability, concentration in food, stability and optimal intake levels. Furthermore, estimations of CRM levels in healthy diet plans are largely elusive and should be evaluated in future studies, as they could add to or be responsible for some of the beneficial effects of these diets.

Overall, the promising and emerging field of dietary CRM candidates needs to be considered with scientific rigor, as large parts of evidence on their effects in humans come from epidemiological and/or small-scale studies, often conducted with plant-based extracts that contain numerous bioactive substances. Problems may also arise when translating pre-clinical and epidemiological evidence of dietary and body-endogenous substances to clinical studies. For many of the herein discussed substances important data yet need to be collected: oral bioavailability, stability throughout the intestinal tract, metabolization, cellular uptake, distribution throughout the body, organ-specific effects, interaction with body-endogenous biosynthesis pathways and bioactive levels, just to name a few. More importantly, epidemiological data on dietary components can only be as good as the underlying food databases. Unfortunately, regionally varying food compositions, quality, the influence of meal preparation techniques and storage conditions are sometimes insufficiently studied or documented.

Link: https://doi.org/10.3389/fnut.2021.717343

This paper is interesting as a first step on the way to further research into compensatory therapies that can reduce the cardiac muscle dysfunction of heart failure. One-time radiation therapy appears to persistently change cardiomyocyte behavior via altered epigenetic regulation of notch signaling, leading to modestly improved heart tissue function. Perhaps this should be taken as supportive of efforts to more directly target this regulatory pathway in the aging heart via other means.

Cardiac radiotherapy (RT) may be effective in treating heart failure (HF) patients with refractory ventricular tachycardia (VT). The previously proposed mechanism of radiation-induced fibrosis does not explain the rapidity and magnitude with which VT reduction occurs clinically. Here, we demonstrate in hearts from RT patients that radiation does not achieve transmural fibrosis within the timeframe of VT reduction. Electrophysiologic assessment of irradiated murine hearts reveals a persistent supraphysiologic electrical phenotype, mediated by increases in NaV1.5 and Cx43. By sequencing and transgenic approaches, we identify Notch signaling as a mechanistic contributor to NaV1.5 upregulation after RT.

Our study presents findings to suggest that radiation therapy, successfully used in patients with refractory VT, may increase levels of the cardiac sodium channel and improve conduction. Indeed, explanted cardiac specimens obtained from a treated patient with refractory VT revealed threefold higher NaV1.5 protein levels in the radiation-targeted region when compared to a nontargeted region of the same heart, restoring NaV1.5 to levels within the range of nonfailing myocardium. As an observation of the potential effect of RT on human physiology, we also report a non-significant decrease in mean QRS duration in the Electrophysiology-guided Noninvasive Cardiac Radioablation for Ventricular Tachycardia (ENCORE-VT) patient cohort, as well as robustly shortened QRS intervals in at least 4 of the 19 patients.

Our findings have direct relevance for patient care. Most surviving patients continue to exhibit reduced VT burden 24 months after a single RT treatment. Our results demonstrate that the functional and molecular effects of RT and Notch reactivation are persistent and expected to directly translate into long-term durability of therapy.

Link: https://doi.org/10.1038/s41467-021-25730-0

The popular science article I'll point out today does a fair job of following the past decade or so of work arising from heterochronic parabiosis, in which the circulatory systems of a young animal and an old animal are joined. The young animal exhibits some degree of accelerated aging, while the old animal exhibits some degree of rejuvenated function. The question all along has been why exactly this happens: what are the underlying mechanisms, and can they be replicated as a basis for therapy.

The obvious first approach was to transfuse young donor blood into old recipients, as positive results would mean that the existing blood transfusion infrastructure could be used to provide a relatively low cost therapy to large number of older people. Unfortunately, this doesn't work. The results from animal studies and human trials indicate that if there are benefits, they are too small and unreliable to care about. There is something about parabiosis that isn't captured by transfusion.

Otherwise, initial research focused on factors in young blood that might be beneficial. This gave rise to the identification of GDF11 as one such factor, followed by considerable debate over whether this work was flawed, in parallel to the establishment of Elevian, a company that continues to work on therapies based on delivery or upregulation of GDF11. Researchers later provided compelling proof that the effect of beneficial factors in young blood is small in comparison to the effect of harmful factors in old blood, and from there identified TGF-β as one such problem factor. The suggestion here is that parabiosis works via a dilution of harmful factors, not via introduction of youthful factors.

Experiments in diluting blood in old animals with saline, while adding significant amounts of albumin because it cannot be diluted in the bloodstream without severe consequences, seemed to bear out this viewpoint. Animals exhibited similar benefits to those undergoing parabiosis. And yet, is the real signal in the albumin, and not in the dilution? Recently, researchers have delivered albumin to old animals without dilution of blood, and this also produces benefits. So is this a case of albumin becoming modified or damaged in increasing proportions in the bloodstream with advancing age, while cells are very sensitive to that form of damage? This is but the latest twist in this ongoing saga, so perhaps, or perhaps not. Give it a few years, and there may be another chapter to come.

Has the fountain of youth been in our blood all along?

In a series of studies over the last 15 years, researchers have shown that, when infused with blood from young mice, old ones heal faster, move quicker, think better, remember more. The experiments reverse almost every indicator of aging the teams have probed so far: It fixes signs of heart failure, improves bone healing, regrows pancreatic cells, and speeds spinal cord repair. It sounds sensational, almost like pseudoscience. It's some of the most provocative aging research in decades. These studies, which use a peculiar surgical method called parabiosis that turns mice into literal blood brothers, show that aging is not inevitable. It is not time's arrow. It's biology, and therefore something we could theoretically change.

Blood itself will not become a treatment for old age. It's too messy, too complicated, too dangerous. But because of these labs' findings, we know that somewhere swirling around in young veins are signals that awaken the natural mechanisms to repair and restore the body. These mystery factors, once researchers can identify and fine-tune them, could become precious medicine. Heterochronic parabiosis, in which researchers pair two animals at different points in the lifespan, was first used to study aging in the 1950s. But by the 1990s, it was largely forgotten - until more recent studies put it back on the map.

On the theory that blood-borne factors might orchestrate the transitions of aging, researchers turned to heterochronic parabiosis. The team's 2005 findings caused a stir. If an older mouse's leg gets frozen with a piece of dry ice, the cells in charge of muscle repair don't respond much; the number of active cells increases by just 10 percent or so. But after heterochronic parabiosis, twice as many cells activate in response to injury - a reaction like that of a young animal. Older mouse livers demonstrate a similarly sprightly cellular turnover. Longevity enthusiasts eagerly discussed the findings, even though there is little evidence that heterochronic parabiosis extends life; even in rodents, all we know for sure is that it undoes some late-in-life decay.

Meanwhile, a cottage industry began selling young plasma. Around 2016, Ambrosia, a California company, offered to infuse customers as part of a clinical trial that charged participants $8,000 to join. (So far, the team has not published any findings in the scientific literature.) Other entities and individuals launched similar efforts, such as a proposed study that would charge large sums to frail elderly people for doses of young plasma. This "therapeutic plasma exchange" is a legitimate treatment for certain rare autoimmune diseases and problems with coagulation, so these providers are not necessarily required to obtain explicit approval from the Food and Drug Administration so long as they make no unsubstantiated health claims about their regimen. But, of course, they did: Companies marketed benefits for people with memory loss, heart disease, and even Parkinson's. The FDA, now stepping into the regulatory role of the 17th-century pope, released a stern memo in 2019 that curbed the trend.

The most straightforward path to a therapy would be to pinpoint a pro-aging factor in old blood, mouse and human, that a drug could block. Many groups have identified such elements. One has found that a protein called CCL11 increases in aged humans and mice and is correlated with reduced brain cell birth. The other obvious tactic is to identify youthful plasma's secret formula and optimize it. Some research suggests the hormone oxytocin might be a candidate; other work has identified the protein GDF11. Combination therapies are also under consideration; a biotech company is exploring mixtures of hundreds of blood-borne proteins as therapies for a variety of age-related diseases.

It's also possible that the rejuvenating effects seen in experiments don't arise from one magic ingredient, or even from some combination of a dozen or a hundred compounds, but happen simply because the procedure dilutes some unknown harmful substances that accumulate in old blood. From this perspective, there's no particular need for young stuff: Any form of plasma replacement will do. It's sort of like changing the oil in your car. One research group is starting a company and are aiming for human clinical trials to determine if simply flushing out the bloodstream can help with problems like frailty and declining cognition.

It is well demonstrated that structured exercise programs improve function and reduce mortality in old humans, in part because the majority of people do not undertake anywhere near enough exercise. For mice, more activity takes place into later life, but how much is quite dependent on the environment in which they are housed. Looking at the study here, I would expect this to be a comparison of exercise trained mice with untrained mice that are less active than they would be if given options such as an exercise wheel. That may be a better match to the human situation than the other options. While looking at the results, it is worth recalling that past data shows that exercise interventions improve healthspan but not lifespan in mice. It isn't as effective as calorie restriction in this regard.

Protein quality control mechanisms decline during the process of cardiac aging. This enables the accumulation of protein aggregates and damaged organelles that contribute to age-associated cardiac dysfunction. Macroautophagy is the process by which post-mitotic cells such as cardiomyocytes clear defective proteins and organelles. We hypothesized that late-in-life exercise training improves autophagy, protein aggregate clearance, and function that is otherwise dysregulated in hearts from old vs. adult mice.

As expected, 24-month-old male C57BL/6J mice (old) exhibited repressed autophagosome formation and protein aggregate accumulation in the heart, systolic and diastolic dysfunction, and reduced exercise capacity vs. 8-month-old (adult) mice. To investigate the influence of late-in-life exercise training, additional cohorts of 21-month-old mice did (old-ETR) or did not (old-SED) complete a 3-month progressive resistance treadmill running program. Body composition, exercise capacity, and soleus muscle citrate synthase activity improved in old-ETR vs. old-SED mice at 24 months. Importantly, protein expression of autophagy markers indicate trafficking of the autophagosome to the lysosome increased, protein aggregate clearance improved, and overall function was enhanced in hearts from old-ETR vs. old-SED mice.

This data provides the first evidence that a physiological intervention initiated late-in-life improves autophagic flux, protein aggregate clearance, and contractile performance in mouse hearts.

Link: https://doi.org/10.1111/acel.13467

Tissue engineering of new cartilage is an important goal in the field of regenerative medicine, but it has proven challenging to obtain the necessary structural properties. Natural cartilage is a resilient, strong tissue. Incremental progress towards this goal has been made over the years, as researchers explored the space of the possible. Now we see demonstrations such as the one noted here, in which sizable sections of engineered cartilage can be produced from embryonic stem cells, and the tissue exhibits the desired structural properties. If this can be achieved with embryonic stem cells, then it can in principle also be achieved with induced pluripotent stem cells, either generated from a patient cell sample, or made universal by knocking out MHC class I and II receptors and other immune-related signals in order to be used in any patient without rejection.

Articular cartilage functions as a shock absorber and facilitates the free movement of joints. Currently, there are no therapeutic drugs that promote the healing of damaged articular cartilage. Limitations associated with the two clinically relevant cell populations, human articular chondrocytes and mesenchymal stem cells, necessitate finding an alternative cell source for cartilage repair. Human embryonic stem cells (hESCs) provide a readily accessible population of self-renewing, pluripotent cells with perceived immunoprivileged properties for cartilage generation.

We have developed a robust method to generate 3D, scaffold-free, hyaline cartilage tissue constructs from hESCs that are composed of numerous chondrocytes in lacunae, embedded in an extracellular matrix containing Type II collagen, sulphated glycosaminoglycans and Aggrecan. The elastic (Young's) modulus of the hESC-derived cartilage tissue constructs (0.91 ± 0.08 MPa) was comparable to full-thickness human articular cartilage (0.87 ± 0.09 MPa). Moreover, we have successfully scaled up the size of the scaffold-free, 3D hESC-derived cartilage tissue constructs to between 4.5 mm and 6 mm, thus enhancing their suitability for clinical application.

Link: https://doi.org/10.1038/s41598-021-97934-9

Atherosclerosis is the growth of fatty, inflamed deposits in blood vessel walls, narrowing and weakening them. It results from processes that are universal, present in every older individual. The oxidative stress and inflammation of aging lead to a raised amount of oxidized lipids and lipid carriers such as LDL particles, and these produce a growing dysfunction in the macrophage cells responsible for clearing unwanted lipids from blood vessel tissue.

It is not surprising to see the data presented in today's research materials, showing that near half of older adults in their 50s and 60s age have measurable atherosclerotic lesions in their blood vessels despite exhibiting no clinical symptoms. This is consistent with past studies using imaging to determine the burden of atherosclerosis in large patient populations. Those lesions grow over time to kill at least 25% every older person via stroke, heart attack, or other cardiovascular disease. A way to reverse atherosclerotic lesions is desperately needed, but the research and development of new therapies remains near entirely focused on lowering of LDL cholesterol in the bloodstream, an approach that can only slow the condition, and is incapable of producing sizable reversal of atherosclerosis.

To make real progress towards reversal of atherosclerosis, macrophage cells must be made resistant to the aged environment, enabling these cells to continue their beneficial maintenance of blood vessels as they did in youth. Researchers recently demonstrated sizable reversal in mice via targeting antioxidants to the lysosomes of macrophages to suppress the harm done by oxidized LDL particles, for example. Other approaches exist, such as sequestration of harmful 7-ketocholesterol, under development at Underdog Pharmaceuticals, or providing macrophages with the ability to break down excess cholesterol in situ, under development at Repair Biotechnologies.

More than 40% of adults with no known heart disease had fatty deposits in heart arteries

Atherosclerosis, or the buildup of fatty deposits in blood vessels that supply blood to the heart, is a major cause of heart attacks. A widely used approach to screen people who are at risk for heart disease but who do not yet have symptoms is cardiac computed tomography, commonly known as a cardiac CT scan, for coronary artery calcification (CAC) scoring. The scan creates cross-sectional images of the vessels that supply blood to the heart muscle to measure the presence and density of calcium-containing plaque in the coronary arteries. However, CAC scoring can miss a percentage of people who are at risk for heart attack even though they have a zero CAC score. "Measuring the amount of calcification is important, yet it does not give information about non-calcified atherosclerosis, which also increases heart attack risk. Non-calcified atherosclerosis is believed to be more prone to cause heart attacks compared with calcified atherosclerosis."

Researchers randomly recruited participants aged 50-64 years old from the Swedish census register from 2013 to 2018 as part of the Swedish CArdioPulmonary BioImage Study (SCAPIS). They report on data from 25,182 participants with no history of a prior heart attack or cardiac intervention who underwent both CAC scans and coronary computed tomography angiography (CCTA) scans. CCTA is a radiologic technique that gives a very detailed image of the inside of the arteries that supply the heart with blood. The researchers wanted to determine the prevalence of atherosclerosis in the general population without established heart disease, and how closely the CCTA findings correlated to CAC scores.

CCTA detected some degree of atherosclerosis in more than 42% of the study participants. CCTA found that in 5.2% of those with atherosclerosis, the build-up obstructed blood flow through at least one coronary artery (out of three) by 50% or more. In nearly 2% of those found to have artery build-up, the atherosclerosis was even more severe. Blood flow was obstructed to the main artery that supplies blood to large portions of the heart, and in some cases, all three coronary arteries were obstructed. Atherosclerosis started an average of 10 years later in women compared to men. Atherosclerosis was 1.8 times more common in people ages 60-64 vs. those ages 50-54. Participants with higher levels of atherosclerosis seen by CCTA also had higher CAC scores. Of those with a CAC score of more than 400, nearly half had significant blockage, where more than 50% of the blood flow was obstructed in one of the coronary arteries. In those with a CAC score of zero, 5.5% had atherosclerosis detected by CCTA, and 0.4% had significant obstruction of blood flow.

It is well established that excess visceral fat is harmful. This tissue is metabolically active, and generates increased chronic inflammation through numerous mechanisms: a greater number of senescent cells; signaling by fat cells that appears similar to that produced by infected cells; increased debris from dead and dying fat cells that provokes the immune system. Overweight and obese people have a shorter life expectancy, greater incidence of age-related disease, and higher lifetime medical costs, with these disadvantages increasing with a larger burden of visceral fat tissue. It is not surprising, therefore, to find that genetic variations that correlate with increased visceral fat accumulation in humans also correlate with a shorter life expectancy.

Several studies have shown that obesity is a risk factor for numerous diseases, including diabetes mellitus, hypertension, coronary artery disease, stroke, fatty liver disease, sleep-disordered breathing, mental health, and cancer. Obesity has also been shown to be closely related to all-cause mortality. Several observational studies revealed that obesity could accelerate the aging process. Moreover, a meta-analysis indicated that people with extreme obesity may have a reduced life expectancy by about 14 years. However, there is little evidence on the causal relationship between genetic influence of visceral adipose tissue (VAT) accumulation and longevity.

Mendelian randomization (MR) analysis is a useful approach for estimating the causal relationship between an exposure factor and outcome based on observational data from genome-wide association studies (GWASs). Single-nucleotide polymorphisms (SNPs) typically serve as the instrumental variables for investigating the causal role of an exposure factor on a disease or disease-related outcome. A valid instrumental variable is one that is (1) associated with the exposure, (2) independent of confounders, and (3) independent of the outcome conditional on the exposure and confounders. In this two-sample MR analysis, we employed the genetic variants (SNPs) of VAT accumulation as instrumental variables to explore the causal relationship with longevity.

Our MR analysis used 221 genetic variants as instrumental variables to explore the causal association between VAT accumulation and longevity. VAT accumulation (per 1-kg increase) was found to be significantly associated with lower odds of surviving to the 90th (odds ratio [OR] = 0.69) and 99th (OR = 0.67) percentile ages. This MR analysis identified a causal relationship between genetically determined VAT accumulation and longevity, suggesting that visceral adiposity may have a negative effect on longevity.

Link: https://doi.org/10.3389/fendo.2021.722187

The aging of large blood vessels in the brain, and their resulting dysfunctions, are quite different from those of the small vessels, the microvasculature. Large vessels are predominantly affected by atherosclerosis, the buildup of fatty plaques that weaken and narrow blood vessels, leading to the catastrophic structural failure of a stroke. Small vessels, on the other hand, appear to be affected by a collection of mechanisms that cause functional deterioration, such as pathological amyloid deposition, with atherosclerosis as only one of that list of harmful processes. This is the point made in the open access paper here, in any case, in which the authors emphasize that cerebral small vessel disease is not as well understood as researchers would like it to be.

Cerebral small vessel disease (SVD) is a leading cause of cognitive decline and functional loss in the elderly. Cerebral SVD is recognised by the resultant parenchymal lesions rather than the underlying small vessel alterations themselves, and typically manifests as lacunar lesions, diffuse white matter lesions (leucoaraiosis) and/or microbleeds. Accordingly, cerebral white matter hyperintensities (WMH) on MRI scan are recognised surrogates of cerebral SVD. Although the aetiopathogenic mechanisms of cerebral SVD are unclear, there is a clear distinction from cerebral large vessel disease. Indeed, with the exception of hypertension, conventional cardiovascular risk factors such as diabetes and hyperlipidaemia have inconsistent correlation with cerebral SVD. Further, after accounting for age and the traditional vascular risk factors, much of the variance in WMH volume remains unexplained.

Cerebral WMH predict incident stroke, dementia, heart failure, disability, and mortality. Despite the lack of correlation with conventional cardiovascular risk factors and with no supporting evidence base, current treatment strategies for managing cerebral WMH are extrapolated from the general management guidelines for the treatment of atherosclerotic disease. As a result, treatment strategies focusing on the use of antiplatelet, statins, aggressive blood pressure (BP) lowering and (in people with diabetes) aggressive glycaemic control may not be effective in the treatment of cerebral SVD. The absence of specific treatments for cerebral SVD precipitates the need for clear targets or strategies for the treatment of cerebral SVD.

We propose the search for such targets should focus on the underlying pathology of cerebral SVD, focusing specifically on the regulation of cerebral microcirculation. However, in order to identify potential treatment strategies, knowledge of the systemic correlates of cerebral SVD is required. As WMH are present in patients with and without history of previous CVD, we aimed to explore this in a general population sample of older adults enriched with patients with proven cerebral SVD.

Link: https://doi.org/10.18632/aging.203557