Fight Aging!

The research community has come to see chronic inflammation and other age-related immune system dysfunctions as an important aspect of neurodegenerative conditions. Inflammation in the short term is necessary for defense against pathogens and regeneration following injury. Unresolved, constant inflammation is harmful to tissue structure and function, however, changing cell behavior for the worse. In brain tissue, the effects of inflammatory signaling on the behavior of innate immune cells called microglia appears particularly important. Neurogenerative conditions are characterized by activated microglia. These microglia are less able to perform maintenance activities, while also contributing to loss of synapses and other pathological changes in the brain.

The authors of today's open access review paper take a broad view of the impact of immune system aging on the brain, and its potential roles in the development of neurodegenerative conditions. All such conditions exhibit changes in cellular biochemistry that can be linked to changed immune activity. Further, an inflammatory state appears correlated with onset and progression of these conditions. There is ample evidence for immunomodulatory, anti-inflammatory approaches to be a sensible way forward in the treatment of neurodegeneration, but adjusting the immune system is not straightforward. The fine details of the inflammatory mechanisms involved in pathology matter when it comes to building a better therapy.

Immunological aspects of central neurodegeneration

The etiology of various neurodegenerative disorders (NDs) that mainly affect the central nervous system including (but not limited to) Alzheimer's disease, Parkinson's disease, and Huntington's disease has classically been attributed to neuronal defects that culminate with the loss of specific neuronal populations. However, accumulating evidence suggests that numerous immune effector cells and the products thereof (including cytokines and other soluble mediators) have a major impact on the pathogenesis and/or severity of these and other neurodegenerative syndromes. These observations not only add to our understanding of neurodegenerative conditions but also imply that (at least in some cases) therapeutic strategies targeting immune cells or their products may mediate clinically relevant neuroprotective effects. Here, we critically discuss immunological mechanisms of central neurodegeneration and propose potential strategies to correct neurodegeneration-associated immunological dysfunction with therapeutic purposes.

While most central NDs appear to originate from genetic or environmental alterations of cellular homeostasis in the brain parenchyma, it is now clear that such perturbations are accompanied by the activation of innate and (at least in some cases) adaptive immune effector mechanisms that contribute to disease pathogenesis. Multiple NDs are associated with mutations in genes encoding components of the innate or adaptive immune system, such as TREM2 or HLA-DRB1. Moreover, hitherto unrecognized connections are emerging between central ND susceptibility genes, such as SNCA, and core immunological functions, such as the development of normal innate and adaptive immune reactions to bacterial challenges. Finally, patients affected by numerous NDs including Alzheimer's disease, Parkinson's disease, Huntington's disease, Lewy body dementia, and frontotemporal dementia exhibit shifts in the circulating levels of pro-inflammatory cytokines or peripheral immune populations, further supporting a pathogenic role for altered immune responses in the central nervous system in the progression of NDs.

With a few exceptions including the robust implication of CD4+ in disease pathogenesis in mouse models of Lewy body dementia, most of the current links between immunological mechanisms and ND pathogenesis rely on observational and correlative rather than mechanistic experimental setups. While at least partially this reflects the limited number of rodent models that recapitulate the emergence and progression of NDs in humans, it will be important to harness currently available models to implement antibody-mediated depletion, pharmacological inhibition, or genetic deletion/downregulation experiments to mechanistically link altered immune functions to ND pathogenesis and potentially identify novel targets for therapeutic interventions. While additional work is required to elucidate the actual therapeutic potential of immunotherapy for patients with central NDs, both innate and immune dysfunctions have been documented in the progression of NDs. It will be important to obtain further mechanistic insights into the immunological aspects of human degeneration in existing and newly developed rodent ND models to develop disease-modifying treatment options for these patient populations.

Mitrix Bio is one of the companies developing the means to produce large amounts of mitochondria for transplantation. Cells will take up new mitochondria from the surrounding environment, and mitochondria can be harvested from cell cultures. Mitochondrial function declines with age, the result of (a) gene expression changes in the cell nucleus that alter mitochondrial dynamics and the quality control process of mitophagy, and (b) damage to mitochondrial DNA. Evidence from animal studies suggests that replacing mitochondria in aged tissues produces benefits to health and organ function that last for long enough to be interesting as a basis for therapy. From a regulatory perspective in the US, harvested mitochondria are in the same class of treatment as harvested stem cells, so it is somewhat easier to progress to initial human trials than is the case for new drugs. It will be interesting to see the results.

We are proud to announce "The 130-Year-Old-Lifespan Trials". Our volunteers - mostly in their 70s and 80s - aim to be the first people in history to break past the current "Lifespan Barrier" for the human species, which stands at 122. We aim to give them average lifespans of 130 with the health, strength, and appearance of 50. This trial will be conducted in our new division - Biotech Explorers. Because there will be very limited space to treat people in the early years, this treatment will be provided initially to current and former astronauts, and children with certain premature aging diseases.

We've known for the past year, from animal trials, that bioreactor-grown mitochondria transplantation had the potential to dramatically speed healing, fight infection, and extend lifespan. We could see in animal tests in the brain, muscles, immune system, and skin, that the effect was real. Other types of mitochondrial transplantation have already been safely used for in human patients for rare diseases. The 130-year-old lifespan treatment will be based on Bioreactor-Grown Mitochondrial Transplantation - a technique that our parent firm Mitrix Bio has been developing for several years. We are now making animals in the lab younger routinely.

Now the job in front of us, is to make the leap with careful, rigorous human trials targeting a 130-year-old lifespan. There is so much work to be done, but our team of top scientists from major universities and other research groups are ready to take on this challenge.

Link: https://www.linkedin.com/posts/activity-7181774280462938112-oLbY

Researchers here look at cellular dysfunction that may form the earliest stages of Alzheimer's disease, prior to the accumulation of misfolded amyloid-β and cognitive decline. In general, intervening early in the progression of a disease will always be easier, given the right target. The challenge lies in identifying and understanding the causative mechanisms, in an environment in which (a) there is little access to brain tissue in the earliest stages of Alzheimer's disease, and (b) the animal models are highly artificial, as mice do not normally develop anything resembling Alzheimer's disease, and thus may not accurately reflect important aspects of the human condition.

Amyloid precursor protein (APP) is found in the cell membranes of brain cells. The brain constantly produces new APP molecules while breaking down and removing old ones. This process involves enzymatic scissors, with gamma-secretase being the final one that generates the well-known and well-studied amyloid-β (Aβ) peptides in Alzheimer's disease (AD). For a long time, it was thought that blocking gamma-secretase would be the logical step to prevent the production of toxic Aβ fragments. However, this leads to the accumulation of their precursor, the APP-C-Terminal Fragments, or APP-CTFs. Now, researchers have discovered that these fragments are also toxic to neurons. They appear to accumulate between the endoplasmic reticulum (ER), the compartment that is crucial for lipid synthesis and calcium storage, and the lysosomes, the so-called 'waste bins' of neurons, which are critical for degrading the cell's waste products.

By doing so, APP-CTFs disrupt the delicate balance of calcium within lysosomes. This disruption triggers a cascade of events. The ER can no longer effectively refill lysosomes with calcium, leading to a buildup of cholesterol and a decline in their ability to break down cellular waste. This results in the collapse of the entire endolysosomal system, a crucial pathway for maintaining healthy neurons. The new study further supports that the APP-CTFs resulting from suppressing gamma-secretase might actually be the culprit behind endolysosomal dysfunction, as observed in the very early stages of AD.

This research significantly advances our comprehension of the potential causes of disease in the early stages of AD. A remarkable outcome of this study is that these early stages could be caused by another fragment of the same APP molecule rather than Aβ. This has significant implications for the current therapeutic approaches that aim to clear the AD brain from amyloid plaques, as they tend to ignore the toxic effects of other fragments. Other attempts focus on tau proteins or neuroinflammation, which are other hallmarks of AD progression that target later events. However, early intervention is likely the key to stopping or even preventing AD.

Link: https://press.vib.be/new-mechanism-uncovered-in-early-stages-of-alzheimers-disease

Like the accumulation of senescent cells, loss of stem cell function is a problematic feature of aging. Also like the accumulation of senescent cells, loss of stem cell function is likely downstream of a combination of forms of molecular damage and consequent changes in cell behavior and cell signaling that are presently incompletely understood in detail and harder to address. Senescent cells can be cleared more readily than prevented, and stem cells may be more readily coerced into activity or replaced entirely than is the case for prevention of their age-related functional decline.

Stemness is a property of stem cells. Tautologically it is what distinguishes stem cells from somatic cells, primarily meaning (a) continual self-renewal of the population and (b) the ability to differentiate into multiple other cell types. Stem cell activity declines with age, but that doesn't necessarily mean that stemness is in decline. In muscle stem cells, for example, there is evidence for aged muscle stem cells to perform just as well as young muscle stem cells once removed from the aged tissue environment, even given a presumably greater burden of many forms of age-related damage inherent to the cells themselves. One can argue that many types of stem cell are restrained by damage to their niches, or by changes in the aged signaling environment, not by any inherent damage that reduces the potential for stemness.

In today's open access paper, researchers generate a stemness score based on transcriptomic data, and see how it changes with age in many tissues in the human body. This may be a blurred measure of capacity for stemness coupled with the impact of the aged microenvironment in which cells find themselves. Another interesting addition to this data would be to take cell samples and put them in a youthful environment, then test again and see how their stemness score changes.

Evidence of a pan-tissue decline in stemness during human aging

Although the aging process is the leading cause of human mortality and morbidity, being associated with several diseases, scientists still debate its causes and mechanisms. Among the biological pathways associated with aging, we can highlight stem cell exhaustion, which argues that during normal aging, the decrease in the number or activity of these cells contributes to physiological dysfunction in aged tissues. This concept is supported by the observation that aging is associated with reduced tissue renewal and repair at advanced ages. Moreover, longevity manipulations in mice often affect growth and cell division, which has been hypothesized to relate to stem cells.

Despite their importance, in vivo detection and quantification of stem cells are challenging, which makes it difficult to study their association with aging, especially in humans. In this context, detecting stemness-associated expression signatures is a promising strategy for studying stem cell biology. Stemness refers to a distinctive attribute marked by a series of molecular processes that delineate the essential properties of stem cells, enabling the generation of daughter cells and self-renewal. While widely employed in oncology, the exploration of this concept in gerontology has been comparatively limited.

In this study, we applied a machine learning method to detect stemness signatures from transcriptome data of healthy human tissues. The methodology, developed by Malta et al., was trained on stem cell classes and their differentiated progenitors and went through rigorous validation steps including tests in several datasets from tumor and non-tumor samples. Although initially used to study oncogenic dedifferentiation, this approach has also been employed to study normal and pathological (non-tumorous) samples. Therefore, we first downloaded expression data of 17,382 samples, divided into 30 tissues aged between 20 and 79 years, from GTEx in transcripts per million (TPM). After that, we followed assigned a stemness score to all GTEx samples.

We found that ~60% of the studied tissues exhibit a significant negative correlation between the subject's age and stemness score. The only significant exception was the uterus, where we observed an increased stemness with age. Moreover, we observed that stemness is positively correlated with cell proliferation and negatively correlated with cellular senescence. Finally, we also observed a trend that hematopoietic stem cells derived from older individuals might have higher stemness scores. In conclusion, we assigned stemness scores to human samples and show evidence of a pan-tissue loss of stemness during human aging, which adds weight to the idea that stem cell deterioration may contribute to human aging.

Exercise is well known to correlate with reduced risk of cardiovascular disease in human epidemiological studies. In animal studies, it is possible to demonstrate that increased physical activity does in fact cause a lower incidence of cardiovascular disease. Here researchers argue that stress has a significant effect on cardiovascular outcomes, as demonstrated by the fact that patients with greater degrees of stress, such as those with major depressive disorder, exhibit a larger beneficial correlation of reduced cardiovascular disease with exercise. It is interesting to ask which mechanisms are causing this association; exercise produces sweeping beneficial effects on body and brain, so picking apart specific contributions to an observed correlation is challenging. Yes, exercise reduces the consequences of stress, but depression tends to lead to reduced activity, and those depressed patients who are exercising were probably better off than their peers to start with. And so forth. For every proposition, there is a counterargument.

To assess the mechanisms underlying the psychological and cardiovascular disease benefits of physical activity, researchers analyzed medical records and other information of 50,359 participants from the Mass General Brigham Biobank who completed a physical activity survey. A subset of 774 participants also underwent brain imaging tests and measurements of stress-related brain activity. Over a median follow-up of 10 years, 12.9% of participants developed cardiovascular disease. Participants who met physical activity recommendations had a 23% lower risk of developing cardiovascular disease compared with those not meeting these recommendations.

Individuals with higher levels of physical activity also tended to have lower stress-related brain activity. Notably, reductions in stress-associated brain activity were driven by gains in function in the prefrontal cortex, a part of the brain involved in executive function (i.e., decision making, impulse control) and is known to restrain stress centers of the brain. Analyses accounted for other lifestyle variables and risk factors for coronary disease.

Moreover, reductions in stress-related brain signaling partially accounted for physical activity's cardiovascular benefit. As an extension of this finding, the researchers found in a cohort of 50,359 participants that the cardiovascular benefit of exercise was substantially greater among participants who would be expected to have higher stress-related brain activity, such as those with pre-existing depression. "Physical activity was roughly twice as effective in lowering cardiovascular disease risk among those with depression. Effects on the brain's stress-related activity may explain this novel observation."

Link: https://www.eurekalert.org/news-releases/1040861

Researchers here discuss some of the results achieved in building the Human Skeletal Muscle Aging Atlas. Focusing on stem cells in muscle tissue, they find numerous changes in gene expression relating to inflammation and reduced activity. The chronic inflammation characteristic of aging, provoked by senescent cells and innate immune reactions to molecular damage, is known to be involved in many of the dysfunctions of aging. Loss of stem cell activity, and thus a reduced supply of daughter somatic cells to replace losses and repair damage, is one of those dysfunctions.

Skeletal muscle aging is a key contributor to age-related frailty and sarcopenia with substantial implications for global health. Here we profiled 90,902 single cells and 92,259 single nuclei from 17 donors to map the aging process in the adult human intercostal muscle, identifying cellular changes in each muscle compartment.

From our in-depth analysis, we identified aging mechanisms acting in parallel across different cell compartments. In the muscle stem cell (MuSC) compartment, we found downregulation of ribosome assembly resulting in decreased MuSC activation as well as upregulation of pro-inflammatory pathways, such as NF-κB, and increased expression of cytokines, such as CCL2. In the MF microenvironment, we found several cell types that expressed pro-inflammatory chemokines, such as CCL2, CCL3, and CCL4. These cytokines may mediate the recruitment of lymphoid cells into muscle and the pro-inflammatory environment of aged muscle. Moreover, our cross-species and cross-muscle integrated aging atlas highlights an overall downregulation in gene expression, an increase in inflammation and a decrease in pro-growth, repair, and innervation pathways. Pan-microenvironment upregulation of CCL2 with age was not recapitulated in mice, suggesting an interesting human-mouse distinction in orchestration of inflammation.

Our atlas also highlights an expansion of nuclei associated with the neuromuscular junction, which may reflect re-innervation, and outlines how the loss of fast-twitch myofibers is mitigated through regeneration and upregulation of fast-type markers in slow-twitch myofibers with age. Furthermore, we document the function of aging muscle microenvironment in immune cell attraction.

Link: https://doi.org/10.1038/s43587-024-00613-3

The Strategies for Engineered Negligible Senescence (SENS) is a view of aging as accumulated damage. Drawing from the extensive scientific literature on aging, the originators of SENS created an outline of the forms of cell and tissue damage that are fundamental causes of aging, in that they occur as a natural side-effect of the normal operation of our cellular biochemistry. So we might consider the loss of vital cells due to declining stem cell function, mutations to nuclear DNA and mitochondrial DNA, cross-linking of vital molecules in the extracellular matrix, accumulated metabolic waste in long-lived cells, generation of amyloids from misfolded proteins, and the accumulation of senescent cells, for example.

These forms of damage accumulate to cause other, downstream forms of damage and dysfunction that, collectively, give rise to degenerative aging and age-related mortality. Aging is a very complex in its details, but only because cellular biochemistry is very complex. Complex systems malfunction in response to damage in complex ways, but the root causes of aging, the forms of damage noted above, are much less complex and thus much easier to visualize, describe, and intervene in.

Because SENS specifies the forms of damage in some detail, it also describes what needs to be done in order to reverse the progression of aging: repair the damage. Removing damage that is disruptive to cell and tissue function allows cell and tissues to improve their function and restore a more youthful environment. That said, there are all too few examples in which an author picks a specific age-related disease and breaks down its pathology into SENS terms. Today's article does that for Parkinson's disease, and notes that multiple different forms of damage are significant in driving its progress, is the case for near all age-related conditions. Any one narrowly focused rejuvenation therapy that addresses only one form of damage will improve matters only somewhat. It won't solve the whole problem. The SENS view of medical development inevitably leads to the development and use of many different therapies in combination.

Repairing the Damage to Shake Off Parkinson's

While most aging people don't suffer clinically-diagnosable Parkinson's, it's unsettlingly common to be afflicted by what are called "mild parkinsonian signs" or "Parkinsonism:" about one in six people ages 65 to 74, nearly one-third of those 75 to 84, and over half of those 85 and older. In addition to having to live with less severe versions of many common symptoms of Parkinson's itself (see below), people with Parkinsonism are at roughly double the risk of death in any given year as people the same age without it. Scientists have made exciting progress against Alzheimer's disease recently, with two new AmyloSENS therapies having proven themselves in clinical trials and more benefits and insights continuing to roll in. So it's a good time to take stock of where we are with cellular and molecular aging damage-repair therapies that would prevent and reverse the second most common neurodegenerative aging disorder.

The most visible symptoms of Parkinson's, and the ones on whose basis people are diagnosed with the "disease," are what are called the "motor symptoms." These symptoms result from the progressive loss of - and damage to - a specific population of neurons located in an area of the brain called the substantia nigra pars compacta (SNc). There is enough built-in redundancy in the SNc that we continue losing these "dopaminergic" neurons for decades without any obvious problems. But once our supply of these neurons dwindles to beneath the "threshold of pathology," we can no longer make these fine adjustments to the movement-control signals, and the motor symptoms of Parkinson's subvert the movement of our faces, hands, and bodies. The rejuvenation biotechnology solution to this problem is to repair the damage by replacing the lost neurons. The good news is that scientists have been working on dopaminergic neuron transplantation for longer than any other kind of true cell replacement (RepleniSENS) therapy. BlueRock Therapeutics uses proprietary bioprocessing to create stable master cell banks of what they call "universal iPSCs," which they have found to be compatible with the immune system of any patient. BlueRock scientists then differentiate these cells into dopaminergic neurons for transplant into the brains of people with Parkinson's. They recently reported positive safety results from a Phase I trial.

Our brains accumulate aggregates comprised of the protein alpha-synuclein (AS) as we age, both inside and between our neurons. People suffering from diagnosed Parkinson's and closely-related neurological aging disorders bear especially high burdens of these aggregates. Fortunately, researchers are currently running clinical trials to test numerous AmyloSENS therapies to clear AS aggregates located outside of cells. Most of these trials are in Phase II. Unfortunately, no one has yet developed LysoSENS therapies to target AS aggregates inside the cell, and it's these intracellular AS aggregates that likely inflict the greatest harm. The main reason for this seemingly backward prioritization is that it's not obvious how you would target AS aggregates inside cells. Fortunately, there is a potential path forward. Several years ago, researchers reported on a novel way to smuggle antibodies into cells intact. If researchers could instead send in catalytic antibodies (catabodies) that would chop pathological aggregates into tiny pieces inside the cell. SENS Research Foundation scientists are working to develop this intracellular aggregate-targeting catabody approach right now.

As we age, a small percentage of long-lived cells that don't divide (such as neurons and muscle cells) get completely taken over by mitochondria that have suffered the loss of huge chunks of their DNA. And of all the cells in the body, the cell type that is most susceptible to this hostile takeover is the critical population of dopaminergic neurons whose loss is central to Parkinson's. It's not clear what the connection is between these DNA deletion-bearing mitochondria and the loss of dopaminergic neurons with age, but it seems safe to assume that even if they don't kill their host neurons, deletion-bearing mitochondria sweeping across the cell leads to an energetic brownout that makes any surviving neurons less effective. The MitoSENS lab at SENS Research Foundation is working to develop three different platform technologies (including the original MitoSENS strategy of allotopic expression) to prevent, replace, or bypass mitochondrial DNA mutations.

Astrocytes are a kind of cellular butler for brain neurons, serving them energy sources and keeping their environment orderly so they can do their job. But like many cell types, astrocytes can turn senescent with age in response to many kinds of stress and injury. Researchers have reported that the brains of people with Parkinson's have a higher burden of senescent astrocytes than do people the same age who are free of the disease. To see if senescent astrocytes were really driving Parkinson's-like degeneration in living mammals, the researchers conducted an experiment using mice in whom they could destroy senescent cells at will. Scientists had engineered these mice with ApoptoSENS "suicide genes" that would detonate in senescent cells anytime the scientists "pulled the trigger" by treating them with a drug that activates the genetic system. They treated one group of these Parkinson's-like mice with the drug that would activate the ApoptoSENS "suicide genes" in any senescent cells they might harbor, while leaving another group of Parkinson's mice untreated for comparison. The control Parkinson's mice suffered a massive loss of dopaminergic neurons, developed movement problems that stand in for the symptoms of Parkinson's, and lost much of their ability to generate new neurons elsewhere in the brain. But much of this damage and dysfunction was prevented when researchers gave Parkinson's mice an ApoptoSENS treatment.

Lipid metabolism is changed and disrupted with advancing age, as is the case for all complex mechanisms in the body. There are a great many different lipids present in the body; even the list of classes of lipid is a long one. Finding specific changes that relate to aging can be interesting, but the challenge lie in better understanding how those changes come about, and whether they causes significant harm to tissues. Many age-related changes in molecular biochemistry are far downstream of the important causes of aging and do not cause much further disruption in and of themselves.

In recent years, laboratory research has shown that we may be able to counteract age-related diseases by intervening in the fundamental processes that lead to ageing. Although science has increasingly mapped out how metabolism changes during aging, large parts remained uncharted. "We wanted to add a new chapter to the atlas. Lipids are an important part of our diet, and crucial for the functioning of our body cells. Specific lipids make up the membrane of cells, which ensures that the inside and outside remain separate."

In order to add this new chapter, the research team investigated how the composition of fats changes in mice. They looked at ten different tissues, including muscles, kidneys, liver and heart. It was noticed that one type of lipid, the bis(monoacylglycero)phosphates (or BMPs), were elevated in all tissues from the older animals. Suggesting an accumulation of these lipids during aging. They then investigated whether this also happens in humans. Although it was not possible to obtain as many different tissues, the accumulation of BMP was also visible in muscle biopsies of older people. Finally, they then completed more muscle biopsies from people before and after a healthy intervention that included one hour of exercise a day and saw the level of BMPs decreased in the active participants.

Link: https://www.eurekalert.org/news-releases/1040554

The causes of idiopathic pulmonary fibrosis remain somewhat unclear, which is often the case for conditions in which treatments struggle to achieve more than a slowed progression. There is evidence for cellular senescence to drive the progression of fibrosis, but most research remains focused on the molecular biochemistry of fibroblasts, the cells responsible for building the collagen deposits characteristic of fibrotic tissue.

The process by which lung injury either leads to healing or fibrosis relies in part on what happens to a cell called a fibroblast, which forms connective tissue. During injury or illness, fibroblasts are activated, becoming myofibroblasts that form scar tissue by secreting collagen. When the job is done, these fibroblasts must be deactivated, or de-differentiated, to go back to their quiet state or undergo programmed cell death and be cleared.

This is the major distinction between normal wound healing and fibrosis - the persistence of activated myofibroblasts. That deactivation is controlled by molecular brakes. The study examined one of these brakes, called MKP1 - which researchers found was expressed at lower levels in fibroblasts from patients with idiopathic pulmonary fibrosis. By genetically eliminating MKP1 in fibroblasts of mice after establishing lung injury, the researchers saw that fibrosis continued uncontrolled.

"Instead of at day 63, seeing that nice resolution, you still see fibrosis. We argued by contradiction: when you knock out this brake, fibrosis that would otherwise naturally disappear, persists and therefore MKP1 is necessary for spontaneous resolution of fibrosis. We demonstrated that neither of the FDA approved drugs for lung fibrosis, pirfenidone and nintedanib, are able to turn off myofibroblasts. That's totally in keeping with the fact that they do slow the progression, but they don't halt or reverse disease."

Link: https://www.michiganmedicine.org/health-lab/study-reveals-potential-reverse-lung-fibrosis-using-bodys-own-healing-technique

The consensus of the research community on senescent cells in old tissues is that (a) their presence causes harm, and (b) treatments based on the selective removal of such cells will be beneficial, reversing many aspects of aging and age-related disease. These cells secrete a pro-inflammatory mix of signal molecules that is disruptive to tissue structure and function when maintained over time. Cells become senescent constantly throughout life, only to be destroyed by programmed cell death or by the immune system. With advancing age, newly created senescent cells are cleared ever more slowly, however, and thus the burden of lingering senescent cells grows throughout the body.

As the authors of today's open access paper note, the presence of senescent endothelial cells in blood vessel walls is considered to be an important contributing cause of many of the age-related dysfunctions of the vasculature. One of the more consequential of these dysfunctions is the loss of capacity to grow new capillaries, leading to a decline in capillary density in tissues throughout the body. A more sparse capillary network reduces blood flow and delivery of oxygen and nutrients to cells, harming tissue function, particularly in energy-hungry tissues such as the brain and muscles. To the extent that senolytic therapies to clear senescent cells can reverse this particular aspect of aging, we should all be in favor of senolytic therapies.

Endothelial Senescence: From Macro- to Micro-Vasculature and Its Implications on Cardiovascular Health

Cellular senescence is originally defined as the irreversible loss of proliferative potential in somatic cells, which enter a viable and metabolically active state of permanent growth arrest that is distinct from quiescence and terminal differentiation. Accumulation of senescent cells contributes to age-related tissue degeneration by developing a complex senescence-associated secretory phenotype (SASP). By secreting a plethora of factors, including pro-inflammatory cytokines, chemokines, growth modulators, matrix metalloproteinases, and compromised extracellular vesicles which represent senescence-associated phenotype, senescent cells reprogram the surrounding microenvironment and cause tissue damage, thus promoting ageing and the development of age-associated diseases.

Intervention experiments have proven that senescent cell accumulation is an important driver of age-associated functional decline, multi-morbidity, and mortality, while systemic clearance of senescent cells delays ageing and extend lifespan. Therapeutically targeting cellular senescence, known as senotherapy, to eliminate senescent cells or induce senolysis, represents a rapidly growing and promising strategy for the prevention and/or treatment of ageing-related diseases. Targeting senescent cells can improve both health-span and life-span in mice.

Endothelial cells line at the most inner layer of blood vessels. They act to control hemostasis, arterial tone/reactivity, wound healing, tissue oxygen, and nutrient supply. With age, endothelial cells become senescent, characterized by reduced regeneration capacity, inflammation, and abnormal secretory profile. Endothelial senescence represents one of the earliest features of arterial ageing and contributes to many age-related diseases.

Compared to those in arteries and veins, endothelial cells of the microcirculation exhibit a greater extent of heterogeneity. Microcirculatory endothelial senescence leads to a declined capillary density, reduced angiogenic potentials, decreased blood flow, impaired barrier properties, and hypoperfusion in a tissue or organ-dependent manner. The heterogeneous phenotypes of microvascular endothelial cells in a particular vascular bed and across different tissues remain largely unknown. Accordingly, the mechanisms underlying macro- and micro-vascular endothelial senescence vary in different pathophysiological conditions, thus offering specific targets for therapeutic development of senolytic drugs.

The balance of microbial populations making up the gut microbiome is different from individual to individual, and changes with age in detrimental ways. Pro-inflammatory microbes, as well as those that create otherwise harmful metabolites, expand in number at the expense of microbial populations that produce beneficial metabolites. Evidence strongly suggests that both variations between individuals and age-related changes in the gut microbiome can contribute to age-related disease and mortality. Here, for example, a study in rabbits shows that specific differences in the gut microbiome correlate well with observed length of life.

Longevity and resilience are two fundamental traits for more sustainable livestock production. These traits are closely related, as resilient animals tend to have longer lifespans. An interesting criterion for increasing longevity in rabbits could be based on the information provided by its gut microbiome. The gut microbiome is essential for regulating health and plays crucial roles in the development of the immune system.

The aim of this research was to investigate if animals with different longevities have different microbial profiles. We sequenced the 16S rRNA gene from soft faeces from 95 does. First, we compared two maternal rabbit lines with different longevities; a standard longevity maternal line (A) and a maternal line (LP) that was founded based on longevity criteria: females with a minimum of 25 parities with an average prolificacy per parity of 9 or more. Second, we compared the gut microbiota of two groups of animals from line LP with different longevities: females that died/were culled with two parities or less (LLP) and females with more than 15 parities (HLP).

Differences in alpha diversity and beta diversity were observed between lines A and LP, and analysis showed a high prediction accuracy (more than 91%) of classification of animals to line A versus LP. Interestingly, some of the most important microbial taxa identified were common to both comparisons (Akkermansia, Christensenellaceae R-7, Uncultured Eubacteriaceae, among others) and have been reported to be related to resilience and longevity.

In summary, our results indicate that the first parity gut microbiome profile differs between the two rabbit maternal lines (A and LP) and, to a lesser extent, between animals of line LP with different longevities (LLP and HLP). Several genera were able to discriminate animals from the two lines and animals with different longevities, which shows that the gut microbiome could be used as a predictive factor for longevity, or as a selection criterion for these traits.

Link: https://doi.org/10.1186/s12711-024-00895-6

As some of you may know, I co-founded Repair Biotechnologies with Bill Cherman. The company is presently on the development of a gene therapy approach now demonstrated to rapidly reverse atherosclerosis in mice, the condition in which fatty plaques grow to narrow blood vessels and weaken blood vessel walls. One of the possible approaches to treating aging as a medical condition is to take the list of causes of human mortality, start at the top, and work down. Atherosclerosis is the single largest cause of death in our species, through the rupture of unstable atherosclerotic plaque leading to heart attack or stroke. The burden of established plaque correlates with mortality risk, but repeatable, sizable reversal of plaque in patients cannot be achieved by the current approaches to treatment that are focused on lifestyle factors and LDL-cholesterol level in the bloodstream.

To date, we have used our Cholesterol Degrading Platform (CDP) to demonstrate rapid and profound reversal of disease in mouse models of (a) metabolic dysfunction-associated steatohepatitis (MASH), a progression of fatty liver towards liver failure that is characterized by fibrosis and loss of liver function, (b) atherosclerosis, the buildup of fatty plaques in blood vessel walls, leading to cardiovascular disease and stroke, and (c) homozygous familial hypercholesterolemia (HoFH), an inherited condition involving loss-of-function mutations in low-density lipoprotein receptors (LDLR) that causes high blood cholesterol and greatly accelerated atherosclerosis.

These three conditions are characterized by being largely irreversible under the present standards of care. While slowing the progression of disease is sometimes possible, few patients have been shown to achieve any meaningful reversal of established liver fibrosis or arterial atherosclerotic plaque, and the methods used to treat those patients are not consistently effective in other patients.

In each case, 6 to 8 weeks of once-weekly injections of CDP therapy produced sizable improvements in blood chemistry, including reductions in alanine aminotransferase (ALT), a measure of liver cell death and stress, and in histological assessments of disease. In MASH model mice, a 52% reduction in liver fibrosis was observed versus untreated controls. In the ApoE-knockout mouse model of atherosclerosis, plaque lipids were reduced by 19% while plaque collagen increased by 23% versus controls, a dramatic stabilization of unstable plaques at risk of rupture. In the LDLR-knockout mouse model of HoFH, plaque cross-sectional area decreased by 17% and mouse treadmill performance improved by 60% versus controls, a considerable improvement in cardiovascular function.

To compare this with other present efforts, the drug, resmetirom (Madrigal Pharmaceuticals), recently approved by the FDA for the treatment of MASH, has no effect on fibrosis in mice over 8 weeks of treatment. In the MAESTRO human trial in patients with comparatively mild MASH, the treated groups saw only a 25% reduction in fibrosis compared to 14% in the placebo group after 52 weeks of treatment. In the case of atherosclerosis, large clinical trials have shown that long-term treatment with statins or other low-density lipoprotein (LDL)-lowering technologies such as PCSK9 inhibitors fails to produce a reduction in atherosclerotic plaque volume of more than a few percentage points. Our CDP therapy far outperforms these approaches to treatment.

Perhaps the most interesting outcome is that we have demonstrated that a localized excess of free cholesterol is indeed a major factor in many conditions, age-related and obesity-related. It had been theorized that this was the case for liver diseases such as MASH, but lacking a technology that selectively cleared only free cholesterol, this had to remain only a compelling theory. Armed with that selective clearance technology, our results have now convincingly demonstrated that free cholesterol toxicity is a major, important target for many conditions.

Link: https://www.lifespan.io/news/new-gene-therapy-reverses-atherosclerosis-in-mice/

Species that exhibit negligible senescence tend to be long-lived, but more interestingly appear to exhibit few to none of the functional declines of degenerative aging until very late in life, quite unlike the situation for most mammals, and particularly for humans. One can argue that the most useful species that exhibit negligible senescence are those with near relative species that age more normally. The closer the relative, the more likely it is that comparing the biochemistry of the two will lead to new knowledge regarding aging. So naked mole rats versus other, less long-lived mole rats, Brandt's bat versus other shorter-lived small bats, or as in today's open access paper, the red sea urchin versus short-lived urchin species.

Whether this work on the comparative biology of aging can cost-effectively produce a basis for useful therapies in human medicine remains an open question. Research into the biochemistry of naked mole rats, probably the closest negligibly senescent species to our own species, has yet to yield a way to build useful treatments for aspects of human aging. The one experiment conducted to date involving the transfer of naked mole-rat genes into mice didn't produce the hoped-for sizable gains. It may turn out to be slow, expensive, and challenging to work towards this sort of modification of our biochemistry, as compared with the more standard approaches to medical research

Genomic signatures of exceptional longevity and negligible aging in the long-lived red sea urchin

A tremendous variety of life history strategies have evolved across the animal kingdom, including some animals that achieve remarkably long lifespans (on the order of centuries) without the physiological decline that typically accompanies aging. This phenomenon, referred to as negligible senescence, is characterized by a lack of increased mortality rate or decreased fecundity as an organism ages, in combination with maintenance of physiological function and disease resistance. Animals with extraordinary longevity and negligible senescence rely on unique mechanisms to promote long-term maintenance of tissue homeostasis and physiological function while avoiding degenerative and neoplastic diseases. Understanding these mechanisms can reveal effective strategies to achieve longevity and healthy aging.

Comparative genomics between long-lived and short-lived species is a powerful approach to understand the evolution of longevity and enables unbiased discovery of genes and pathways that regulate lifespan. This approach has been used to identify molecular signatures related to longevity and has uncovered both shared and distinct strategies to modulate aging and disease resistance. Sea urchins represent a promising group of organisms to advance our understanding of lifespan determination and healthy aging. There are approximately 1,000 extant sea urchin species that exhibit a wide range of lifespans, including species with exceptional longevity and negligible senescence.

Life history data indicates that the red sea urchin, Mesocentrotus franciscanus, is one of the Earth's longest-living animals. It is reported to live more than 100 years and shows negligible senescence as defined by indeterminate growth, life-long reproduction, and no age-associated increase in mortality rate or increased incidence of disease, including no known cases of cancer. Negligible senescence has also been reported for other sea urchin species despite a wide range of lifespans. This includes the variegated sea urchin, Lytechinus variegatus, which is reported to live 3-4 years, the painted sea urchin, Lytechinus pictus, reported to live 5-7 years, and the purple sea urchin, Strongylocentrotus purpuratus, reported to live longer than 50 years.

Studies to date, conducted within the framework of known theories of aging, have demonstrated that both short-lived and long-lived sea urchin species lack many hallmarks of aging. Sea urchins maintain telomere length, antioxidant and proteasome enzyme activities, and regenerative capacity, and exhibit little accumulation of oxidative cellular damage with age. Gene expression studies using tissues of long-lived species indicate that key cellular pathways involved in protein homeostasis, tissue regeneration, and neurological function are maintained with age. Although genomes have been assembled for several sea urchin species, including S. purpuratus, L. variegatus, and L. pictus, to date no high-quality genome has become available for the long-lived red sea urchin M. franciscanus. Here we report a chromosome-level assembly for the red sea urchin genome. Targeted analysis of this genome and comparisons between long- and short-lived species sheds light on the molecular, cellular, and systemic mechanisms that promote longevity and negligible senescence.

A number of large epidemiological studies provide evidence for long-term exposure to greater levels of air pollution to accelerate the onset and progression of age-related disease. A few of these manage to control for the tendency for wealthier people to avoid living in areas with higher particulate air pollution, and the correlation with worse health remains. Mechanistically, it is thought that particulates provoke greater chronic inflammation via their interaction with lung and other tissues, and this in turn contributes to the cell and tissue dysfunction that leads to age-related disease.

The present study assessed cognitive test performance in English older adults in relation to long-term air pollution exposure at the residential address. The follow-up period of 15 years and the large number of repeated measurements make the present study unique in terms of design and data availability. Increasing exposure to NO2, PM10 and PM2.5 was consistently found to be associated with decreased memory and executive function test performance, whilst ozone showed the opposite effect. The results remained similar in the analysis including residents of London only, for whom exposure to NO2 and PM was higher. As an illustrative example, the decline in memory and executive function scores per interquartile range (IQR) increase in long-term NO2 exposure was found equivalent to ageing by about 1.5 and 4 years respectively.

In order to fully elucidate the potentially adverse cognitive effects of air pollution, further study into the underlying biological pathways and mechanisms through which air pollution may contribute to cognitive decline is required alongside the expanding epidemiological work. Translocation of inhaled particles from the lung to the brain via the bloodstream provides one possible pathway through which particulate matter may affect cognition, as well as inhalation through the nose and transportation to the olfactory bulb via olfactory nerves. Evidence for such pathways is currently limited and further experimental studies are required.

Link: https://doi.org/10.1186/s12940-024-01075-1

Many compounds are now known to have some positive influence on mitochondrial function. The biochemistry is complex and incompletely understood. Even in the well-studied cases, there are hypotheses regarding the mechanism of action, but little certainty. In general, improvement of the quality control mechanism of mitophagy appears to be a necessary factor in the improvement of mitochondrial function in old tissues, but that appears to happen as the result of many different types of intervention. Here, researchers note that a class of bacterial peptides originating from the gut microbiome appear to improve mitochondrial function in intestinal tissue. This may be the basis for yet another type of treatment or supplement to modestly improve mitochondrial function. Those developed to date struggle to improve on the effects of exercise, however.

Mitochondrial dysfunction critically contributes to many major human diseases. The impact of specific gut microbial metabolites on mitochondrial functions of animals and the underlying mechanisms remain to be uncovered. Here, we report a profound role of bacterial peptidoglycan muropeptides in promoting mitochondrial functions in multiple mammalian models. Muropeptide addition to human intestinal epithelial cells (IECs) leads to increased oxidative respiration and ATP production and decreased oxidative stress. Strikingly, muropeptide treatment recovers mitochondrial structure and functions and inhibits several pathological phenotypes of fibroblast cells derived from patients with mitochondrial disease.

In mice, muropeptides accumulate in mitochondria of IECs and promote small intestinal homeostasis and nutrient absorption by modulating energy metabolism. Muropeptides directly bind to ATP synthase, stabilize the complex, and promote its enzymatic activity in vitro, supporting the hypothesis that muropeptides promote mitochondria homeostasis at least in part by acting as ATP synthase agonists. This study reveals a potential treatment for human mitochondrial diseases.

Link: https://doi.org/10.1016/j.celrep.2024.114067