Fight Aging! Newsletter, March 25th 2024

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Reporting on a Nine Month Self-Experiment in Taurine Supplementation

Today's post is a report from the community on the impact of taurine supplementation on a few biomarkers of interest. Taurine is a dietary amino acid, and circulating levels of taurine influence any number of biological processes. Taurine levels decrease with age in a variety of species; in humans circulating taurine is halved by age 50. You might recall that supplementation with taurine was demonstrated to modestly extend life in mice and improve health in old non-human primates. This may be largely due to enhanced performance of the antioxidant glutathione, and you might recall that other approaches to upregulation of glutathione activity have been shown to produce benefits in old humans, dampening oxidative stress and associated inflammation.

A few human clinical trials of taurine supplementation have been conducted, but the results are not all that conclusive, other than to demonstrate that this form of intervention is very safe. So why not give it a try, and see what results? If you look back in the Fight Aging! archives, you'll find an outline for a self-experiment with taurine supplementation. Taurine is cheap and readily available as as a supplement, and inexpensive blood tests can be used to assess outcomes. Here, the self-experimenter chose to focus on phenotypic age and the biomarkers used to construct this assessment of phenotypic age. Only one marker of oxidative stress was used, an assessment of circulating oxidized LDL particles.

  • The self-experimenter was a vegetarian in his 50s.
  • 3 grams per day of taurine was taken orally for 9 months.
  • Diet and lifestyle was kept consistent, as much as possible in a busy life.
  • Phenotypic age acceleration: -9.00 to -10.85 years
  • Albumin: 4.1 to 4.3 g/dL (reference range is 3.6-5.1 g/dL)
  • Creatine: 0.72 to 0.65 mg/dL (desired range is 0.70-1.30 mg/dL)
  • Fasting Glucose: 93 to 90 mg/dL (desired range: 65-99 mg/dL)
  • C-Reactive Protein: 0.30 to 0.34 mg/L (considered low risk under 1.00 mg/L)
  • Alkaline Phosphatase (ALP) 53 to 50 U/L (reference range is 35-144 U/L)
  • Lymphocyte Percentage 33.1% to 40.7% (normal range is 20% to 40%)
  • Mean Cell Volume (MCV): 87.8 to 88.6 fL (desired range is 80.0-100.0 fL)
  • Red Cell Dist Width (RDW): 13.3% to 13.5% (desired range is 11.0-15.0%)
  • White Blood Cells (WBC): 4.8 to 3.9 Thousand/uL (reference range is 3.8-10.8 Thousand/uL)
  • Taurine: 43.6 to 114.9 umol/L (reference range is 29.2-132.3 umol/L)
  • Oxidized LDL: 105 to 82 ng/mL (reference range is 10-170 ng/mL)
  • LDL and HDL cholesterol levels were largely unchanged.
  • Absolute Lymphocytes: 1589 to 1587 cells/uL (desired range is 850-3900 cells/uL)
  • Absolute Monocytes: 312 to 269 cells/uL (desired range is 200-950 cells/uL)
  • Absolute Neutrophils: 2832 to 1981 cells/uL (desired range is 1500-7800 cells/uL)
  • Lymphocyte: Monocyte Ratio: 5.1 to 5.9
  • Other complete blood count statistics were largely unchanged.

Going from the data provided, the supplementation successfully increased a low circulating taurine level to a high circulating taurine level as intended, and modestly reduced phenotypic age. The most interesting change seen in the biomarkers making up the phenotypic age metric is the increased lymphocyte percentage. This change was entirely due to the absolute neutrophil count decreasing from 2832 to 1981 cells/uL, while other absolute counts for white blood cell types remained much the same. Neutrophil counts can be raised temporarily by transient infection or inflammation, but per the self-experimenter, ~2800 had been a fairly consistent level for absolute neutrophil count for some years prior to this self-experiment. The observed reduction is thus a novel change, and likely due to the taurine supplementation.

A second interesting point is the reduction in oxidized LDL, a marker of oxidative stress and also a contributing factor in the development of atherosclerosis. As a sidebar, also note the low creatine levels, characteristic of vegetarians since dietary creatine is mostly found in meat.

The modestly favorable results shown here form only a single data point and should be taken as an anecdote, of course. It would be interesting to see the results of a few hundred participant clinical trial of taurine supplementation that focused on the various modern approaches to measuring biological age, such as epigenetic clocks. One shouldn't expect there to be a rush to do this, however. Trials are expensive, and there is little spare funding to be found in the business of selling well-established supplement compounds. At the end of the day modest effect sizes are modest effect sizes, and we'd like to focus on better approaches to the problem of aging - but if the intervention is both very cheap and very safe, then it may well be worth the effort to further establish the degree to which it can be useful.

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Mitochondrial Dysfunction in the Aging of the Brain

Mitochondria are the power plants of the cell, primarily responsible for packaging adenosine triphosphate (ATP) molecules as chemical energy stores for use throughout the cell. Hundreds of mitochondria swarm inside every cell, the descendants of ancient symbiotic bacteria. These organelles retain many features characteristic of bacteria. For example, mitochondria contain a small circular genome, depleted of genes that have moved into the cell nucleus over evolutionary time. Mitochondria also constantly divide, fuse together, and swap component parts. Mitochondrial quality is controlled by the processes of mitophagy that recycle worn or damaged mitochondria, delivering them to a lysosome to be engulfed and then dismantled into raw materials.

Dysfunction of mitochondria is characteristic of aging. Cells in aged tissues exhibit changes in mitochondrial dynamics, failure of mitophagy, damage to mitochondrial DNA, increased oxidative stress as the result of changes in the way mitochondria produce ATP, and reduced ATP production. When taking place in all cells throughout a tissue, this has a profoundly harmful effect on tissue function. This is particularly true in energy-hungry tissues such as muscle and the brain. The latter is the subject of today's open access review paper, a look at what is known of the role of age-related mitochondrial dysfunction in the aging of the brain.

Mitochondrial Dysfunction: A Key Player in Brain Aging and Diseases

Despite the human brain weighing only 2% of the total body weight, almost 20% of the basal oxygen is consumed by this organ in order to produce enough energy for the approximately 86 billion neurons and 85 billion glial cells that comprise it. Glucose is the main source of energy in the adult brain and its oxidation produces ATP almost entirely through oxidative phosphorylation (OXPHOS) in the mitochondria, thus underpinning the importance of this organelle for brain homeostasis. Energy is constantly required to sustain the synthesis of neurotransmitters as well as to maintain the membrane potential needed for action potential propagation and synaptic transmission, including the re-uptake of neurotransmitters from the synaptic cleft.

A large body of evidence demonstrates that bioenergetic impairments as well as disturbances in the OXPHOS machinery of mitochondria occur in the brain during aging. Although efficient, OXPHOS produces reactive oxygen species (ROS) as a byproduct, and the brain is especially susceptible to oxidative damage because it contains a plethora of oxidizable substrates, such as fatty acids, an abundance of catalytic transition metals, and a high rate of oxygen consumption per gram of tissue. Several studies have demonstrated an association between the oxidative damage of DNA (8-OH-dG), lipids (MDA and 4-HNE), and proteins (carbonyls and protein 3-nitrotyrosine) with brain aging.

It has been proposed that the impairment of brain mitochondrial function during aging might be the result of the decreased electron transfer rate of Complex I and Complex IV. Interestingly, gene expression of mitochondrial subunits for Complexes I, III, IV, and V have been found to be down-regulated in old TG2576 mice and Ndufs4 knock-out mice, models of Alzheimer's disease pathology and of Complex I deficiency, respectively.

Importantly, the effects of neuronal oxidative stress are normally counteracted by a well-developed antioxidant system; however, during aging the antioxidant defense system may become overwhelmed. A shift to a pro-oxidized state, determined by a decrease in the GSH/GSSG ratio, with GSH serving as the body's "master" antioxidant and GSSG as the oxidized form of GSH, was found in forebrain and cerebellum from 21 month-old mice, as compared to 3 month-old controls. As the brain ages, the effects of oxidative stress on mtDNA may lead to mutations and deletions and subsequently impair the OXPHOS complexes, increase ROS production, and further exasperate oxidative stress levels. This vicious cycle may lead to decreased energy supply, increased susceptibility to apoptosis, and a progressive decline in tissue function. A 10-fold increase in mtDNA levels of 8-OHdG as well as elevated mtDNA point mutations and deletions in frontal cortex, substantia nigra, and putamen from elderly individuals above the age of 67 have been reported.

Mitochondrial quality control mechanisms, such as fusion, fission, and mitophagy, are important processes used to preserve cells against damage; however, reports indicate that as the mtDNA mutation load increases during aging these processes may begin to lose their efficiency. For example, Drp1, a protein essential for mitochondrial fission, has been shown to be down-regulated in old C57BL/6 mice, and its removal in adult mouse forebrain resulted in altered mitochondrial morphology and mitochondrial transport to the synapse, as well as decreased oxygen consumption and ATP production. Importantly, these findings suggest that mitochondrial dynamics, mitophagy, and biogenesis become impaired during aging, and may be involved in the pathogenesis of various neurodegenerative diseases.

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The Puzzling Lack of Autoimmunity in Centenarians

Today's open access paper presents an interesting discussion of the apparent lack of age-related autoimmunity in centenarians. The immune system becomes ever more dysfunctional with age, and some of that dysfunction can take the form of maladaptive changes that either (a) allow the immune system to direct attack tissues or (b) disrupt important relationships between immune cells and the rest of a tissue. Far from all of these issues are well understood or even well identified as discrete problems distinct from the rest of degenerative aging. A potential type 4 diabetes was only comparatively recently discovered, for example.

The oldest of old people tend to be robust in comparison to age-matched peers who die at younger ages. In one sense this is self-evident, as they would have to be robust in order to avoid a higher risk of mortality that would lead to an earlier death. In another sense, it is interesting to examine the physiological and biochemical details of this robustness. That said, centenarians are rare survivors from a very large birth cohort, and it doesn't take much of a change in the odds of survival over decades of later life to tilt the characteristics of centenarians in one direction or another. Thus it isn't clear that discoveries made in long-lived people actually have much practical application to medicine; they may largely represent only small gains.

Still, as asked by the authors of today's paper, why is it the case that age-related autoimmunity seems absent from the oldest segment of the population? Is this actually an absence, or a case of too little examination of the fine medical details in these usually frail individuals? If it is an absence, what does that say about the function of the immune system in late life, and the details of the role of immune system alterations, damage, and adapative and maladaptive changes in age-related mortality?

Autoimmunity in centenarians. A paradox

Autoimmune diseases (ADs) constitute one of the most prevalent chronic conditions. During the aging process and through continuous exposure to various stressors, pathogens, and other environmental factors throughout life (i.e., exposome), accompanied by the aging of the immune system (i.e., immunosenescence) and the onset of age-related chronic diseases, a persistent proinflammatory systemic environment can theoretically increases the probability of developing an AD. This is because the immune system's responsiveness would be lower and irregular when exposed to a greater number of stressors and causes of cellular dysregulation. For this reason, age has been considered to be an important risk factor for autoimmunity.

Aging implies a complex array of changes and remodeling in homeostatic mechanisms that control the immune system, both in terms of numbers and functions of the different cellular subsets. Rather than being a mere process of immunosenescence, age-related transformations redesign the immune architecture and the balance between proinflammatory and anti-inflammatory protective factors. Cellular senescence occurs in response to endogenous and exogenous stresses, including telomere dysfunction, oncogene activation, and persistent DNA damage. Immunosenescence includes three events: a reduction in immune response, an increase in the inflammatory and oxidation background (inflammaging and oxiinflammaging), and a production of autoantibodies.

However, there is a group of humans, increasingly observed, that contradicts this paradigmatic view, and whose health phenotype raises numerous questions for which there are currently no answers. Centenarians represent the most successful model of biological aging in humans. These individuals, who have a chronological age equal to or greater than 100 years, have special health characteristics, mostly partially known, that contradict the previously described theoretical concept of autoimmunity in the elderly.

Unfortunately, there is a lack of robust evidence describing or discussing autoimmunity in centenarians. Even studies describing the health phenotypes of centenarians worldwide report that the prevalence of ADs in this population is practically nil, except for some series mentioning imprecise data and methodology. Therefore, this field represents a niche of original, novel, and relevant knowledge for the in-depth understanding of new pathophysiological mechanisms, protective and risk factors for autoimmunity, based on the identification of new markers, signaling pathways, and targets related to aging, adaptation, or remodeling of the immune system. Herein we discuss current questions and gaps regarding the understanding of autoimmunity in centenarians, proposing possible hypotheses that would explain this scenario.

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TDP-43 Pathology May Extend to the Vasculature and Blood-Brain Barrier

TDP-43 is one of a small number of proteins that can become altered in ways that lead to the formation of solid aggregates that, directly and indirectly, cause cell dysfunction and death in the brain. In the case of TDP-43, this proteopathy contributes to amyotrophic lateral sclerosis (ALS), frontotemporal lobar degeneration (FTLD), and what is now called limbic predominant age-related TDP-43 encephalopathy (LATE). This was a more recent discovery than other aggregates involved in neurodegenerative conditions, such as amyloid-β, tau, and α-synuclein, and so the pace of discovery for TDP-43 is a little faster; more remains to be uncovered of the biochemistry of TDP-43 pathology than is the cost for the other problematic proteins.

In today's research materials, the scientists involved report on a potential role for TDP-43 in dysfunction of the vasculature and blood-brain barrier in the aging brain. Unmodified TDP-43 appears necessary for a number of processes, and depletion may be a contributing cause of some of the vascular issues seen in neurodegenerative conditions associated with TDP-43 aggregation. An important vascular issue is leakage of the blood-brain barrier, allowing unwanted cells and molecules to enter the brain to cause inflammatory reactions or other damage. That said, the usual challenges apply to the finds here, in that knowing that a mechanism exists doesn't tell us how important it is versus other mechanisms known to contribute to this problem.

The integrity of the blood-brain barrier depends on a protein that is altered in some neurodegenerative diseases

The TDP-43 protein is a key factor in nervous system function and neuronal plasticity. It is a DNA- and RNA-binding protein that regulates gene expression, and its dysfunction has been associated with various neurodegenerative disorders. Although much progress has been made recently in understanding the functions of TDP-43 in neurons, its exact role in the endothelial cells that make up the circulatory system, the formation of new blood vessels (angiogenesis), and vascular function was not yet known.

The vascularization of the central nervous system and the formation of the blood-brain barrier are regulated by different signalling pathways. For example, the integrin signalling pathway that regulates the interaction of cells with the extracellular matrix and the signalling carried out by the transcription factor β-catenin. "In the study, we found that TDP-43 deficiency alters the extracellular matrix that surrounds blood vessels and reduces β-catenin signalling in endothelial cells. Thus, mice without endothelial TDP-43 protein show multiple haemorrhages and vascular degeneration in the brain and spinal cord."

The authors also identify TDP-43 in endothelial cells as a potential contributing factor to the vascular defects that trigger the inflammatory response observed in patients diagnosed with TDP-43-associated diseases. "Some alterations in the blood vessels of the central nervous system - defects in the integrity of the blood-brain barrier or degeneration of endothelial cells - are associated with inflammatory and immune responses that can cause neuronal loss. This process of neuronal degeneration underlies the origin or progression of various neurological disorders - stroke, diabetic retinopathy - and some neurodegenerative diseases such as Alzheimer's disease, ALS, or LATE (Limbic-predominant age-related TDP-43 encephalopathy)."

Endothelial TDP-43 controls sprouting angiogenesis and vascular barrier integrity, and its deletion triggers neuroinflammation

TAR DNA-binding protein 43 (TDP-43) is a DNA/RNA-binding protein that regulates gene expression, and its malfunction in neurons has been causally associated with multiple neurodegenerative disorders. Although progress has been made in understanding the functions of TDP-43 in neurons, little is known about its roles in endothelial cells (ECs), angiogenesis, and vascular function. Using inducible EC-specific TDP-43-knockout mice, we showed that TDP-43 is required for sprouting angiogenesis, vascular barrier integrity, and blood vessel stability.

Postnatal EC-specific deletion of TDP-43 led to retinal hypovascularization due to defects in vessel sprouting associated with reduced EC proliferation and migration. In mature blood vessels, loss of TDP-43 disrupted the blood-brain barrier and triggered vascular degeneration. These vascular defects were associated with an inflammatory response in the CNS with activation of microglia and astrocytes. Mechanistically, deletion of TDP-43 disrupted the fibronectin matrix around sprouting vessels and reduced β-catenin signaling in ECs. Together, our results indicate that TDP-43 is essential for the formation of a stable and mature vasculature.

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Human Exosomes Harvested from Stem Cells in Urine Produce Rejuvenation in Mice

Exosomes are a class of extracellular vesicle, membrane-wrapped packages of molecules that carry a sizable fraction of the chemical communications that takes place between cells. The various types of extracellular vesicle are presently ordered in a taxonomy by their size rather than any more subtle combination of features. Those subtle features definitely exist; exosomes from different cell types and different environmental circumstances are quite different from one another in any number of ways. The present taxonomy of extracellular vesicles is indicative of a lack of detailed understanding regarding (a) the mechanisms determining formation of extracellular vesicles, as well as (b) the factors determining the contents of extracellular vesicles.

The stem cell therapies that have long been available via medical tourism, and were later approved by regulators, are slowly morphing into exosome therapies. Extracellular vesicles are more easily harvested, stored, and delivered than is the case for cells. Since transplanted cells die quickly, the benefits of first generation stem cell therapies, such as months-long reductions in chronic inflammation, are mediated by cell signaling, such as the release and uptake of extracellular vesicles. Exosome therapies are now broadly available in overseas clinics, and are working their way into the more heavily regulated medical system. It is even possible to purchase amniotic fluid derived exosomes from providers in the US, provided one has a physician who agrees to accept delivery and make use of them.

The approach to exosome therapy noted in today's open access paper is an interesting one. The source of cells is those that are shed into urine. When humans are the donors, this is a good way to obtain enough material for a mouse study, but a scaling process would have to be put in place for use in human patients. That means either a great deal of harvesting from many donors, or the more challenging approach of developing a well-managed cell line that can produce exosomes in bulk.

Extracellular vesicles from human urine-derived stem cells delay aging through the transfer of PLAU and TIMP1

Transplantation of young and healthy stem cells has been shown to increase health and lifespan in aged mice. A study has reported that the intraperitoneal injection of muscle stem/progenitor cells from young mice can extend healthspan and lifespan in progeroid mice. Interestingly, the transplanted cells are not detected in many rejuvenated tissues, suggesting that their anti-aging effects are mainly mediated by activating endogenous cells in the host through paracrine factors.

Secretion of extracellular vesicles (EVs) is a part of normal physiology in both prokaryotes and eukaryotes. EVs are selectively enriched with various molecules such as proteins and nucleic acids from their parent cells and serve as a key mediator of cell paracrine action by transferring these molecules to their recipient cells. Stem cells-derived EVs have become an attractive option for therapeutic uses because these nanoparticles have fewer safety concerns and are easy to store, transport, and use compared with stem cells themselves. Recent studies have reported that EVs from embryonic stem cells, induced pluripotent stem cells, adipose stem cells, hypothalamic stem/progenitor cells, and umbilical cord- or umbilical cord blood-derived mesenchymal stem cells (MSCs) can alleviate aging-related phenotypes in aged mice, indicating the promising potential of EVs as an anti-aging agent. Nevertheless, the use of these stem cells as the "factory" to harvest EV are limited by many problems, such as the ethical issue for cell use, the lack of enough source to obtain cells, or/and the requirement of fast, convenient, and invasive procedures for cell isolation.

As compared with stem cells from other sources, urine-derived stem cells (USCs) can be collected by a low-cost, simple, and safe method without ethical concerns. We have previously demonstrated that the local injection of USC-derived EVs (USC-EVs) can accelerate wound repair in diabetic mice by enhancing angiogenesis. We have also found that the intravenous injection of USC-EVs can reduce bone loss and enhance bone strength in osteoporotic mice. Moreover, these nanovesicles can exert protective effects against glucocorticoid-induced osteonecrosis by promoting angiogenesis, and suppress cell apoptosis after systemic administration. In our previous study, we obtained proteomic data regarding the differentially expressed proteins between USC-EVs and USCs. In this study, we further analyzed these data and found that a class of USC-EVs-enriched proteins have been previously shown to possess anti-aging function, such as tissue inhibitor of metalloproteinases 1 (TIMP1), plasminogen activator urokinase (PLAU), insulin-like growth factor binding protein 5, senescence marker protein-30, and connective tissue growth factor. Thus, we hypothesized that USC-EVs might be capable of rejuvenating old organs from aging via transferring of anti-aging proteins.

Here, we tested the effects of USC-EVs on cellular senescence in vitro and on the aging-related phenotypes in different organs of both senescence-accelerated mice and natural aging mice. The intravenous injection of USC-EVs improves cognitive function, increases physical fitness and bone quality, and alleviates aging-related structural changes in different organs of senescence-accelerated mice and natural aging mice. The anti-aging effects of USC-EVs are not obviously affected by the USC donors' ages, genders, or health status. Proteomic analysis reveals that USC-EVs are enriched with PLAU and TIMP1. These two proteins contribute importantly to the anti-senescent effects of USC-EVs associated with the inhibition of matrix metalloproteinases, cyclin-dependent kinase inhibitor 2A (P16INK4a), and cyclin-dependent kinase inhibitor 1A (P21cip1). These findings suggest a great potential of autologous USC-EVs as a promising anti-aging agent by transferring PLAU and TIMP1 proteins.

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Calorie Restriction Induces Plasminogen Production to Protect Muscle Tissue

Researchers here identify a mechanism by which the practice of calorie restriction promotes muscle stem cell function, and thus repair and maintenance of muscle tissue. In animal studies calorie restriction is shown to produce both (a) a short-term effect associated with improved regeneration, and (b) a long-term effect in the sense of slowing the progressive loss of muscle mass and strength leading to sarcopenia. The research community will no doubt build on the findings here to suggest pharmaceutical approaches to mimic this aspect of calorie restriction.

Using an unbiased proteomics approach, we report here that calorie restriction (CR) promotes a hypersecretion of proteins from the liver, including those involved in coagulation and fibrinolysis. We also demonstrated the role of liver-derived plasminogen in mediating satellite cell expansion and enhanced muscle regeneration during CR. We showed that the mediation was accomplished by an upregulation of the plasminogen receptor Plg-RKT specifically on muscle satellite cells, promoting downstream ERK signaling and subsequent proliferation. We therefore propose that CR induces a distinct crosstalk between liver and muscle that increases muscle resilience.

Using the MetRSL274G/bio-orthogonal non-canonical amino acid tagging (BONCAT) model to characterize an organ-specific secretome in vivo, our study aimed to investigate the systemic and extracellular effects of CR and how this could alter tissue resilience. We chose to investigate metabolic tissues with known effects of CR, including liver, skeletal muscle, and adipose tissue. We were intrigued by the induction of secreted proteins from the liver with CR, which was not evident in proteins secreted by either adipose or muscle tissues. The induction of the secretome was observed just 2 weeks after CR and continued throughout the 3-month CR period.

Interestingly, CR increased secretion of proteins associated with the resolution of both coagulation and hemostasis. Although not the focus of this paper, these findings suggest increased secretion of fibrinolytic factors from the liver as a possible mechanism to improve cardiovascular health with CR, given that elevated hemostatic factor levels are typically associated with worsened clinical cardiovascular outcomes, such as increased risk of cardiovascular death. Conversely, CR dampened secretion of proteins associated with increased inflammation, which is consistent with known anti-inflammatory effects of CR and further validates our proteomics approach.

To demonstrate the relevance of our findings to human biology, we analyzed tissues from the CALERIE trial of human CR. We observed replication of many of the mouse phenotypes, including increased circulating plasminogen, decreased PAI-1, satellite cell expansion, and increased Plg-RKT expression on the satellite cells of human CALERIE study participants. This study also reports the expansion of satellite cells in human muscle with CR. This finding is critical to suggest translational relevance to the rodent data observed for more than a decade. Moreover, the increased expression of the plasminogen receptor Plg-RKT observed on human satellite cells during CR provided additional support for the theory that our rodent model is relevant to human biology.

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Interesting Insight into the Relationship Between TP53, Telomerase, and Telomere Length

Telomeres are repeated sequences at the end of chromosomes. A little of that length is lost with each cell division, and in this way telomere length acts as a countdown. Somatic cells become senescent or self-destruct when telomere length becomes too short, thanks in large part to the activity of TP53. This is a protective mechanism, removing cells that can become cancerous or otherwise harmful. Stem cells employ telomerase to maintain long telomeres, and supply a tissue with new daughter somatic cells to take the place of those lost to telomere shortening. Thus a tissue has some turnover of cells, allowing a degree of protection from the most harmful cell malfunctions. This study provides some insight into how these relationships play out in practice by sabotaging telomerase and p53, and observing the results.

Telomerase activity is restricted in humans and telomere attrition occurs in several tissues accompanying natural aging. Critically short telomeres trigger DNA damage responses and activate p53 which leads to apoptosis or replicative senescence. These processes reduce cell proliferation and disrupt tissue homeostasis, thus contributing to systemic aging. Similarly, zebrafish have restricted telomerase expression, and telomeres shorten to critical length during their lifespan.

Telomerase-deficient zebrafish (tert -/-) is a model of premature aging that anticipates aging phenotypes due to early telomere shortening. tert -/- zebrafish have impaired cell proliferation, accumulation of DNA damage markers and p53 response. These cellular defects lead to disruption of tissue homeostasis, resulting in premature infertility, gastrointestinal atrophy, sarcopenia, and kyphosis. Such consequences contribute to its premature death.

Here we reveal a genetic interdependence between tp53 and telomerase function. Mutation of tp53 abrogates premature aging of tert -/- zebrafish, prolonging male fertility and lifespan. However, it does not fully rescue healthspan. tp53mut tert -/- zebrafish retain high levels of inflammation and increased spontaneous cancer incidence. Conversely, loss of telomerase prolongs the lifespan of tp53mut single mutants. Lack of telomerase reduces two-fold the cancer incidence in double mutants and increases lifetime survival. Thus, we observe a reciprocal rescue of tp53mut and tert -/- that ameliorates lifespan but not spontaneous cancer incidence of tp53mut, likely due to higher levels of inflammation.

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Aspects of Skin Aging Encourage Metastasis in Melanoma

There are many ways in which the aging of tissue makes cancer both more likely to occur and more aggressive once it does occur. Here researchers focus in on specific changes in aged skin tissue that make melanoma cancers more likely to become metastatic and spread to other organs. Interestingly, it is an indirect effect on cell signaling that is mediated by increased stiffness of the skin extracellular matrix, an issue in many aging tissues that has many root causes, not just the one noted here. Nonetheless, if metastasis could be shut down, then cancer would become a much more tractable problem, particularly if control of metastasis were to be combined with improved approaches to the early detection of cancer.

Previous research has shown that a protein called HAPLN1 helps maintain the structure of the extracellular matrix, a network of molecules and minerals that provide structural support, to keep the skin supple. As people age, they release less HAPLN1, which causes the skin to stiffen. A new study shows that reduced HAPLN1 indirectly increases ICAM1 levels by causing stiffening, which alters cellular signaling. The increase in ICAM1 contributes to angiogenesis, or the growth of new blood vessels that supply the tumors with nutrients and help them grow. The blood vessels are also leakier, making it easier for tumor cells to escape from the initial tumor site and spread to distant areas of the body.

Treating older mice with melanoma with drugs that block ICAM1, however, prevents these changes, shrinking their tumors and reducing metastasis, researchers demonstrated. The researchers are now studying ICAM1's activities to develop more precise ways of targeting it with drugs, which might lead to new approaches to treating older people with melanoma. The discoveries might also lead to new approaches to treating other age-related cancers. Previous therapies targeting growth factors that contribute to angiogenesis have failed in many tumor types, including melanoma. But ICAM1 provides a promising new target.

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Yet More Development of Proteomic Signatures of Longevity

The cost of obtaining transcriptomic and proteomic data, and then using machine learning techniques to develop insights based on that data, has fallen dramatically over the past decade. As a result there is a proliferation of signatures of aging and longevity, as many different research groups analyze many different large transcriptomic and proteomic databases. The example here is one of a number of such signatures created with the idea of finding potential targets for therapy. It is far from clear that one can alter any of the various protein levels related to aging and longevity and obtain meaningful benefits, however. A change can be a side-effect of aging, and end-stage consequence that causes few downstream consequences in and of itself, and will achieve little if reversed.

The identification of protein targets that exhibit anti-aging clinical potential could inform interventions to lengthen the human health span. Most previous proteomics research has been focused on chronological age instead of longevity. We leveraged two large population-based prospective cohorts with long follow-ups to evaluate the proteomic signature of longevity defined by survival to 90 years of age. Plasma proteomics was measured using a SOMAscan assay in 3,067 participants from the Cardiovascular Health Study (CHS) and 4,690 participants from the Age Gene/Environment Susceptibility-Reykjavik Study (AGES-Reykjavik). Logistic regression identified 211 significant proteins in the CHS cohort using a Bonferroni-adjusted threshold, of which 168 were available in the AGES-Reykjavik replication cohort and 105 were replicated.

The strongest associations in CHS that were replicated in AGES-Reykjavik were for GDF-15, NT-pro-BNP, b2-microglobulin, RNase 1, and HE4, providing confidence in such previously identified proteins in aging research. Less-established markers of mortality in the general population, such as angiopoietin-2, and PXDN, also had support in both cohorts. Our study design leveraging a longevity outcome, as opposed to overall survival only, paired with long follow-up time revealed that nearly half (269 out of 471) of proteins associated with overall survival were not associated with exceptional longevity in the CHS, though the strongest associations remained consistent between the two outcomes.

A larger share of significant proteins was associated with both overall survival and longevity in AGES-Reykjavik, which may have occurred due to increased power to detect significant associations in AGES-Reykjavik. This observation suggests that extrapolating findings from associations with overall survival to longevity might be inappropriate. Moreover, we demonstrate for the first time in proteomics studies of longevity that physical and cognitive function may partially mediate associations between proteins and longevity, and that the amount of mediation may depend in part on which particular functional measures are used in the analysis.

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Aging Affects the Neural Regulation of Metabolism and Desired Food Intake

Researchers here make an interesting discovery in rats, finding an age-related change in the structure of specific neurons that encourages greater intake of calories and dysfunctional metabolism by suppressing satiation feedback. In rats this mechanism can be manipulated by diet and genetics to alter the pace at which older rats become overweight and metabolically abnormal. As is often the case in research, this discovery is a proximate cause to the problem of metabolic regulation, and it is entirely unclear as to how the deeper mechanisms of aging, such as chronic inflammation, mitochondrial dysfunction, and so forth, are causing it or otherwise relate to it.

As we get older, we become more prone to being overweight and obesity. Obese people are more susceptible to diabetes, hyperlipidemia, and other chronic diseases. Previous studies have suggested that middle-age weight gain is caused by a decline in overall metabolism due to aging, but the mechanism was unclear. A protein called melanocortin-4 receptor (MC4R) detects overnutrition and regulates metabolism and appetite to prevent obesity. MC4Rs stimulate metabolism and suppress food intake in response to an overeating signal from melanocortin.

Initially, a research team examined the distribution of MC4Rs in the rat brain by utilizing an antibody they had developed specifically to make MC4Rs visible. They found that MC4Rs are present exclusively in primary cilia of specific groups of hypothalamic neurons. The team next investigated the length of the primary cilia that had MC4Rs (MC4R+ cilia) in the brains of 9-week-old (young) rats and 6-month-old (middle-age) rats. The team found that MC4R+ cilia in middle-aged rats were significantly shorter than those in young rats. Accordingly, the metabolism and the fat-burning capacity of middle-aged rats were much lower than those of young rats.

The team next analyzed MC4R+ cilia in rats under different dietary conditions. The results showed that MC4R+ cilia in rats on a normal diet gradually shortened with age. On the other hand, MC4R+ cilia in rats on a high-fat diet shortened at a faster pace, while those in rats on a restricted diet shortened at a slower pace. Interestingly, the team also found that MC4R+ cilia that once disappeared with age were regenerated in rats raised under two months of dietary restriction. In the study, the team also used genetic technologies (knockdown of CILK1) to make MC4R+ cilia shorter in young rats. These rats showed increased food intake and decreased metabolism, leading to weight gain.

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Improving Stem Cell Therapies that Promote Blood Vessel Generation in Ischemic Tissue

Stem cell therapies are one of the approaches to treating progressive loss of blood flow to tissues, such as results from severe atherosclerosis, in which important blood vessels are narrowed or even blocked. Unfortunately first generation stem cell therapies are variable in outcome, cellular senescence in cell cultures prior to transplantation is poorly controlled, and the transplanted cells die quite quickly. Thus even though the benefits of treatment arise from signaling generated by transplanted cells, rather than cell integrating into tissues, there is much that can be improved. One of the ways in which researchers are producing that improvement is via the use of scaffold materials to extend the lifespan of transplanted cells and better steer their behavior, as illustrated here.

Critical limb ischemia is a condition in which the main blood vessels supplying blood to the legs are blocked, causing blood flow to gradually decrease as atherosclerosis progresses in the peripheral arteries. Current treatments include angioplasty procedures such as stent implantation and anti-thrombotic drugs, but there is a risk of blood vessel damage and recurrence of blood clots, which is why there is a strong interest in developing a treatment using stem cells.

Stem cell therapies have high tissue regeneration capabilities, but when stem cells are transplanted alone, hypoxia at the site of injury, immune responses, and other factors can reduce cell viability and prevent the desired therapeutic effect. Therefore, it is necessary to develop a material that delivers stem cells using biodegradable polymers or components of extracellular matrix as a support to increase cell viability.

Researchers processed collagen hydrogels to micro-scale to create porous, three-dimensional scaffolds that are easy to inject in the body and have a uniform cell distribution. Collagen, a component of the extracellular matrix, has excellent biocompatibility and cellular activity, which can induce cell self-assembly by promoting interactions between the microgel particles and collagen receptors on stem cells. In addition, the spacing between microgel particles increased the porosity of the three-dimensional constructs, improving delivery efficiency and cell survival.

The microgel-cell constructs developed by the researchers expressed more pro-angiogenic factors and exhibited higher angiogenic potential than cell-only constructs. When microgel-cell constructs were injected into the muscle tissue of mice with critical limb ischemia, blood perfusion rate increased by about 40% and limb salvage ratio increased by 60% compared to the cell-only constructs, confirming their effectiveness in increasing blood flow and preventing necrosis in the ischemic limb.

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TREM2 Influences the Formation of Unstable Atherosclerotic Plaque

The growth of atherosclerotic plaques in blood vessels is harmful, not least because it restricts blood flow, even blocking entire vessels in the worst cases. The vast majority of cardiovascular mortality results from the rupture of fatty, unstable plaques, however, leading to stroke and heart attack when the fragments block downstream vessels. If the development of plaque instability could be slowed or reversed, this would have a sizable impact on cardiovascular mortality - even given that this goal is a step down from reversal of plaque in general. Thus researchers are interested in finding the mechanisms that determine whether a plaque is more fatty and less fibrous, and thus more prone to rupture.

Atherosclerosis is a chronic disease of the vascular wall driven by lipid accumulation and inflammation in the intimal layer of arteries, and its main complications - myocardial infarction and stroke - are the leading cause of mortality worldwide. Recent studies have identified triggering receptor expressed on myeloid cells 2 (TREM2), a lipid-sensing receptor regulating myeloid cell functions, to be highly expressed in macrophage foam cells in experimental and human atherosclerosis. However, the role of TREM2 in atherosclerosis is not fully known.

Here we show that hematopoietic or global TREM2 deficiency increased, whereas TREM2 agonism decreased, necrotic core formation in early atherosclerosis. We demonstrate that TREM2 is essential for the efferocytosis capacities of macrophages and to the survival of lipid-laden macrophages, indicating a crucial role of TREM2 in maintaining the balance between foam cell death and clearance of dead cells in atherosclerotic lesions, thereby controlling plaque necrosis.

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Low Socioeconomic Status Correlates with Raised Dementia Risk

It is well known that low socioeconomic status correlates with a raised risk of age-related disease and mortality, though it is challenging to determine which of the possible causes are in fact more or less important. A web of correlations are linked to socioeconomic status: intelligence, access to medical services, education, personality traits, lifestyle choices, and more. Here the focus of the study is on location of residence as a marker of socioeconomic status, and in this context it is interesting to note the studies that have compared the differences in particulate air pollution versus mortality in wealthier versus poorer neighborhoods in US metropolitan areas. Higher particulate air pollution is by now a noted contribution to age-related disease and mortality, though clearly only part of the story when it comes to how wealth, status, and life expectancy are related.

Dementia risk may be elevated in socioeconomically disadvantaged neighborhoods. Reasons for this remain unclear, and this elevation has yet to be shown at a national population level. We tested whether dementia was more prevalent in disadvantaged neighborhoods across the New Zealand population (N = 1.41 million analytic sample) over a 20-year observation. We then tested whether premorbid dementia risk factors and MRI-measured brain-structure antecedents were more prevalent among midlife residents of disadvantaged neighborhoods in a population-representative NZ-birth-cohort (N = 938 analytic sample).

People residing in disadvantaged neighborhoods were at greater risk of dementia (hazard ratio, HR, per-quintile-disadvantage-increase = 1.09) and, decades before clinical endpoints typically emerge, evidenced elevated dementia-risk scores (CAIDE, LIBRA, Lancet, ANU-ADRI, DunedinARB; β 0.31-0.39) and displayed dementia-associated brain structural deficits and cognitive difficulties/decline. Disadvantaged neighborhoods have more residents with dementia, and decades before dementia is diagnosed, residents have more dementia-risk factors and brain-structure antecedents. Whether or not neighborhoods causally influence risk, they may offer scalable opportunities for primary dementia prevention.

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The Longevity-Associated BPIFB4 Variant is Anti-Inflammatory

A variant in the gene BPIFB4 has been found to correlate with longevity in humans. In these matters it is worth noting that even small effects on mortality risk result in noticeable correlations with sustained over decades, and indeed all of the known human associations between longevity and genetic variation identified in large study populations are thought to have only modest effect sizes. What are the underlying mechanisms for BPIFB4, however? Researchers here make an argument for suppression of the chronic inflammation of aging as the reason for the association between BPIFB4 and longevity. Certainly chronic inflammatory signaling is disruptive to tissue function, and a major issue in aging.

Increased levels of pro-inflammatory proteins in plasma can be detected in older individuals and associate with the so called chronic low-grade inflammation, which contributes to a faster progression of aged-related cardiovascular (CV) diseases, including frailty, neurodegeneration, gastrointestinal diseases, and disorders reflected by alterations in the composition of gut microbiota. However, successful genetic programme of long-living individuals alters the trajectory of the ageing process, by promoting an efficient immune response that can counterbalance deleterious effects of inflammation and the CV complications. This is the case of BPIFB4 gene in which, homozygosity for a four single-nucleotide polymorphism (SNP) haplotype, the Longevity-Associated Variant (LAV) correlates with prolonged health span and reduced risk of CV complications and inflammation.

The relation between LAV-BPIFB4 and inflammation has been proven in different experimental models, here we hypothesized that also human homozygous carriers of LAV-BPIFB4 gene may experience a lower inflammatory burden as detected by plasma proteomics that could explain their favourable CV risk trajectory over time. We used high-throughput proteomic approach to explore the profiles of circulating proteins from 591 baseline participants selected from the Progressione delle Lesioni Intimali Carotidee (PLIC) cohort according to the BPIFB4 genotype to identify the signatures and differences of BPIFB4 genotypes useful for health and disease management. The observational analysis identified a panel of differentially expressed circulating proteins between the homozygous LAV-BPIFB4 carriers and the other alternative BPIFB4 genotypes highlighting in the latter ones a higher grade of immune-inflammatory markers.

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Thoughts on What is Revealed in the Trial Data for Amyloid-β Clearance

There are now several immunotherapies capable of clearing amyloid-β aggregates from the aging brain, and a sizable amount of clinical trial data to look through. Sadly, this approach doesn't much help patients in later stages of Alzheimer's disease, but the evidence to date suggests that it may be useful in prevention if the clearance is conducted early enough. Amyloid-β aggregation causes mild cognitive impairment in and of itself, but really just sets the stage for a set of different processes, inflammation and tau aggregation, that drive later Alzheimer's disease. At that point, clearing amyloid-β makes little difference to the outcome. It is worth noting that these immunotherapies bear a meaningful risk of serious side-effects. That side-effect profile will have to improve if anti-amyloid-β therapies are to become widely used as a preventative treatment in patients prior to evident cognitive impairment.

Clinical trials have proven that the anti-amyloid therapies donanemab and lecanemab slow the terrible fall into neurodegenerative aging of the Alzheimer's type (AD). As we noted, one key reason these trials succeeded where many promising antibodies had failed is that they started giving people these treatments earlier in the course of the disease. The reason why early treatment is critical is not primarily because there's less beta-amyloid in the brain earlier on in the course of AD. Instead, the benefit of acting early comes from the greater opportunity for beta-amyloid clearance to hold off other kinds of aging damage that occur downstream of it in the brain.

In the original Phase III trial for donanemab, the researchers didn't just compare all the subjects who received the antibody to those who received the placebo, but also compared people who received the treatment and who had "moderate" levels of tau aggregates in their brains to all the treated subjects combined (that is, those with moderate levels plus those with high levels together). Donanemab slowed the downward drag of the disease in all groups, but it was more effective in people who were less burdened by brain tau aggregates. When scientists used the integrated Alzheimer Disease Rating Scale (iADRS) to test donanemab's effectiveness in preserving the ability of people in the trial to carry on the day-to-day business of life and social interaction, they found that it slowed the fall by 35% in people with a medium tau burden, but by only 22% in the combined population. And on top of all that, early donanemab treatment yielded a significantly greater reduction in the number of cells called astrocytes in the brain that had abandoned their normal housekeeping activities and become "reactive."

These trials provide robust evidence supporting the classical "Amyloid Cascade" - the idea that neurodegenerative aging of the Alzheimer's type is a domino-tumble of destruction that starts as beta-amyloid drives tau aggregates to invade additional regions of the brain, leading to neurons first failing to interact with each other and eventually dying, all culminating in dementia. Following this logic, it seems increasingly likely that clearing out beta-amyloid early enough might forestall AD for decades - intervene in outwardly healthy middle-aged people with seemingly intact brains, and keep treating them indefinitely to save their minds.

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