Fight Aging! Newsletter, October 7th 2019

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  • Methionine Metabolism and the Pace of Aging
  • Towards a More Glial-Centric View of Alzheimer's Disease
  • Help to Crowdfund the SENS Research Foundation Transgenic Mouse Project to Move a Mitochondrial Gene into the Cell Nucleus
  • A Deeper Delve into the Mechanisms of Thymic Atrophy
  • Targeting GAS1 to Put Muscle Stem Cells Back to Work in Old Tissues
  • FGF23, Klotho, and Vascular Calcification
  • Permanently Boosting Levels of Natural Killer Cells in Mice to Increase Cancer Resistance
  • Arguing that People are Emotionally Fragile, and thus Should be Prevented from Using Metrics that Correlate with Age
  • NRF2 and Age-Related Impairment of Endothelial Tissue Maintenance
  • Age-Related Changes in Insulin Signaling in the Development of Sarcopenia
  • Mitochondria as a Form of Intracellular Signaling Important in the Aging Brain
  • Reviewing AGEs and ALEs in Oxidative Stress and Aging
  • Upregulation of Nrf2 Slows Progession of Intervertebral Disc Degeneration
  • A Profile of Tissue Engineering Efforts at LyGenesis
  • Leptin as the Link Between Obesity and Hypertension

Methionine Metabolism and the Pace of Aging

The prevailing wisdom in the research community is that a reduced level of the essential amino acid methionine is the primary trigger for the sweeping changes to metabolism that take place due to the practice of calorie restriction. Essential amino acids are not manufactured in the body, and thus must be obtained through the diet. The changes provoked by a reduced calorie intake lead to a slowing of aging and increased healthy life span and overall life span, largely mediated via an increase in the cellular maintenance processes of autophagy. Many other processes are involved as well, however, each adding their own small contribution, and animal studies suggest that reduced levels of other essential amino acids also have their own, lesser triggers that contribute to the whole.

That the response to calorie restriction does change just about everything in cellular metabolism makes it a challenging research topic, though the usual approaches have worked well: disable specific proteins one by one and see what happens. There is a lot of ground to cover and only so many researchers and so much funding to cover it with. The modern phase of the investigation of calorie restriction has been running in earnest for more than 25 years, but a complete understanding of calorie restriction will likely only slightly predate a complete understanding of cellular metabolism - a goal that is in no way near term.

Comparatively recent genomics, transcriptomics, and proteomics tools have added a great deal of data to the study of metabolism, and thus a great deal more work to the existing task list leading to the aforementioned complete understanding. Transcriptomics and other approaches to measuring gene expression patterns show that calorie restriction, intermittent fasting (with and without consequent calorie restriction), methionine restriction, and restriction of other specific nutrients (one by one), are all somewhat different. Yet the experiments showing that disabled autophagy prevents extension of life via calorie restriction suggest that it all converges at the same place.

While mapping the calorie restriction response and searching for calorie restriction mimetic drugs has made up the lion's share of translational gerontology to date, it is a sad truth that this class of intervention, meaning the upregulation of stress responses such as autophagy, works a great deal better in short-lived species such as mice than it does in long-lived species such as humans. Mice live 40% longer when calorie restricted, and humans most certainly don't. So while the long term health benefits of calorie restriction are meaningful, when compared with the little that modern medicine has been able to do to maintain the health of basically healthy people, they are not meaningful enough to merit major research funding, given the far better options on the table, those outlined in the SENS rejuvenation research programs.

Methionine metabolism and methyltransferases in the regulation of aging and lifespan extension across species

Methionine restriction (MetR) extends lifespan across different species and exerts beneficial effects on metabolic health and inflammatory responses. In contrast, certain cancer cells exhibit methionine auxotrophy that can be exploited for therapeutic treatment, as decreasing dietary methionine selectively suppresses tumor growth. Thus, MetR represents an intervention that can extend lifespan with a complementary effect of delaying tumor growth.

Beyond its function in protein synthesis, methionine feeds into complex metabolic pathways including the methionine cycle, the transsulfuration pathway, and polyamine biosynthesis. Manipulation of each of these branches extends lifespan; however, the interplay between MetR and these branches during regulation of lifespan is not well understood. In addition, a potential mechanism linking the activity of methionine metabolism and lifespan is regulation of production of the methyl donor S-adenosylmethionine, which, after transferring its methyl group, is converted to S-adenosylhomocysteine. Methylation regulates a wide range of processes, including those thought to be responsible for lifespan extension by MetR.

Although the exact mechanisms of lifespan extension by MetR or methionine metabolism reprogramming are unknown, it may act via reducing the rate of translation, modifying gene expression, inducing a hormetic response, modulating autophagy, or inducing mitochondrial function, antioxidant defense, or other metabolic processes. Although it is clear that each of the three branches of methionine metabolism - the methionine cycle, the transsulfuration pathway, and polyamine biosynthesis - plays a significant role in lifespan extension, how these branches crosstalk during regulation of lifespan is unknown. Moreover, how activity in these different branches of methionine metabolism change with age in different tissues and organs remains to be elucidated.

Towards a More Glial-Centric View of Alzheimer's Disease

The progression of Alzheimer's disease is very complicated, and yet to be fully understood, for all that there is a good catalog of the individual pathological mechanisms involved as the condition progresses: aggregation of amyloid-β and tau; persistent viral infection; chronic inflammation; dysfunction in the immune cells of the brain; and more. The question is how these mechanisms fit together into chains of cause and effect, a process of discovery that is complicated by the fact that order of progression or importance of specific mechanisms may be quite different between individuals, and some mechanisms have two-way relationships, in which either is capable of aggravating the other.

Is Alzheimer's disease a condition in which various factors cause amyloid-β deposition over the years, which causes glial cells in the brain to become dysfunctional and inflammatory, which leads to formation of the toxic tau protein aggregates known as neurofibrillary tangles and consequent cell death? Or is Alzheimer's disease due to the age-related disarray of glial cells, that in turn leads initially to amyloid-β pathology, and then later to tau pathology as the state of disarray worsens? There is good evidence to support either position. That clearing amyloid-β from the brain has failed persistently to improve patients is a strike against the amyloid-β as first cause arguments, but equally it may be that these efforts have taken place at too late a stage in the progression of Alzheimer's disease, long after it would have been effective.

Microglia in Alzheimer Disease: Well-Known Targets and New Opportunities

Microglia cells are the main immunocompetent cells in the brain. They colonize the brain in the early prenatal period, but contrary to other tissue resident macrophages, they remain secluded within the central nervous system (CNS) throughout life and self-renew at slow pace. Should the brain homeostasis be compromised, microglia change their phenotype and initiate a defense program. Thus, under pathological conditions, they adopt reactive states characterized by multiple morphological and functional changes including but not limited to increased phagocytosis and increased expression of receptors, cytokines, chemokines, and additional inflammation related molecules.

Alzheimer's disease (AD) classical hallmarks include brain atrophy, extracellular amyloid-beta (Aβ) deposits, intracellular aggregated phosphorylated tau, dystrophic neurites, synapses, and neurons loss. The presence of reactive glial cells within the neuritic plaques was described by Alois Alzheimer himself and further studies identified both reactive astrocytes and microglia in the vicinity of the Aβ deposits. Long considered as a consequence of the pathology, reactive glia and associated neuroinflammation are now regarded as playing key roles in both disease initiation and progression. Evidence strongly supports a causal involvement of microglial cells in AD pathogenesis and generated a strong interest for studying these cells. Yet, the roles of microglia in AD initiation and progression are unclear and heavily debated, with conflicting reports regarding their detrimental or protective contribution to the disease.

The involvement of microglia in AD is a relatively new area of research, but it is growing at a fast pace. Recent genome-wide association studies have established that the majority of AD risk loci are found in or near genes that are highly and sometimes uniquely expressed in microglia. This leads to the concept of microglia being critically involved in the early steps of the disease and identified them as important potential therapeutic targets.

Over the recent years, several technological breakthroughs have been achieved, allowing scientists to address new challenging questions. These technical developments now allow studying microglia roles with medium or high throughput workflows, and perform fine analysis of their functions in preserved environments. A better understanding of the contribution of microglia cells to AD initiation and progression is expected to renew the interest of big pharma to re-invest in the field and will pave the way toward better designed strategies.

Help to Crowdfund the SENS Research Foundation Transgenic Mouse Project to Move a Mitochondrial Gene into the Cell Nucleus

The SENS Research Foundation science team is taking the next step in their work on moving mitochondrial genes into the cell nucleus, a process called allotopic expression. Having proven that they can carry out this task with the ATP8 gene in cells, they are now aiming at proof of principle in mice. This will require the production of transgenic mice, using a novel technology funded by the SENS Research Foundation called the maximally modifiable mouse. This mitochondrial project is being crowdfunded at you, I, and everyone else can contribute to advancing the state of the art one step further towards eliminating mitochondrial DNA damage as a cause of aging.

Mitochondria are the power plants of the cell, a herd of organelles descended from ancient symbiotic bacteria. They reproduce by replication and are recycled when damaged by cellular maintenance processes. Mitochondria carry the remnant of the original bacterial DNA, encoding thirteen genes vital to the process by which mitochondria package chemical energy store molecules. Unfortunately mitochondria generate reactive molecules as a byproduct of their operation, and this DNA is less well protected than the DNA of the cell nucleus. Some forms of damage to this DNA can break mitochondrial function in ways that allow the broken mitochondria to outcompete their functional peers, leading to dysfunctional cells that export massive quantities of damaging, oxidative molecules into the surrounding tissue. This contributes to conditions such as atherosclerosis, via the production of significant amounts of oxidized cholesterol in the body.

Allotopic expression of mitochondrial genes will work around this issue by providing a backup source of the proteins necessary to mitochondrial function. It has been demonstrated to work for ND4, and that project has been running for some years at Gensight Biologics to produce a therapy for inherited conditions that involve mutation of that gene. This work must expand, however, to encompass all thirteen genes of interest. So lend a hand, and help the SENS Research Foundation team take the next step forward in this process.

MitoMouse: SENS Transgenic Mouse Project

The SENS Research Foundation (SRF) has formulated seven practical repair strategies to the common drivers of aging. Whereas some of these strategies are now widely researched by the scientific establishment the MitoSENS strategy for dealing with mitochondrial damage is among the most novel. Our theory is, through allotopic expression, that is by placing functional copies of critical mitochondrial DNA (mtDNA) genes in the nucleus of the cell one could alleviate defects arising due to mutations in mtDNA.

When it was proposed, this unique and ambitious strategy was perhaps too daring for mainstream labs and funding agencies to contemplate. Consequently, the MitoSENS approach has been an in house project for SENS that would not have been possible without community support. So far, this community-funded approach has an excellent track record leading to groundbreaking discoveries. In 2013 SENS organized its first crowdfunding campaign specific to MitoSENS in partnership with LongeCity. The small initiative seeded significant research momentum and paved the way for a larger fundraiser in 2015 at Breakthrough discoveries followed and a proof-of-principle for the MitoSENS approach was established for the first time in human cells. Here, the MitoSENS team in collaboration with scientists from the Buck Institute showed that allotopic expression of two mtDNA genes could bring back several functions in a patient cell line with a severe mutation in one of the mtDNA genes, namely ATP8.

To move this strategic advancement toward the clinic, SRF then created the "maximally modifiable mouse model". This mouse has a unique modification in their nuclear genome to allow a targeted insertion of new genes at a specific location. Using this mouse, we are ready to take the next step and pursue mitochondrial gene therapy in an animal model.

Mice of the C57/BL6MT-FVB strain (let's call them "SickMice") have a mitochondrial gene defect, a mutation in the mitochondrial ATP8 gene, and exhibit several age-related symptoms including lower fertility, arthritis, type II diabetes, and neurological impairments. Since mitochondria are only inherited from the mother, cross-breeding female SickMice with male mice from other models will result in the same mitochondrial dysfunction.

We will use the maximally modifiable model to create a new transgenic mouse (the "allotopic ATP8 transgenic mouse - Mitomouse"). This mouse will have the ATP8 gene that is important for mitochondrial function hidden in the cell nucleus and thus capable of being passed on to offspring irrespective of gender. Our hypothesis is that both male and female offspring from SickMice x MitoMice will result in rescued mitochondrial function. This would prove the viability of the MitoSENS strategy by showing that functional backup copies of mitochondrial DNA genes in the nucleus can replace their mutated counterparts in live animals.

A Deeper Delve into the Mechanisms of Thymic Atrophy

The faltering quality of the immune system in later life is driven by several quite different factors, but the one that is perhaps most evident in the immune declines of middle age is the atrophy of the thymus. The thymus is a small organ located under the sternum and over the heart; it is where thymocytes produced in the bone marrow mature into T cells. As ever more of the active tissue of the thymus is replaced with fat, the ongoing supply of new T cells diminishes. The adaptive immune system becomes ever more a closed system and its cells become ever more dysfunctional: exhausted, senescent, misconfigured and overly focused on persistent viral infections such as cytomegalovirus, lacking the ability to respond to new threats. Thus older people have increased cancer risk, increased senescent cell burden, and reduced ability to defend themselves against infectious pathogens. This is why a number of research groups and biotech startups, including the company that I cofounded with Bill Cherman, Repair Biotechnologies, are working on ways to regenerate the thymus.

Why does the thymus atrophy? There are at least two stages. Initially thymic involution takes place in early life. By the end of teenage years, the thymus is much reduced from childhood. This is a developmental program. Afterwards, however, different mechanisms take over: evidence strongly suggests chronic inflammation to play an important role in reducing the ability of thymic progenitor cells to sustain thymic tissue. This may or may not be linked to cellular senescence. Senescent cells are highly inflammatory, but it seems unlikely that cellular senescence plays an important role prior to middle age. The senescent cell burden is thought to be very low up until that time - since the immune system plays an important role in culling senescent cells, it isn't until the immune system starts to decline in earnest that senescent cells really begin to play a significant role in aging. So the slow decline of the thymus from early adulthood to early middle age is more of a question mark, while for later declines we can point to the usual culprit of significantly increased inflammation and presence of senescent cells. There are no doubt other mechanisms at work as well, of course.

In this open access paper, researchers delve more deeply into the atrophy of the thymus and its regrowth via the mechanism of sex steroid ablation. They provide evidence for this to involve existing cells expanding their structure rather than generation of new thymic cells, at least for this method of thymic regrowth. It makes for interesting reading in the context noted above; it is worth thinking about the various processes noted here in relation to chronic inflammation. It is perhaps more interesting as a reminder that sex steroid ablation in mice has been shown by other research groups to only produce transient regrowth of the thymus (it is unclear as to whether this is also the case in humans, as long term data is lacking), and that this regrowth doesn't reproduce the youthful structure of the thymus, even while it certainly seems to boost the output of T cells.

Dynamic changes in epithelial cell morphology control thymic organ size during atrophy and regeneration

Since T cells must be continuously produced throughout life, the accelerated atrophy of the thymus with age is enigmatic, especially given its latent regenerative potential. Age-associated atrophy is common to many tissues (for instance, muscle, central nervous system, skin, and testes), and can be a consequence of cell loss (death), but often is associated with the shrinkage (atrophy) of individual cells, collectively resulting in tissue atrophy. Likewise, regeneration may be attributed to proliferation of stem or end stage cells (hyperplasia), but can also result from growth of existing cells (hypertrophy) that is independent of proliferation. Despite the magnitude of atrophy and regeneration in the thymus, the underlying mechanisms for these processes have remained obscure, although our previous findings show that both are attributable to changes in cortical thymic epithelial cells (cTEC). Our non-presumptive analysis of global gene expression in young cTEC, aged cTEC, or aged cTEC in the regenerating thymus suggested that genes associated with cell size and shape dominated the dynamic landscape. However, the size and shape of individual cTEC has been difficult to discern using conventional methods, thus obscuring any changes that might occur during age atrophy or regeneration.

In other tissues, epithelial cells exhibit distinctive morphologies, and are polarized (with respect to a basement membrane) in either a single simple layer or in multiple stratified layers. In the thymus, with the exception of a small proportion of conventional epithelial cells lining the capsule and blood vessels, most TEC lack classical epithelial morphology. Instead, they are defined as epithelial mainly based on biochemical features, such as the appearance of desmosomes or keratin filaments. Various histochemical markers indicate that cTEC, in particular, form an extensive network of finely branched cell processes, but the morphology and number of individual cells in this network has been very difficult to define, due to this elaborate branching morphology and their relatively uniform staining with various antibody markers. Medullary thymic epithelial cells (mTEC) appear to be less dense, and therefore more easily defined as individual cells, but extensive heterogeneity among lineage markers has rendered the morphology of individual mTEC vague as well. Consequently, defining the size, shape, and interconnectivity of these essential cells has remained enigmatic.

Given the need for continuous T cell production during life, the thymus is paradoxically the most rapidly aging tissue in the body. It reaches peak tissue mass (in all species studied) prior to the onset of adolescence, and exhibits rapid and progressive atrophy afterwards, such that by mid-life most healthy mass is lost. Except at very late age, thymic lymphocytes are essentially unchanged in the atrophied thymus, while these age related changes are primarily manifest in stromal cells, particularly cortical. Niche availability provided by cTEC is the rate limiting feature for lymphoid cellularity and thymus size. Thus, as cTEC deteriorate during aging, the thymus becomes proportionally smaller. Since new T cells are produced proportionally to thymic mass, peripheral homeostasis thus becomes more dependent on homeostatic expansion of existing T cells, with the repertoire gradually drifting towards immunologic memory, with diminished broad spectrum immunity as a result.

Remarkably, the atrophied thymus retains potent regenerative capacity, and can be induced to attain its full peak size by stimuli such as androgen ablation. Quite logically, albeit without much evidence, thymic atrophy is assumed to result from senescence-associated cell death among TEC, while regeneration is believed to result from proliferative expansion from an epithelial stem cell or progenitor cell population. Consistent with these concepts, experimental loss of cTEC does result in decreased thymus size, while induction of cTEC proliferation results in a larger thymus. However, the fact that thymus size changes in response to TEC number (and resulting lymphoid capacity) does not mean that atrophy or regeneration, under physiologic conditions, necessarily involve changes in TEC number.

The present study stems from a large temporal database of stromal transcriptional profiles during aging and regeneration. Non-presumptive analysis indicates that dynamic changes in genes associated with cell size and cell morphology dominated the regeneration response. Here we use two different conditional reporter models to morphologically define and enumerate TEC in young, aged, or regenerated thymuses. Both models confirm the predictions of informatic analysis, showing that age atrophy of the thymus represents contraction of unique cell projections that characterize cTEC, while regeneration involves their regrowth. Both atrophy and regeneration occur independently of changes in cTEC number, and appear to solely reflect changes in projection morphology. Although mTEC morphology does not change appreciably with age, dynamic analysis suggests that medullary stroma may play an important role in modulation of cTEC morphology via paracrine production of known morphogens and growth factors. Our findings reconcile diverse existing concepts, and provide a revised view of atrophy and regeneration based on structural remodeling of a novel cTEC morphology that is unique among metazoan tissues.

Targeting GAS1 to Put Muscle Stem Cells Back to Work in Old Tissues

A great many projects at various stages of development are characterized by their goal of forcing greater stem cell activity in old tissues, but without meaningfully addressing the underlying causes of stem cell decline in later life. This sort of research and development operates at the level of proximate causes, adjusting protein levels to change cell behavior. Among the potential therapies I'd place into this category: telomerase gene therapy; GDF11 upregulation; FGF2 inhibition; NAD+ upregulation; and so on. Muscle stem cells known as satellite cells are one of the better studied stem cell populations in this context, and many of the interventions are focused here. Today's open access research is a representative example, in that the authors describe a portion of the network of genes and proteins that control stem cell behavior, finding that it can be adjusted in order to force greater activity, overriding the normal reaction to an aged and damaged environment.

The loss of stem cell activity with age is thought to be an evolved response to rising levels of DNA damage, inflammation, and immune dysfunction that serves to reduce risk of early death by cancer, at the cost of a certain later decline into frailty. It is a part of the parcel of adjustments that lead our lengthy life spans in comparison to other similarly sized mammals. There has been, and still is, concern that putting cells back to work in this sort of way, without fixing the problems that lead to cancer, will raise cancer risk over the years following intervention. It will be slow and costly to understand whether or not this is the case in humans, but the evidence to date from animal studies show that these and analogous efforts result in far less cancer than might be expected. Perhaps this is due to improvement in immune function in those therapies, such as telomerase gene therapy, for which there is good data on cancer risk in animal models, but a firm answer on mechanisms is yet to arrive.

Possible therapeutic target for slow healing of aged muscles discovered

Skeletal muscles have a tremendous capacity to make new muscles from special muscle stem cells. These "blank" cells are not only good at making muscles but also at generating more of themselves, a process called self-renewal. But their amazing abilities diminish with age, resulting in poorer muscle regeneration from muscle trauma. A research team figured out that a protein called GAS1 is the culprit for this age-related decline.

The protein is found in only a small number of young muscle stem cells, but is present in all aged muscle stem cells, they discovered. Tinkering with muscle stem cells to express GAS1 in the entire young stem cell population resulted in diminished regeneration. By contrast, removing GAS1 from aged muscle stem cells rejuvenated them to a youthful state that supported robust regeneration. They also discovered that GAS1 inhibits another protein, a cell-surface receptor called RET, which they showed to be necessary for muscle stem cell renewal. The more GAS1 protein is present, the more RET's function is reduced. The inhibition of RET by GAS1 could be reversed by the third protein called GDNF, which binds to and activates RET. Indeed, when the researchers injected GDNF directly into the muscles of aged mice, muscle stem cell function and muscle regeneration were restored.

Muscle stem cell renewal suppressed by GAS1 can be reversed by GDNF in mice

Muscle undergoes progressive weakening and regenerative dysfunction with age due in part to the functional decline of skeletal muscle stem cells (MuSCs). MuSCs are heterogeneous, but whether their gene expression changes with age and the implication of such changes are unclear. Here we show that in mice, growth arrest-specific gene 1 (Gas1) is expressed in a small subset of young MuSCs, with its expression progressively increasing in larger fractions of MuSCs later in life. Overexpression of Gas1 in young MuSCs and inactivation of Gas1 in aged MuSCs support that Gas1 reduces the quiescence and self-renewal capacity of MuSCs. GAS1 reduces RET signalling, which is required for MuSC quiescence and self-renewal. Indeed, we show that the RET ligand, glial-cell-line-derived neurotrophic factor can counteract GAS1 by stimulating RET signalling and enhancing MuSC self-renewal and regeneration, thus improving muscle function. We propose that strategies aimed at targeting this pathway can be exploited to improve the regenerative decline of MuSCs.

FGF23, Klotho, and Vascular Calcification

Klotho and FGF23 interact with one another in a number of mechanisms that might explain the effects of klotho on longevity in mice: more klotho slows aging, while loss of klotho accelerates it. Vascular function is fairly high on that list, given the importance of the cardiovascular system in aging. The mechanism of interest in the research here is calcification of blood vessels, the dysfunction in cell populations in blood vessel walls that leads to mineralization akin to that involved in generation of bone tissue. Some of this is clearly the result of rising levels of cellular senescence and the harmful signaling that is produced by senescent cells. Investigations of the sort noted here are more concerned with proximate causes, however, in the sense of altered levels and interactions of various proteins.

Vascular calcification (VC) constitutes a major risk factor for cardiovascular (CV) morbidity and mortality and involves a complex regulated process of biomineralization that resembles osteogenesis. This process is mainly driven by the vascular smooth muscle cells (VSMCs), and includes the transformation of these cells into an osteoblastic phenotype.

Chronic kidney disease (CKD) is a major risk factor for CV disease (CVD) and is a clinical scenario closely related to the development of VC. In addition to the traditional CV risk factors, subjects with CKD are also exposed to other non-traditional factors predisposing for this pathology. Fibroblast growth factor (FGF) 23 is the most potent phosphatonin. This is an osteocyte-derived hormone produced in response to phosphate levels which, in combination with its cofactor Klotho, reduces the reabsorption of phosphate and the synthesis of active vitamin D in the kidneys. In patients with CKD, FGF23 concentrations increase with declining renal function and reach extremely high levels in end-stage renal disease. Clinical epidemiological studies have shown that FGF23 strongly predicts mortality in patients with CKD independently of other risk factors. These results suggest that FGF23 may causally be related to the high mortality observed in CKD patients and, importantly, that may exert direct effects on CV system besides its function as a phosphaturic hormone.

FGF23 binds to its cognate receptors (FGFRs), which are activated in the presence of the co-receptor Klotho. Our group and others described the expression of FGFR and Klotho in the human vascular wall, allowing to speculate that vascular tissue may be an objective for the actions of FGF23. Moreover, the synthesis of FGF23 by calcified vascular tissues and its contribution to CVD is an intriguing question not adequately studied. Only two previous works have explored the expression of FGF23 in calcified tissues, although solely coronary arteries and carotid atheroma plaques were analyzed. Moreover, the relationships of vascular FGF23 gene and protein expression levels with soluble FGF23 concentration and with the expression of Klotho and FGFRs in the vessels have not been previously established.

In this work, we determined the levels of both intact and fragmentary circulating FGF23 in 133 patients with established cardiovascular disease, the expression of FGF23, its receptors, and its co-receptor Klotho in vascular fragments of aorta, carotid, and femoral in 43 out of this group of patients, and in a control group of 20 organ donors. Patients with atherosclerosis and vascular calcification presented increased levels of FGF23 respect to the control group. Vascular immunoreactivity for FGF23 was also significantly increased in patients with vascular calcification as compared to patients without calcification and to controls. Finally, gene expression of FGF23 and RUNX2 were also higher and directly related in vascular samples with calcification. Conversely, expression of Klotho was reduced in patients with cardiovascular disease when comparing to controls. In conclusion, our findings link the calcification of the vascular tissue with the expression of FGF23 in the vessels and with the elevation of circulating levels this hormone.

Permanently Boosting Levels of Natural Killer Cells in Mice to Increase Cancer Resistance

Researchers here demonstrate a very interesting approach to immunotherapy: they introduce engineered stem cells in mice that will give rise to additional natural killer T cells, boosting the capability of the immune system for the entire life span of the mouse. Even if this class of treatment is not actually permanent in the same way in humans, and merely long-lasting, it still seems a promising step towards enhancing the immune system at any age, not just trying to repair it when it fails in later life.

They've been called the "special forces" of the immune system: invariant natural killer T cells. Although there are relatively few of them in the body, they are more powerful than many other immune cells. Scientists have hypothesized that iNKT cells could be a useful weapon against cancer because it has been shown that they are capable of targeting many types of cancer at once - a difference from most immune cells, which recognize and attack only one particular type of cancer cell at a time. But most people have very low quantities of iNKT cells; less than 0.1% of blood cells are iNKT cells in most cases. Still, previous clinical studies have shown that cancer patients with naturally higher levels of iNKT cells generally live longer than those with lower levels of cells.

The researchers' goal was to create a therapy that would permanently boost the body's ability to naturally produce more iNKT cells. They started with hematopoietic stem cells - cells found in the bone marrow that can duplicate themselves and can become all types of blood and immune cells, including iNKT cells. The researchers genetically engineered the stem cells so that they were programmed to develop into iNKT cells.

They tested the resulting cells, called hematopoietic stem cell-engineered invariant natural killer T cells, or HSC-iNKT cells, on mice with both human bone marrow and human cancers - either multiple myeloma (a blood cancer) or melanoma (a solid tumor cancer) - and studied what happened to the mice's immune systems, the cancers and the HSC-iNKT cells after they had integrated into the bone marrow. They found that the stem cells differentiated normally into iNKT cells and continued to produce iNKT cells for the rest of the animals' lives, which was generally about a year.

While mice without the engineered stem cell transplants had nearly undetectable levels of iNKT cells, in those that received engineered stem cell transplants, iNKT cells made up as much as 60% of the immune systems' total T cell count. Plus, researchers found they could control those numbers by how they engineered the original hematopoietic stem cells. Finally, the team found that in both multiple myeloma and melanoma, HSC-iNKT cells effectively suppressed tumor growth.

Arguing that People are Emotionally Fragile, and thus Should be Prevented from Using Metrics that Correlate with Age

I have never liked the class of argument, often presented whenever new biomarkers are close to realization, that suggests people should be prevented from using them because they are emotionally fragile and cannot handle the information responsibly. Ignorance wielded as shield, a sentiment that should be - but isn't - deeply offensive to all in this era of information and communication. This argument has been voiced for biomarkers for conditions without viable therapies, such as Alzheimer's disease. Here it is voiced for biomarkers of aging, a field in which there exist rejuvenation therapies, senolytics, with ample animal evidence, but that are not yet conclusively proven to produce rejuvenation in published human trials.

To me, this eagerness to forbid seems little more than control for the sake of control, a sadly widespread state of affairs in the heavily regulated medical field. There are any number of people willing to argue that medical technologies and medical information should be even more locked away behind walls and rules, even harder to obtain and use, than is presently the case. Those arguing inevitably count themselves among the enlightened few, defending the benighted and the ignorant masses from their own self-sabotaging ways. This is a form of dehumanization of the other, and it is a part of the road to truly unpleasant end stages for regional governance, as well illustrated over the course of the past century or so.

Over the past several years, scientists have identified four genetic and molecular biomarkers that potentially predict human and animal longevity. The first is the rate at which an individual's telomeres shorten in length. There is increasing evidence from both human and animal studies that the slower the rate of telomere shortening, the longer that individual is likely to live. The second is the rate of gene methylation, indicating an increased level of methylation was correlated with shortened longevity. The third is the polygenic risk. A recently reported genetic analysis can identify "10 percent of people with the most protective genes, who will live an average of five years longer than the least protected 10 percent," according to a statement from a scientist who developed the method.

The fourth approach was described in a study this year that identified 14 blood-based biomarkers of metabolism that when combined into a predictive score was statistically associated with predicting the end of life. Screening individuals using these metabolite profiles appeared to be predictive of a high risk of mortality within 10 years. In this study, scientists included more 44,000 people from 12 cohorts who were followed between three and 17 years to establish a correlation with these blood metabolites and longevity. There are no comparable studies that have examined such a large population using telomere length or gene methylation as longevity predictors.

Each of the four approaches to predicting longevity raises several scientific and ethical concerns that need to be addressed. The blood-based biomarker studies differ from current clinical end-of-life predictors, such as blood pressure and cholesterol levels, because there are established behavioral and drug interventions to reduce blood pressure and cholesterol levels. Were biomarkers to be developed for clinical applications, we propose that they should only be used if they provide actionable results. We should be cautious in applying both premature and unproven longevity results in a clinical situation that has such serious implications.

Several companies are already offering consumers tests to assay their telomere length. We would not be surprised if in the future companies will use other biological or genetic predictors to assess human longevity or offer ways to reverse our biological clocks. We also caution consumers against seeking out such longevity predictions should they be offered direct to the public, unless companies present the results to the consumer by a certified genetic counselor, as the psychological effect from these data could be devastating. Furthermore, the unintended consequences of using end-of-life predictions based on these preliminary studies can be unsettling. Do we want our life insurance agents canceling any policy or raising rates based on our biomarkers? In conclusion, we have not reached the point when it is ethical and scientifically valid to use biomarkers to predict longevity.

NRF2 and Age-Related Impairment of Endothelial Tissue Maintenance

Researchers here examine a proximate cause of age-related dysfunction in a progenitor cell population responsible for tissue maintenance of the endothelium of blood vessels. Declining blood vessel function and integrity is an important part of aging, with many contributing causes, and there is considerable interest in the research community when it comes to identifying ways to restore these losses. As is the case here, however, most researchers focus on possible adjustments to the age-distorted state of cellular metabolism, meaning raising or lowering specific protein levels in order to override cell behavior to some degree, rather than looking to repair the deeper causes of that age-distorted state. I, and others, think that this focus on proximate causes rather than root causes is a poor strategy, doomed to marginal results and slow progress.

Cardiovascular disease (CVD) remains the leading cause of death in the elderly, and treatment is costly. The reduced endothelial function with aging contributes to the development of CVD, so maintaining the normal endothelial integrity is an important therapeutic approach to reduce the age-related risk of CVD. Endothelial progenitor cells (EPCs) are thought to promote postnatal neovascularization and maintain endothelial integrity and function. These cells have aroused the interest of researchers, especially given the limited regenerative capacity of mature endothelial cells. It has been suggested that EPCs not only foster the continuous recovery of the endothelium after injury/damage, but also stimulate angiogenesis.

The function and number of circulating EPCs decreases with aging. Aging impairs the ability of EPCs to regenerate and migrate to damaged blood vessels and ischemic areas to repair the vasculature and promote angiogenesis. Aging EPCs exhibit reduced capacities. Therefore, therapeutic interventions that stimulate EPCs to enhance endothelial repair in elderly individuals have important clinical implications for the aging population. Different mechanisms of EPC senescence have been reported, including telomere shortening, age-related declines in pro-angiogenic factors, increased oxidative stress, reduced nitric oxide (NO) bioavailability and chronic low-grade inflammation. However, the complex molecular network responsible for EPC senescence requires further investigation.

We explored the effects of nuclear factor (erythroid-derived 2)-like 2 (NRF2) on EPC activity during aging. Both in vitro and in vivo, the biological functioning of EPCs decreased with aging. The expression of NRF2 and its target genes also declined with aging, while Nod-like receptor protein 3 (NLRP3) expression increased. Aging was associated with oxidative stress, as evidenced by increased reactive oxygen species and malondialdehyde levels and reduced superoxide dismutase activity. Nrf2 silencing impaired the functioning of EPCs and induced oxidative stress in EPCs from young mice. On the other hand, NRF2 activation in EPCs from aged mice protected these cells against oxidative stress, ameliorated their biological dysfunction and downregulated the NLRP3 inflammasome. These findings suggest NRF2 can prevent the functional damage of EPCs and downregulate the NLRP3 inflammasome through NF-κB signaling.

Age-Related Changes in Insulin Signaling in the Development of Sarcopenia

Insulin signaling and IGF-1 is one of the more intensely studied portions of biochemistry, in mammals and lower animals, when it comes to the interaction between metabolism and pace of aging. Researchers here look at how changes in this signaling might contribute to sarcopenia, the age-related loss of muscle mass and strength. Sarcopenia is a condition with many, many contributing factors, and it is important to think about the chains of cause and effect when reading about them. Different processes operate upstream or downstream of one another, but nonetheless tend to be studied in isolation of the bigger picture. There are first causes and downstream, proximate causes, and changes in insulin signaling have the look of being a fair way downstream of the root causes of aging.

Sarcopenia is defined as the combined loss of skeletal muscle strength, function, and/or mass with aging. This degenerative loss of muscle mass is associated with poor quality of life and early mortality in humans. The loss of muscle mass occurs due to acute changes in daily muscle net protein balance (NPB). It is generally believed a poor NPB occurs due to reduced muscle protein synthetic responses to exercise, dietary amino acid availability, or an insensitivity of insulin to suppress breakdown. Hence, aging muscles appear to be resistant to the anabolic action of exercise and protein (amino acids or hormonal) when compared to their younger counterparts.

The mechanisms that underpin anabolic resistance to anabolic stimuli (protein and resistance exercise) are multifactorial and may be partly driven by poor lifestyle choices (increased sedentary time and reduced dietary protein intake) as well as an inherent dysregulated mechanism in old muscles irrespective of the environmental stimuli. The insulin like growth factor 1 (IGF-1), Akt/Protein Kinase B and mechanistic target of rapamycin (mTOR) pathway is the primary driver between mechanical contraction and protein synthesis and may be a site of dysregulation between old and younger people.

Therefore, our review aims to describe and summarize the differences seen in older muscle in this pathway in response to resistance exercise (RE) and describe approaches that researchers have sought out to maximize the response in muscle. Furthermore, this review will present the hypothesis that inositol hexakisphosphate kinase 1 (IP6K1) may be implicated in IGF-1 signaling and thus sarcopenia, based on recent evidence that IGF-1 and insulin share some intracellular bound signaling events and that IP6K1 has been implicated in skeletal muscle insulin resistance.

Mitochondria as a Form of Intracellular Signaling Important in the Aging Brain

Researchers in the field of neurodegeneration here provide evidence for supporting cells in the brain, specifically microglia, to use their own mitochondria as a form of signaling. Mitochondria are the power plants of the cell, responsible for packaging chemical energy store molecules. Their function declines with age for a range of poorly understood reasons, and this is important in numerous age-related conditions, particularly those in energy hungry tissues such as the brain. The researchers here report that microglia eject both whole and fragmentary mitochondria that other cells react to. Where the microglia are stressed, these ejected mitochondria are more often fragmentary, and are harmful to the surrounding environment.

This is all quite fascinating, given (a) past work on the ability of cells to take up mitochondria from their surroundings or pass mitochondria between one another, and (b) the growing body of evidence showing that senescent microglia are important in the progression of numerous age-related neurodegenerative conditions. Senescent cells, of course, cause harm to their surroundings via active signaling, consisting of secreted molecules and extracellular vesicles - and perhaps also mitochondria.

Researchers report that when microglia spat out damaged mitochondria, these cast-offs inflamed astrocytes, which in turn expelled their own mitochondrial fragments. Jetsam from either cell sickened neurons as well, limiting their energy production. Conversely, an inhibitor of mitochondrial fission protected astrocytes and neurons from the effect of externally added mitochondrial fragments, suggesting that mitochondrial fragmentation cascades from cell to cell. Curiously, adding whole, functional mitochondria to neuronal cultures mitigated the damage from fragmented organelles. Mitochondria are ancient bacterial invaders of eukaryotic cells, but are tolerated by the body because they are sequestered inside cells. Once released, their proteins and other macromolecules may trigger inflammation.

In mouse models of neurodegenerative conditions, P110 improved survival and motor skills. Exactly how P110 protected neurons in these mouse models was unclear. Researchers added the inhibitor to microglia expressing a 73-amino-acid polyglutamine expansion (Q73) that causes mitochondria to malfunction and fragment. P110 treatment reduced mitochondrial fission, boosted ATP production, and lowered reactive oxygen species. How might microglia in these models affect other cell types? The authors added media from Q73 microglia to mouse primary astrocyte cultures. In response, the astrocytes pumped out TNF-α and IL-1β. Their mitochondria became dysfunctional and fragmented, and 75 percent more astrocytes died. Adding P110 directly to astrocytes also protected them from the Q73 microglia-conditioned media.

Taken together, the data implied that fragmentation of mitochondria causes microglia and astrocytes to release factors that can somehow damage mitochondria in other cell types. The authors wondered if those released "factors" might be mitochondria themselves. Confirming this, the authors found intact functional mitochondria in media from healthy microglial cultures. Media from Q73 microglia cultures contained the same total number of mitochondria as media from the healthy cultures, but only half as many were whole and functional. At the same time, the amount of free-floating mitochondrial proteins in Q73 culture medium rose, suggesting the organelles were leaking contents. Treating Q73 microglial cultures with P110 bumped the number of functional mitochondria almost back to that of control cultures.

While the damaged organelles may trigger inflammation by activating microglia or astroglia, their direct effect on neurons remains puzzling, as does the effect of whole mitochondria. Researchers are investigating the idea that neurons take up whole or fragmented organelles, with the former bolstering cellular respiration and the latter spreading damage.

Reviewing AGEs and ALEs in Oxidative Stress and Aging

Advanced glycation end products (AGEs) and the less discussed advanced lipoxidation end products (ALEs) are an interesting topic in the context of aging. There are in fact two distinct topics here. The first is the presence of persistent cross-links, in which glucosepane AGEs form links between extracellular matrix molecular, degrading the structural properties of tissue, particularly elasticity. These cross-links, arising from the normal operation of metabolism, are resilient and not broken down by our biochemistry. Some form of biotechnology, such as therapies based on enzymes mined from bacterial species that can metabolize glucosepane, will be required to remove their contribution to the aging process.

The second topic is that a menagerie of many different short-lived AGEs and ALEs emerge in greater numbers in the aged or diabetic metabolism, and cause chronic inflammation via their interaction with the receptor for AGEs, RAGE. They also produce other significant changes for the worse in cellular behavior. There is also some debate over whether or not AGEs and ALEs in the diet are important in these processes, with evidence for either answer to that question. It isn't clear as to what might be the best approach to this side of the problem, but researchers are considering targeting RAGE as a single influential point of intervention.

Oxidative stress is a consequence of the use of oxygen in aerobic respiration by living organisms and is denoted as a persistent condition of an imbalance between the generation of reactive oxygen species (ROS) and the ability of the endogenous antioxidant system (AOS) to detoxify them. The oxidative stress theory has been confirmed in many animal studies, which demonstrated that the maintenance of cellular homeostasis and biomolecular stability and integrity is crucial for cellular longevity and successful aging.

Mitochondrial dysfunction, impaired protein homeostasis (proteostasis) network, alteration in the activities of transcription factors such as Nrf2 and NF-κB, and disturbances in the protein quality control machinery that includes molecular chaperones, ubiquitin-proteasome system (UPS), and autophagy/lysosome pathway have been observed during aging and age-related chronic diseases. The accumulation of ROS under oxidative stress conditions results in the induction of lipid peroxidation and glycoxidation reactions, which leads to the elevated endogenous production of reactive aldehydes and their derivativesm, giving rise to advanced lipoxidation and glycation end products (ALEs and AGEs, respectively).

Both ALEs and AGEs play key roles in cellular response to oxidative stress stimuli through the regulation of a variety of cell signaling pathways. However, elevated ALE and AGE production leads to protein cross-linking and aggregation resulting in an alteration in cell signaling and functioning which causes cell damage and death. This is implicated in aging and various age-related chronic pathologies such as inflammation, neurodegenerative diseases, atherosclerosis, and vascular complications of diabetes mellitus. In the present review, we discuss experimental data evidencing the impairment in cellular functions caused by AGE/ALE accumulation under oxidative stress conditions. We focused on the implications of ALEs/AGEs in aging and age-related diseases to demonstrate that the identification of cellular dysfunctions involved in disease initiation and progression can serve as a basis for the discovery of relevant therapeutic agents.

Upregulation of Nrf2 Slows Progession of Intervertebral Disc Degeneration

Researchers here make an interesting observation relating to the function of the nucleus pulposus cell population critical to the progression of intervertebral disc degeneration. They provide evidence suggesting that upregulation of Nrf2 can slow progression of the condition by making these cells more resilient to stress, preventing cell death and cellular senescence and consequent fibrosis, and thus reducing the pace of tissue degeneration due to cell loss or dysfunction.

A normal intervertebral disc (IVD) consists of an outer annulus fibrosus (AF) that forms a ring structure to enclose the central nucleus pulposus (NP) and is connected to adjacent vertebral bodies by the cartilaginous endplates. The NP is crucial to maintain biomechanical function of IVD by counteracting and dissipating compressive loads, which depends on the extracellular matrix (ECM) secreted by nucleus pulposus cells (NPCs). However, the NP changes from a gel-like substance into a fibrous tissue with age, resulting in the structural and functional failure of IVD. Although the molecular mechanism of these pathological changes has not been fully understood, the apoptosis and senescence of NPCs are proven to be crucial to the development of intervertebral disc degeneration (IDD).

At present, increasing studies have demonstrated that reactive oxygen species (ROS) is closely related to the apoptosis and senescence of NPCs, contributing to the initiation and progression of IDD. As the main site of intracellular ROS generation, mitochondrion is also adversely influenced by ROS. Mitochondrial dysfunction is regarded as an important factor in NPC apoptosis and senescence, and accelerates disc degeneration. Thus, the strategies that aim at antioxidation and maintenance of mitochondrial homeostasis are promising to prevent or retard IDD.

Here we present evidence that a lower level of Nrf2 is closely associated with higher grade of IDD. The apoptosis and senescence of nucleus pulposus cells (NPCs) were exacerbated by Nrf2 knockdown, but suppressed by Nrf2 overexpression under oxidative stress. Based on findings that Kinsenoside could exert multiple pharmacological effects, we found that Kinsenoside rescued the NPC viability under oxidative stress and protected against apoptosis, senescence, and mitochondrial dysfunction in a Nrf2-dependent way. Further experiments revealed that Kinsenoside activated a signaling pathway of AKT-ERK1/2-Nrf2 in NPCs. Moreover, in vivo study showed that Kinsenoside ameliorated IDD in a puncture-induced model. Together, the present work suggests that Nrf2 is involved in the pathogenesis of IDD and shows the protective effects as well as the underlying mechanism of Kinsenoside on Nrf2 activation in NPCs.

A Profile of Tissue Engineering Efforts at LyGenesis

LyGenesis is the company founded to develop the technique of implanting organoid tissue into lymph nodes in order to allow it to survive and grow in the body. Some organs can carry out much or all of their function more or less regardless of location in the body, such as the liver and thymus. Thus any viable transplant strategy that leads to functional tissue thriving in the body should help patients. LyGenesis is initially focused on restoring liver function via this approach, but the thymus is next in line, with an eye to reversing some of the age-related decline in immune function.

Let's spend a little bit of time talking about your therapy. Let's say I hop into a time machine and go to the future, to whatever time it may be for it to have fully hit the market. What's your procedure going to look like?

So let's start with the present. Today, when a person needs a new liver, then a major transplantation surgery is their last option. This is an expensive and major operation - if you ever search online for "liver transplantation," you really do want to brace yourself. And then there's our approach, which uses endoscopic ultrasound to engraft cells into a patient's lymph nodes, and transforms the transplantation process into an outpatient procedure. That's one of the fundamental value propositions of our technology. The patient would be put under light sedation, the endoscope would be moved into a place where it can access your lymph nodes - the mesentery, in your abdominal region - and thirty minutes later you'd have multiple ectopic cell clusters placed there, engrafted by a cellular therapy, and you'd potentially even be able to leave the same day. Over the course of the next few weeks and months your lymph nodes would serve as bioreactors to grow multiple ectopic organs - a process called 'organogenesis' - that would begin filtering your blood and providing life-saving support. That's our vision of the future for our lead candidate in liver regeneration.

So the question that follows from that is: is this a therapy that would be a final procedure? Or is it a stopgap for those who are waiting on a transplant list for a full replacement?

One group of patients, for whom we hope this will be a single procedure and a curative therapy, are the many people with end stage liver disease. Those who have gradually and progressively lost liver function over time. Right now, once you get to a certain threshold where you've lost enough liver function, if you're healthy enough (and don't have any contraindicated medical comorbidities) you might make it onto the liver transplant list. Once you've made it on there you'll wait, oftentimes hundreds of days, or even longer, to receive an organ. And that's if you're lucky. So there's a huge unmet need. Patients need a new liver, but they're too ill and that prevents them from being eligible for a full organ transplantation. Right now there's no viable therapy for these people. So we think our therapy will be the first in line therapy for those patients.

How many lymph nodes, on average, would you need to use for this to work? Are there going to be any side effects from this process?

Right now, our best guess is that we will be grafting ectopic livers into, probably, three to five lymph nodes. You spread the mass of the ectopic organs across multiple lymph nodes, not just a single lymph node. That's our best guess and clinical development plan right now. In the research we've been doing for almost decade now, we've tried everything from a single lymph node to twenty lymph nodes or more, in the different animal models. And we've seen no adverse effects in terms of the transition from the lymph node to an ectopic organ. One thing we stress is that when you look at what happens over time, the lymph node disappears. The lymph node acts like a bioreactor in this process - once it's kicked the organ growth into gear, the organ takes over and the lymph node disappears. And because our bodies have hundreds of lymph nodes distributed throughout, we don't expect that losing a handful of them will produce any untoward effects.

How could this enhance people's longevity going forward?

Another great regenerative medicine story from our platform is based on our work on the thymus, which is fascinating. So, we have proof-of-concept data showing that we can regenerate the thymus ectopically inside the lymph nodes, as well. The thymus, as you may know, has a complicated biology; it does a lot of different things. But there is some indication that one of the effects of rebooting the thymus is to reboot the immune system - which absolutely could have regenerative, and therefore potential longevity, effects. We have try to be very careful about this, lots of things work in small animals that do not translate to people - there are jokes that the medical field has cured cancer in mice so many times over by now. We have to be careful when talking about longevity. Here's this dream of man since the beginning of time, to live longer. I think with some of the regenerative medicine and our understanding of biology we can start to make some inroads but, for what it's worth, I'm very careful not to promise that we're unlocking the fountain of youth. That's not the case. We're trying to develop science-based, FDA-regulated therapies to address unmet medical needs - even though, admittedly, the famous one would be potential downstream effects on aging and longevity.

Leptin as the Link Between Obesity and Hypertension

Hypertension, chronically raised blood pressure, is very damaging. It is an important mechanism by which low-level molecular damage and disarray in aging is converted into structural damage to important tissues in the brain, kidneys, and other organs. It is so influential in aging that lowering of raised blood pressure reduces mortality and disease risk even without addressing the underlying causes of the condition. Obesity is well known to cause raised blood pressure, and researchers here identify a novel mechanism for this effect involving leptin signaling. Since leptin signaling does change with age, it will be interesting to see whether or not this mechanism also operates to a significant degree in the aging and hypertension of non-obese individuals.

There's no question that as body weight increases, so too does blood pressure. Now, in a study of mice, researchers have revealed exactly which molecules are likely responsible for the link between obesity and blood pressure. Nearly a third of American adults have high blood pressure, and only about half of those people have their blood pressure under control through medications and lifestyle changes. Hypertension can be especially difficult to treat in obese patients.

The new work revolves around leptin, a molecule that controls appetite and metabolism in response to food. Obese people often become resistant to leptin, so rising levels of the molecule after a meal no longer boost metabolism or cause a feeling of fullness. In response to this resistance, leptin levels continue to rise with obesity. Leptin has also been shown to increase blood pressure and, surprisingly, obesity doesn't change that link - even when people are resistant to leptin's effects on metabolism and appetite, their blood pressure rises in response to the molecule. Until now, researchers weren't sure why.

Previous studies had revealed that there were high levels of leptin receptors in the carotid bodies - tiny clusters of cells along the carotid arteries on either side of the throat that respond to changing levels of oxygen and carbon dioxide in the blood. Researchers wondered whether this could be where leptin affects blood pressure, completely separate from its effects on appetite and metabolism in the brain.

Researchers first confirmed that giving high doses of leptin to lean mice triggered a rise in blood pressure of 10.5 to 12.2 mm Hg, while having no effect on heart rate or food intake. Then, they repeated the experiment in mice without functioning carotid bodies. This time, the animals' blood pressure didn't change in response to leptin. Next, the team studied obese mice that had no leptin receptors - despite their weight, they had normal blood pressure. But when the researchers injected the genes for leptin receptors directly into the carotid bodies of these mice, the animals' blood pressure readings rose by 9.4 to 12.5 mm Hg.

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