Food overconsumption and obesity are also contributing factors to chronic hyperglycemia and enhanced glycolysis, which enhance the production of reactive a-dicarbonyls (a-DC's), such as methylglyoxal (MGO). MGO reacts nonenzymatically with biomolecules such as proteins, lipids, and DNA to form advanced glycation end-products (AGEs). These covalent adducts contribute to pathogenesis across several diseases by compromising protein function, forming extracellular crosslinks that disrupt tissue architecture, and modifying lipids and nucleic acids. Cellular protection against AGEs occurs by endogenous glyoxalase enzymes, which detoxify MGO and prevent AGEs formation. Given that increased sugar consumption, which drives obesity, is accompanied by enhanced glycolysis and concomitant production of toxic glycolytic byproducts, we hypothesized that detoxification of AGEs may be a viable therapeutic against obesity and its associated pathologies.

To develop a therapeutic for AGEs burden we utilized compounds previously reported to reduce MGO. In vitro treatment of N27 cells with alpha lipoic acid, nicotinamide, piperine, pyridoxamine, and thiamine was effective in rescuing neurite length retraction following exposure to MGO. The combination of these compounds, termed Gly-Low, displayed synergistic effects in protecting against MGO toxicity, and showed improvement compared to treatment with a single compound. In vivo treatment of C57BL/J6 control mice with Gly-Low resulted in significant lowering of body weights and food consumption compared to those on a control diet. Intraperitoneal injection of Gly-Low, as well as standard starving procedures, also reduced food consumption ruling out taste aversion as a potential caveat in reduction of food intake.

Administration of Gly-Low reduced food consumption and body weight, improving insulin sensitivity and survival in both leptin receptor deficient (Lepr db) and wildtype control mouse models. Unlike calorie restriction, Gly-Low inhibited ghrelin-mediated hunger responses and upregulated Tor pathway signaling in the hypothalamus. Gly-Low also extended lifespan when administered as a late life intervention, suggesting its potential benefits in ameliorating age-associated decline by inducing voluntary calorie restriction and reducing glycation.

Vascular calcification (VC) is associated with increased risk of major adverse cardiovascular events in several clinical conditions, such as chronic kidney disease and atherosclerosis and aging. The formation of VC is associated with complex pathological mechanisms, including osteogenic differentiation and apoptosis of vascular smooth muscle cells (VSMCs) and release of matrix vesicles loaded calcium (Ca) and phosphate (Pi). By inhibiting these processes, VC can be effectively treated.

Klotho, a protein highly expressed in the kidney, is thought to be involved in various aging-associated pathologies. Studies have reported that Klotho-deficient mice developed obvious aortic VC, which can be reversed by Klotho overexpression. To date, the mechanisms whereby Klotho protects against VC have focused on not only its role as an obligate co-factor for FGF23 signaling in regulating Pi and vitamin D systems in kidney, but also its direct effects on the vasculature as a circulating anti-calcific factor. However, the mechanisms of this direct effects have not yet been fully explored.

Growing evidence indicates that autophagy, defined as the dynamic, refined, and controlled process of cellular self-digestion, protects VSMCs against calcification. Although autophagic activity reportedly increases in the aorta of Klotho-deficient mice, its role in the Klotho's regulation of VC remains unclear. The present study investigated whether Klotho deficiency could induce protectively-increased autophagy and whether Klotho administration ameliorated calcification through said autophagy increase.

Results indicated that, based on Agatston score, serum Klotho level was negatively associated with aortic calcification. Then, Klotho-deficient mice exhibited aortic VC, which could be alleviated with the supplementation of Klotho protein. Moreover, autophagy increased in the aorta of Klotho-deficient mice and protected against VC. Finally, we found that Klotho ameliorated calcification by promoting autophagy both in the aorta of Klotho-deficient mice and in mouse vascular smooth muscle cells under calcifying conditions. These findings indicate that Klotho deficiency induces increased autophagy to protect against VC and that Klotho expression further enhances autophagy to ameliorate calcification.

Frailty is one of the most complicated clinical syndromes and is defined as a decrease in the reserve and restoring capacity of the body. For frail people, a slight irritant can result in strong responses, which require a longer period to recover. Thus, frailty can also be regarded as a decline in the ability to maintain homeostasis. Multiple organs and systems, such as the skeletal muscle, immune, endocrine, hematopoiesis, and cardiovascular systems, are involved in the process of frailty. Patients with frailty have a high risk of developing age-related diseases, including neurodegenerative diseases (such as dementia), type II diabetes, atherosclerosis, and chronic heart failure.

Although there are a few hypotheses at present, the mechanisms involved in frailty remain unknown. Researchers have different opinions about the origin of frailty. It is generally accepted that frailty is related to aging. With the increasing focus on frailty, emerging evidence has increased our understanding of this syndrome. Findings from centenarians suggest that specific gut microbiota (GM) constituents may contribute to healthy aging. The diversity and abundance of the GM vary between elderly adults and centenarians.

However, the bridge between the GM and the occurrence of frailty remains unclear. In this review, we proposed the possible mechanisms involved in frailty from the perspective of the GM and oxidative stress (OS). Specific GMs and their metabolites stimulate the production of ROS and affect OS in the body, leading to damage to multiple biological macromolecules. The occurrence of OS may be the intermediate process of the GM that leads to frailty, producing a direct action on the body. This may be one of the precipitating factors of frailty syndrome.

The idea of using GM biomarkers to predict frailty is proposed prospectively. Notably, frailty is not an irreversible status. Timely interventions have the potential to revert the prefrailty or frailty state to a nonfrailty state. By understanding the role of the GM and OS in frailty, several interventions have been proposed to improve this syndrome and to achieve the goal of healthy aging. According to existing research, dietary interventions are the most commonly used treatment for frailty.

John Davis (New Methuselahs: The Ethics of Life Extension) advances a novel ethical analysis of longevity science that employs a three-fold methodology of examining the impact of life extension technologies on three distinct groups: the "Haves", the "Have-nots" and the "Will-nots". In this essay, I critically examine the egalitarian analysis Davis deploys with respect to its ability to help us theorize about the moral significance of an applied gerontological intervention.

Rather than characterizing, as Davis does, an aging intervention as a form of "life extension", in this article, I argue that an ethical analysis of an aging intervention should focus on what the primary health impact of such an intervention would likely have on population health - namely, increasing the human healthspan so that the risks of disease, frailty, and disability would be reduced in late life. A by-product of such an intervention is that it may increase the number of years people also live.

Rather than deploying an egalitarian analysis into the far future of a potential new longevity-caste society, I believe it is more prudent and practical to deploy such an ethical analysis to the intrinsic health inequalities that exist between persons at different stages of the human lifespan, e.g., between young adults (age 20-30) and older persons (age 85+), as well as the health inequalities that already exist with respect to variations in the rate of biological aging.

In this essay, I will deploy a comprehensive "present-day" (vs. futuristic) egalitarian analysis that highlights the health consequences of the "status quo" of biological aging, including the health inequalities that exist between persons with "accelerated" aging (e.g., progeria), "normal" aging, and "retarded" aging (e.g., centenarians and supercentenarians). Doing so can help re-frame the ethical arguments concerning intervening in aging, so that an applied gerontological intervention is recognized as a significant form of preventative medicine, rather than a technology that raises serious concerns about radical life extension, boredom, or the creation of a new caste system between the "longevity-haves" and "have-nots".

Like Davis, I believe "that developing life extension is, on balance, a good thing and that we should fund life extension research aggressively". But unlike Davis, I do not believe the best way to promote societal discussion about, or the policy regulation of, an applied gerontological intervention should begin by contemplating the potential future inequalities radical life extension might potentially create. Instead, I believe an ethical analysis should begin from (1) the existing health vulnerabilities of today's aging populations, (2) the existing inequalities of the "aging status quo", and (3) address the most likely aging technology to be developed in the immediate future and reasonable empirical assumptions concerning its fair diffusion.

Aspiring to increase the healthspan, vs. merely delaying death, could constitute an innovative approach to human health and help us realize the noble aspiration of "adding life to years" vs. "adding years to life". Given where the science is today, the goal of a century of disease-free life is a realistic and compelling aspiration. The priority should be on making an applied gerontological intervention a top public health priority for the world's aging populations. If we do this, then the 2 billion persons over age 60 by the year 2050 could enjoy more health and a compression of disease, frailty, and disability.

Cellular reprogramming turns an old person's cells young again. So can't we fix aging by just reprogramming a person's old cells with reprogramming factors? This is a tantalizing idea that's on a lot of our supporters' minds these days. On the one hand, it's certainly true that we lose cells with aging and that other cells become dysfunctional. And on the other hand, the cellular reprogramming experiments have in some senses rejuvenated cells in a way that can and should spark excitement - first and foremost, because the technology will greatly enable cell therapy of various kinds, which will be critical to the medical defeat of aging. But the quite rational enthusiasm for a specific technology can sometimes spark a kind of irrational biomedical exuberance so great that even some very prominent geroscientists seem to have begun to fall into a kind of fallacy of composition: the body is made up of cells; therefore, if we rejuvenate all our cells, we will rejuvenate our entire bodies.

People making this intuitive leap are in for an inelegant crash. We simply are not composed entirely of cells, and replacing lost cells and restoring the original differentiation of cells with epigenetic changes won't do anything to remove or repair aging damage to the many other functional units that are lost or damaged as we age and that contribute to diseases and disabilities of aging.

For one thing, there's aging damage to the extracellular matrix (ECM). The ECM is the lattice of proteins that provide both physical structure and signaling cues for our cells and tissues, and that also have important roles of their own in the body's movement and plumbing. In addition to damage to the ECM, another critical kind of aging damage that would impair the youthful function even of pristine reprogrammed cells is the various extracellular aggregates ("amyloids") that accumulate outside cells. These are damaged proteins that either physically impede cells' ability to carry out their function, or cause cellular dysfunction in other ways.

We've been thinking about using reprogramming technology either to create replacement cells for those that have been lost to aging processes, or to reprogram cells already in the tissues in order to (as advocates would have it) rejuvenate their function. These applications could in principle deal with cells that are either missing entirely, or that are still present but behaving badly due to reversible changes in their epigenetics - but they can't do anything about cells that survive, but have suffered certain other kinds of aging damage.

For instance, cells overtaken by mitochondria with large deletion mutations (which are the most problematic kind of mitochondrial damage in aging) almost certainly can't be restored to normal functioning through reprogramming. In all probability, the presence of mitochondrial mutations and other aging damage (such as intracellular aggregates, the abnormal splice protein lamin A, and some mutations and epimutations) is one of the main reasons why only a tiny fraction of cells exposed to reprogramming factors ever actually get reprogrammed. And in addition to not repairing all aging damage, reprogramming itself causes other kinds of damage to some cells that make them useless for rejuvenation biotechnology, such as the newly-created mitochondrial DNA mutations, or abnormal numbers of chromosomes, or the paradoxical mixed bag of reprogramming-induced senescence (RIS).

And there are even narrowly cellular forms of aging damage that you can't or wouldn't want to "repair" using reprogramming. Yes, you can reverse cellular senescence by reprogramming, and with a few additional tricks you can even reverse reprogramming-induced senescence, but is that a good idea? Remember, the cellular senescence machinery is a kind of emergency brake, which the cell pulls when it is in danger of careening out of control, such as by progressing to become a cancer or by laying down excessive collagen after an injury, leading to fibrosis.

Chronic calorie restriction (CR) results in lengthened lifespan and reduced disease risk. Many previous studies have implemented 30-40% calorie restriction to investigate these benefits. The goal of our study was to investigate the effects of calorie restriction, beginning at 4 months of age, on metabolic and physical changes induced by aging. Male calorie restricted and ad libitum fed control mice were obtained from the National Institute on Aging (NIA) and studied at 10, 18, 26, and 28 months of age to better understand the metabolic changes that occur in response to CR in middle age and advanced age.

Food intake was measured in ad libitum fed controls to assess the true degree of CR (15%) in these mice. We found that 15% CR decreased body mass and liver triglyceride content, improved oral glucose clearance, and increased all limb grip strength in 10- and 18-month-old mice. Glucose clearance in ad libitum fed 26- and 28-month-old mice is enhanced relative to younger mice but was not further improved by CR. CR decreased basal insulin concentrations in all age groups and improved insulin sensitivity and rotarod time to fall in 28-month-old mice.

The results of our study demonstrate that even a modest reduction (15%) in caloric intake may improve metabolic and physical health. Thus, moderate calorie restriction may be a dietary intervention to promote healthy aging with improved likelihood for adherence in human populations.

Research explains that when exercise is personally prescribed based on what is called "critical power," the results show greater improvement in endurance and greater long-term benefits for the individual. The authors define critical power as the highest level of our comfort zone. "It's the level at which we can perform for a long period of time before things start to get uncomfortable."

It works something like this: Suppose two friends have the same Max Heart Rate. Previous understanding of exercise would suggest that if they run together at the same speed, they should have very similar experiences. However, it so happens that when these two friends run at 6 mph, the exercise is easy for one, but difficult for the other. These distinctive experiences at the same speed and same percent of Max Heart Rate are because 6 mph is below the one friend's critical power, but above the other's critical power.

When exercise is below a person's critical power, their body can compensate for the energy challenge and reach a comfortable and controlled homeostasis. However, when exercise is above one's critical power, their body cannot completely compensate for the energy demand, resulting in exhaustion. Traditionally, individualized exercise has been recommended based on a fixed percentage of one's maximum rate of oxygen consumption (VO2 Max) or their Max Heart Rate.

Researchers discovered that prescribing exercises based on VO2 Max as a reference point results in alarming variability in results. There were participants who benefited significantly from the training period and others who did not, even though the training was personalized to them. They compared this to each individual's critical power and found that it accounted for 60% of the variability in their findings. If exercises had been prescribed using critical power as a reference point versus their heart rate, the results would have varied less, meaning the training sessions would have been more effective and beneficial for each participant. Using "critical power" is a better way of prescribing exercise because it not only accurately serves athletes and those in great shape, but it also serves those who are older or have a more sedentary lifestyle.

Aging is accompanied by the decline of organismal functions and a series of prominent hallmarks, including genetic and epigenetic alterations. These aging-associated epigenetic changes include DNA methylation, histone modification, chromatin remodeling, non-coding RNA (ncRNA) regulation, and RNA modification, all of which participate in the regulation of the aging process, and hence contribute to aging-related diseases. Therefore, understanding the epigenetic mechanisms in aging will provide new avenues to develop strategies to delay aging. Indeed, aging interventions based on manipulating epigenetic mechanisms have led to the alleviation of aging or the extension of the lifespan in animal models.

Small molecule-based therapies and reprogramming strategies that enable epigenetic rejuvenation have been developed for ameliorating or reversing aging-related conditions. In addition, adopting health-promoting activities, such as caloric restriction, exercise, and calibrating circadian rhythm, has been demonstrated to delay aging. Furthermore, various clinical trials for aging intervention are ongoing, providing more evidence of the safety and efficacy of these therapies.

Here, we review recent work on the epigenetic regulation of aging and outline the advances in intervention strategies for aging and age-associated diseases. A better understanding of the critical roles of epigenetics in the aging process will lead to more clinical advances in the prevention of human aging and therapy of aging-related diseases.

In 2021, about 6.2 million U.S. adults aged 65 or older lived with dementia. Because age is the strongest risk factor for dementia, it has been predicted that increasing life expectancies will substantially increase the prevalence of Alzheimer's disease and related dementias from about 50 million to 150 million worldwide by 2050. However, there is growing evidence that age-adjusted dementia prevalence has been declining in developed countries, possibly because of rising levels of education, a reduction in smoking, and better treatment of key cardiovascular risk factors such as high blood pressure.

A new study employs a novel model to assess cognitive status based on a broad set of cognitive measures elicited from more than 21,000 people who participate in the national Health and Retirement Study, a large population-representative survey that has been fielded for more than two decades. The model increases the precision of dementia classification by using the longitudinal dimension of the data. Importantly for the study, the model is constructed to ensure the dementia classification is calibrated within population subgroups and, therefore, it is equipped to produce accurate estimates of dementia prevalence by age, sex, education, race, and ethnicity, and by a measure of lifetime earnings.

The prevalence of dementia in the United States dropped 3.7 percentage points from 2000 to 2016. The age-adjusted prevalence of dementia declined from 12.2 percent of people over age 65 in 2000 to 8.5 percent of people over age 65 in 2016 - a nearly one-third drop from the 2000 level. The prevalence of dementia decreased over the entire period, but the rate of decline was more rapid between 2000 and 2004. The study further found that education was an important factor that contributed, in a statistical sense, to the reduction in dementia, explaining about 40 percent of the reduction in dementia prevalence among men and 20 percent of the reduction among women.

The principal process by which overall mitochondrial quality is maintained is through selective culling of dysfunctional and damaged organelles by mitochondrial autophagy, or mitophagy. It is posited that age-related deterioration in mitophagy, and the consequent interruption of mitochondrial quality control, can contribute to adverse aging phenotypes partly because of increased elaboration of mitochondria-derived ROS from improperly retained damaged organelles. A corollary to this hypothesis is that improving the overall fitness of the cellular mitochondrial collective by forced mitophagy activation might delay age-related cell degeneration and ameliorate age-associated diseases. Experimental systems using overexpression of mitophagy and related factors support this proposition.

Mitochondrial quality control is the canonical role for mitophagy, and likely the mechanism by which its enhancement prevents premature senescence. However, culling defective mitochondria is not the sole purpose of mitophagy, nor is the PINK-Parkin pathway the only pathway to mitophagy. Accumulating evidence in mammalian systems suggests that Parkin-mediated mitophagy may be more important as a stress-induced or developmentally regulated mechanism, and that other paths comprise the major mechanism for homeostatic quality control through "maintenance mitophagy". Moreover, Parkin-mediated mitophagy can play an essential role during cell-wide mitochondrial replacement, generally accelerating mitochondrial turnover for either quantity control (i.e., removing excess mitochondria) or provoking a metabolic adaptation in response to an altered environmental context (as in converting the mitochondrial collective from lipid- to carbohydrate-based metabolism and vice versa).

Mitochondrial abnormalities such as fragmentation, loss of inner membrane polarization and increased ROS production have been widely reported in both chronically progressive neurodegenerative diseases and genetic neurological syndromes manifesting an age-dependent phenotype. There is growing interest in developing approaches to correct secondary mitochondrial abnormalities as one component of an ensemble therapy approach to these incurable and largely untreatable diseases. One promising approach attacks the problem of mitochondrial fragmentation, either by inhibiting mitochondrial fission or stimulating mitochondrial fusion. It is intriguing to speculate that these tactics might act synergistically with pharmaceutical activation of mitophagy to correct mitochondrial abnormalities in neurodegenerative diseases.

Understanding the mechanisms governing selective turnover of mutation-bearing mitochondrial DNA (mtDNA) is fundamental to design therapeutic strategies against mtDNA diseases. Here, we show that specific mtDNA damage leads to an exacerbated mtDNA turnover, independent of canonical macroautophagy, but relying on lysosomal function and ATG5. Using proximity labeling and Twinkle as a nucleoid marker, we demonstrate that mtDNA damage induces membrane remodeling and endosomal recruitment in close proximity to mitochondrial nucleoid sub-compartments.

Targeting of mitochondrial nucleoids is controlled by the ATAD3-SAMM50 axis, which is disrupted upon mtDNA damage. SAMM50 acts as a gatekeeper, influencing BAK clustering, controlling nucleoid release and facilitating transfer to endosomes. Here, VPS35 mediates maturation of early endosomes to late autophagy vesicles where degradation occurs.

In addition, using a mouse model where mtDNA alterations cause impairment of muscle regeneration, we show that stimulation of lysosomal activity by rapamycin, selectively removes mtDNA deletions without affecting mtDNA copy number, ameliorating mitochondrial dysfunction. Taken together, our data demonstrates that upon mtDNA damage, mitochondrial nucleoids are eliminated outside the mitochondrial network through an endosomal-mitophagy pathway. With these results, we unveil the molecular players of a complex mechanism with multiple potential benefits to understand mtDNA related diseases, inherited, acquired or due to normal ageing.

Previous research by another group showed that when macrophages from an old mouse were put into a young mouse, and cells looked young again. Signs pointed to a lipid immune modulator known as prostaglandin E2 (PGE2) with wide ranging effects. The study team discovered there is more PGE2 in the lungs with age. This increase in PGE2 acts on the macrophages in the lung, limiting their overall health and ability to generate. The team suspects that the buildup of PGE2 is yet another marker of a biological process called senescence, which is often seen with age.

The study showed that with age, the cells lining the air sacs in the lungs become senescent, and these cells lead to increased production of PGE2 and suppression of the immune response. To test the link between PGE2 and increased susceptibility to influenza, they treated older mice with a drug that blocks a PGE2 receptor. "The old mice that got that drug actually ended up having more alveolar macrophages and had better survival from influenza infection than older mice that did not get the drug." The team plans to next investigate the various ways PGE2 affects lung macrophages as well as its potential role in inflammation throughout the body.

Multiple sclerosis (MS) is an autoimmune disease in which the body's own immune system attacks the myelin sheath of the nerve cells in the brain and spinal cord. The disease leads to paralysis, pain, and permanent fatigue, among other symptoms. Fortunately, there have been great advances in therapies in recent decades. 80 percent of patients remain disease-free long-term or even forever following an autologous hematopoietic stem cell transplant. During the treatment, several chemotherapies completely destroy the patients' immune system - including the subset of T cells which mistakenly attack their own nervous system. The patients then receive a transplant of their own blood stem cells, which were harvested before the chemotherapy. The body uses these cells to build a completely new immune system without any autoreactive cells.

Previous studies have shown the basic workings of the method, but many important details and questions remained open. Some unclear aspects were what exactly happens after the immune cells are eliminated, whether any of them survive the chemotherapy, and whether the autoreactive cells really do not return. In a recently published study, researchers systematically investigated these questions for the first time by analyzing the immune cells of 27 MS patients who received stem cell therapy. The analysis was done before, during and up to two years after treatment. This allowed the researchers to track how quickly the different types of immune cells regenerated.

Surprisingly, the cells known as memory T cells, which are responsible for ensuring the body remembers pathogens and can react quickly in case of a new infection, reappeared immediately after the transplant. Further analysis showed that these cells had not re-formed, but had survived the chemotherapy. These remnants of the original immune system nevertheless posed no risk for a return of MS, as they were pre-damaged due to the chemotherapy and therefore no longer able to trigger an autoimmune reaction.

In the months and years following the transplant, the body gradually recreates the different types of immune cells. The thymus gland plays an important role in this process. This is where the T cells learn to distinguish foreign structures, such as viruses, from the body's own. Adults have very little functioning tissue left in the thymus. But after a transplant, the organ appears to resume its function and ensures the creation of a completely new repertoire of T cells which evidently does not trigger MS or cause it to return.

Studies have demonstrated that physical exercise reduces the risk for some types of cancer by up to 35%. This positive effect is similar to the impact of exercise on other conditions, such as heart disease and diabetes. In this study researchers added new insight, showing that high-intensity aerobic exercise, which derives its energy from sugar, can reduce the risk of metastatic cancer by as much as 72%. If so far the general message to the public has been 'be active, be healthy', now researchers can explain how aerobic activity can maximize the prevention of the most aggressive and metastatic types of cancer.

The study combined an animal model in which mice were trained under a strict exercise regimen, with data from healthy human volunteers examined before and after running. The human data, obtained from an epidemiological study that monitored 3,000 individuals for about 20 years, indicated 72% less metastatic cancer in participants who reported regular aerobic activity at high intensity, compared to those who did not engage in physical exercise.

The animal model exhibited a similar outcome, also enabling the researchers to identify its underlying mechanism. Sampling the internal organs of the physically fit animals, before and after physical exercise, and also following the injection of cancer, they found that aerobic activity significantly reduced the development of metastatic tumors in the lymph nodes, lungs, and liver. The researchers hypothesized that in both humans and model animals, this favorable outcome is related to the enhanced rate of glucose consumption induced by exercise.

With age, the brain's ability to clear aggregating proteins such as amyloid-β (Aβ) wanes. Researchers have found that the macrophages that cozy up to arteries in the brain help thin out extracellular matrix around these vessels. Macrophages inhabit spaces that border the brain parenchyma, namely along blood vessels and in the meninges. In both locations, they make direct contact with cerebrospinal fluid (CSF). Although these cells have been implicated in conditions such as hypertension, stroke, and Alzheimer's disease (AD), no one knew exactly what they did in healthy brain.

To explore this, researchers killed off border macrophages in wild-type mice by injecting liposomes containing a toxin into the CSF, where they were selectively taken up by macrophages. One week later, researchers injected a fluorescent tracer into CSF at the base of the brain, and tracked its diffusion along vessels. In control mice, arterial pulsing pushed the tracer into parenchyma. In liposome-treated mice, however, it penetrated only half as far as it did in control mice, indicating weaker CSF flow. To see why this was, the authors directly examined arterial movement through a cranial window while they stimulated brain activity by tickling the mice's whiskers. In mice lacking perivascular macrophages, blood vessels dilated less than they did in controls.

Why might this be? Perivascular macrophages are known to pump out matrix metalloproteases (MMPs), which chew up extracellular matrix (ECM) proteins. The authors found that MMP activity around brain blood vessels was suppressed after macrophage depletion, and the ECM was thicker. This overgrowth hindered dilation of blood vessels, in effect making them stiffer. In addition, nearby fibroblasts released more ECM proteins in the absence of macrophages. The authors concluded that macrophages keep vessels supple both by breaking down ECM and via crosstalk with fibroblasts that regulates their output.

Not all perivascular macrophages contribute to CSF flow. An analysis of gene expression revealed two subsets. One expressed the immune marker MHCII, and clustered around veins. Based on their expression profile, the authors believe these cells may recruit circulating leukocytes to brain. The other group expressed LYVE1, a membrane glycoprotein. These cells resided mainly around arteries and arterioles, and were scavengers, engulfing nearby debris. LYVE1 cells seem to be the ones controlling CSF flow, as genetically ablating only this subset thickened ECM and stiffened vessels.