Fight Aging! Newsletter, February 1st 2021

Inflammation and cellular senescence are hallmarks of aging. Almost two decades ago, dystrophic microglia were described with beading and fragmentation of the branches of the microglia. In contrast to the hypertrophic microglia often seen following central nervous system injury, the dystrophic microglia were proposed to be a form of microglia senescence. While there is no single specific marker of cellular senescence, a handful of markers, such as p16INK4a, have some affinity for identifying senescent cells. Using a p16INK4a approach to target the removal of senescent cells in a mouse model of tauopathy resulted in reduced tau pathology, neuronal degeneration, and cognitive deficits. Given the necessary cellular stressors, microglia can become senescent/dystrophic.

Throughout the body, cellular senescence is associated with the secretion of inflammatory mediators, defined as the senescence-associated secretory phenotype. Even a small number of senescent cells in any organ can contribute to disease and by the spread of the senescence phenotype to neighboring healthy cells. The hypothesis that dystrophic microglia is an age-associated microglia morphology has not been experimentally tested. While cellular senescence generally increases with age, it can occur at any stage of life in response to stressors. This led our first question: are dystrophic microglia associated with chronological age in people? We hypothesized that with increasing years, there would be an increasing proportion of dystrophic microglia. Previous work, including our own, has found dystrophic microglia in aged humans without neurodegenerative pathology.

In contrast to the view that dystrophic microglia are purely an age-related change in microglial morphology, there is compelling evidence that dystrophic microglia are more closely associated with neurodegenerative disease. Previous studies identified dystrophic microglia in people with age-related neurodegenerative disease, including Alzheimer's disease (AD). These findings lead to our second question: is increased dystrophic microglia a disease associated phenomenon? We hypothesized that the absolute numbers, and/or percentage of dystrophic microglia, would be greater in people with neurodegenerative disease than age-matched controls.

To address these questions, we studied brains from the University of Kentucky Department of Pathology and the UK-ADRC biobank, covering the adult lifespan from 10-90+ years of age. Stereological counts of the total number of microglia, number of hypertrophic microglia, and the number of dystrophic microglia were conducted in 3 brain regions: hippocampal CA1, frontal cortex, gray matter, and white matter. We found that in the absence of neurodegenerative disease, there was only a modest increase in dystrophic microglia with age. However, with neurodegenerative pathology, the percentage of microglia observed to be dystrophic was much greater than aged-matched controls.

Your history is that of a technology entrepreneur turned technology investor; what drew your interests to biotech and the longevity industry?

I like really tough problems - I've done a lot of work in artificial intelligence and 30 years ago speech recognition was really tough yet we now see these technologies being used everywhere. Just as speech recognition predominately started out in university labs, it was commercialization that really got it into people's hands. I'm a big believer in the entrepreneurial process to speed things along, and I think in biotech and longevity the entrepreneurial process is going to accelerate the field. I'm still view myself as an entrepreneur as well as an investor - I really get involved with the companies I invest in - I have about 60 positions and I think the entrepreneurs appreciate working with someone who has been where they are currently. The empathy is important to have enhanced communication to help solve problems.

You have many fellow travelers in the technology investor and AI community, folk with an interest in aging. Why do you think there is such an overlap between software, technology, AI, longevity?

Today there is currently an inflection point where the tools of mathematics and computer science are accelerating the developments in biotech. We now live in a world where no one person has all the skills individually to solve problems and so I feel I can contribute mathematically, scientifically and commercially. Like artificial intelligence before, which is still quite difficult, biotech is also difficult - unlike physics, laws of biology are difficult to come by. Biology is beginning to turn into an engineering subject and I think we are seeing that subject can be accelerated and deployed at lower cost than previously. Biotech is notoriously expensive, and also takes a long time. We now have the vision that solutions can simply be "calculated"; we still have to do clinical trials which take actual time, but even there we can use Bayesian tests to efficiently implement trials.

Over at R42, we have a very wide definition of longevity from curing age related diseases in biotech, searching for solutions to the root cause of aging, but also technologies to assist people as they age, robots and the like.

My end of the longevity community is much more interested in biotech than in infrastructure technologies such as AI for drug discovery. What is on your investment radar in pure biotech for longevity?

Well, I would say that AI for drug discovery could actually find new drugs to solve aging, and quite optimistic on that, making several bets in that area, and a fundamental thesis is that computation can spit many more candidates for longevity that anyone can do manually. On the radar for pure biotech really looking at mechanisms that start to crumble as we get older. One is the thymus which helps us build out our immune system but goes away in our late teens. There are a few efforts looking at regrowing the thymus when we need it again when we are 80. We have an investment in Repair Biotechnologies, your company! Another area we are looking at is mitochondrial mechanisms. Mitochondria provide 90% of the energy of our cells, and as we age, they don't work the same. Looking at how we can correct them or replace them with fresh ones is an area to look at.

None of us are getting any younger yet, at least not meaningfully so. What is your take on what we should be doing to speed up progress towards human rejuvenation?

We do need more focused funds like R42 to able to sort the wheat from the chaff and be triage systems for larger funds to follow with more money in the best ideas. These early funds need to surround these early stage ideas with resources - people, connections, partners to make sure they flourish. Since aging is a significant source of mortality, matching government funds would be able to accelerate more efforts given the risk in the field. I think once we have a poster child of a successful aging company going public there will be an acceleration of investment.

You are big on education, formally and informally; what do you hope to be the outcome of your efforts to raise the profile of work on longevity?

Yes, education is important. I teach courses on AI and Longevity both at the R42 Institute and at Stanford University. The main thing here is to provide people from many disciplines the tolls to be able to contribute in their own way. If people can contribute then people will participate. There is a natural interest in living healthy and having a long life. There are many disciplines - physicists, psychologists, chemists, engineers, even ethicists, economists and lawyers who can bring their perspectives and with more people talking about from different fields it will naturally raise the profile of longevity science.

While many companies in Longevity are focused on addressing one or more of the hallmarks, or pillars, of aging, the founders of Gerostate Alpha always saw things a little differently. "People take the hallmarks of aging as a launching off point, thinking that if they can forestall a particular pillar, let's say inflammation, then they'll get beneficial outcomes - but this is a biased approach. We've always been interested in looking at aging mechanisms in an unbiased way, whether through genetic interventions, or pharmacological interventions, we're not beholden to a particular mechanism, per se."

"Having been involved in the basic biology of aging and trying to understand the degenerative changes of aging from a mechanistic perspective for many years, that resonated with us. And so we put together a proposal focused around some of the ideas, particularly with regard to an unbiased way to identify molecules which might retard the aging process. We pitched it to Y Combinator, they really liked us and gave us a million in funding to start the company. It was certainly the fastest million we ever made in our careers!"

"You often hear people say they 'target aging' but you have to ask what does that mean - does it mean targeting a pillar of aging: senescence, inflammation, mitochondrial dysfunction? That's not targeting aging - that's targeting something other people have said is linked to aging processes. Everyone is very familiar now with using those terms, but it roots you in the idea that we understand what aging is, and we don't think we do. We believe that these pillars of aging are just one of many, and we think that the major modulators of aging remain to be discovered."

At the platform's "front end", the high throughput screen is predominantly based on lifespan extension data from a variety of strains and species of Caenorhabditis nematodes - simple, short-lived organisms, which allow manipulations of lifespan to be studied more easily. "At the back end, we phenotype the successful interventions that target different aspects of aging, in mice. And we're looking at multiple indications simultaneously, whether muscle dysfunction, lung function, bone function, cardiac function, the central nervous system to some extent. All of these things are screened for simultaneously. And I would argue this is something we can do better than anyone else."

The founders' confidence is largely because of the infrastructure that has been built up at the Buck Institute over many decades, and which would cost tens of millions if a start-up were to attempt to replicate it. "Our initial strategy was to screen small molecule libraries, so we did that on around 60,000 compounds, and we identified over 30 hits that have been validated. We're now prepping those and derivatives of those into lead candidates to move into our preclinical mouse models. But in parallel to that, we screened some libraries of off-patent compounds, and we've moved those through into preclinical mouse models already. We've had some really interesting hits and we're now doing our follow up experiments on the pathways involved in those and the efficacy of those compounds, in those specific tissues."

Chemotherapy may cause cell death, often by apoptosis, resulting clinically in tumour regression. It may also cause cellular senescence, leading clinically to tumour stasis (growth arrest). The role of senescence in response to chemotherapy is complicated, however, in that the senescence-associated secretory phenotype (SASP) of senescent cells induced by treatment varies between tissues and cell types, according to the precise senescent stimulus. In particular, some senescent cells secrete exosomes and these may have a tumour promoter function. Consequently, senescence induced by some cancer therapies may be harmful and promote tumour growth.

Whilst cells that undergo apoptosis are permanently removed from a cancer, senescent cells remain and secrete various inflammatory cytokines, which may have both positive and negative impacts. There have been concerns that these senescent cells may resist further chemotherapy damage and be a potential reservoir for recurrence. There is evidence that senescent cells may also be re-programmed to re-enter the cell cycle after certain types of chemotherapy and may acquire a more "stem cell"-like phenotype, which may in turn contribute to tumour regrowth and evolution.

Radiotherapy, which is one of the mainstays of cancer therapy, acts by causing direct DNA damage and has wide ranging impacts on cancer cells mediated by reactive oxygen species. The DNA damage response is triggered and if repair is not possible, cells either die if the damage is severe or enter senescence if less severe. Radiotherapy also triggers an immune response, making the treated cells more immunogenic in a variety of ways. Part of this immunogenicity may be due to the release of SASP factors from senescent cells. Another way in which senescence may be a clinically important part of radiotherapy response is in causing radiation-induced fibrosis. This can be a potentially severe complication of radiotherapy, especially in the lung where pulmonary fibrosis may occur. Senescent cells also appear to be linked to skin fibrosis and ulceration following radiotherapy.

In the context of chemotherapy tolerance, there is evidence that some of the adverse effects of chemotherapy are mediated by the therapy-induced senescent cells which have a pro-inflammatory effects (due to SASP) in a doxorubicin or paclitaxel treated mouse model. Removal of these therapy-induced senescent cells abrogated many of the adverse effects of chemotherapy (reduced fatigue, increased activity levels, reduced cardiac functional impairment). In a separate study, again in a mouse model, the elimination of senescent cells by the use of dasatinib and quercetin, reduced the impact of radiotherapy, improved cardiac function and exercise tolerance, and increased life expectancy. Data in humans are also available that show that higher levels of senescence biomarkers are linked with higher rates of treatment-induced adverse events following doxorubicin chemotherapy.

Senotherapies refers to a group of pharmacological agents that interact with senescent cells to interfere with their pro-aging impacts. There are two main categories: senolytic drugs, which selectively destroy senescent cells and senostatic drugs, which inhibit their function by suppression of their release of SASP factors. Of the two drug groups, senolytics have been more extensively studied and show promise of therapeutic value. These are of particular interest as an adjunct to chemotherapy, where the senolytic drug may be able to target cells induced to become senescent by the cancer. They may also improve treatment resilience. There are several agents under investigation.

It is already recognised that long-term survivors of cancer have increased rates of frailty and reduced longevity, some of which are thought to be due to the direct and indirect induction of senescent cells by cancer therapies (chemotherapy and radiotherapy). A trial is currently running to assess the impact of senolytic therapy on stem cell transplant survivors using dasatinib and quercetin in a small number of patients and assessing the impact on frailty.

Another important patient group is the elderly with cancer. It is well recognized that treatments such as surgery and chemotherapy have a significant negative impact on physical function, with studies showing an increase in measures of frailty after treatment, which may never recover back to baseline levels. This loss of function is one of the reasons that older patients require longer hospital admission after surgery and sometimes require social care support in the longer term after surgery. If use of senolytic therapies could reduce the frailty phenotype and enhance resilience, this would be a major advance in cancer therapies.

Late last year, Silicon Valley start-up Rubedo Life Sciences secured a sizeable seed funding round of 12 million to develop senolytic therapies that selectively target and clear senescent cells from aged or pathological tissues. The company is now conducting preparatory work for IND-enabling studies, ahead of moving to Phase 1 clinical trials, potentially as early as 2022.

Appropriately, in alchemy, the word "rubedo" refers to the final phase of the creation of the mythological elixir of life, which delivers rejuvenation and immortality. And Rubedo has borrowed another term from alchemy to name its discovery platform, Alembic, which refers to the apparatus used by alchemists to prepare their medicine. "I'm so happy to see that in the past 10 years, and even more in the past five, the scientific and biotech communities have reached that level of initial maturity, the critical mass to accept the idea that aging is the main driving process of age-related diseases. There is a change in biology, and we accept this idea that it can be probably targeted. Aging is not a clinical indication yet, but the chronic diseases that result from it are, and they are mostly all unmet needs."

"We are not a senolytic company, per se. Our first and most advanced programme is our senolytic programme, but the Alembic platform that we have developed is agnostic." Alembic is used is to profile and identify the biological changes that emerge with age and disease. It can be used, for example, to identify metabolic signatures as specific characteristic of certain cells. "What is emerging with age, what's happening at that inflection point? What are the cells that are emerging, or the changes in any cell types, in different tissues, across ages, across species, across diseases? Alembic allows us to identify novel targets, to identify the specific signatures, and use this information to design and engineer more molecules that are special, targeted therapeutics."

Seattle-based Oisín Biotechnologies is creating therapies to combat a variety of age- related diseases. Their breakthrough gene therapy platform clears senescent cells in a highly precise way. Promising preclinical studies have already shown a significant median lifespan extension in mice. Oisín's therapy has been shown to efficiently eliminate senescent cells body-wide in multiple animal models and has demonstrated therapeutic benefit in both disease burden and lifespan. Treated mice lived 20% longer even when treatment was started in old age, and after a single treatment, senescent cell removal rates reached as high as 70%.

"The ultimate goal is to eliminate unnecessary suffering. I think that everyone who believes in the mission of longevity is striving towards this. By realizing these therapies, we can start to fundamentally change the way that humans think about aging and disease. Our approach is pretty much the exact opposite of the traditional pharmaceutical approach. With our approach, there is no drug, no poison at all - just a little program written in DNA. We've effectively taken targeting out of the realm of chemistry and brought it into the realm of information."

Oisín has seen that the effects of their therapy are comparable to transgenic mouse studies conducted by the Mayo Clinic and the Buck Institute. The company is now moving to functional studies and disease models in order to create a clinically approved therapy. They are currently working with European collaborators as well as others to develop their kidney disease clinical package and future pipeline indications.

Given the complex heterogeneities of cell and tissue aging in any single individual and the notion of the most rapidly aging tissues being the driver of the aging of that organism, do those more rapidly aging tissues accelerate the aging of other tissues in the body? Does the aging of one cell affect the age of another cell? Is aging contagious? The notion of the aging process spreading from one cell to another is highlighted by the field of cellular senescence. The secretome of senescent cells has been shown to induce senescence of neighboring cells. In that sense, there can be cellular leaders that accelerate the aging of other cells in the tissue.

The notion of cell-to-cell spreading of cellular dysfunction is of course not limited to the biology of senescence. This is becoming an increasingly recognized phenomenon in the pathogenesis of neurodegenerative diseases. In many diseases, including Alzheimer's disease, Huntington's disease and Parkinson's disease, a cardinal feature of the pathology is intracellular aggregation of proteins. While seemingly a cell-intrinsic phenomenon, one of the curious features of the pathology of these diseases is the apparent spread of the cellular abnormalities to anatomically connected brain regions.

The general concept of this kind of spreading proteinopathy from one cell to another, locally, arises from the biology of prions and prion diseases. Of course, some prions are truly contagious, in the sense of being transmissible between individuals or across species, but the spread within the central nervous system of an individual suggests cell-to-cell spread. As with senescence, this phenomenon could represent the conversion of cells from one state (free from aggregates) to another (aggregate-laden) since protein aggregation can be self-propagating. As protein aggregation is one of the key features of cellular aging, it is intriguing to consider the possibility of aged cells achieving a sufficiently dysfunctional state as a result of protein aggregation, then conferring an aging signal to nearby cells through non-cell autonomous regulation of proteostasis.

If aging is indeed contagious, is the spread restricted to neighboring cells or might it spread to distant tissues via the systemic circulation? Based on early work from our laboratories that ushered in a new era of the use of the technique of parabiosis in aging research, it is clear that systemic factors originating from distant tissues in the body are able to either promote or reverse cell and tissue aging phenotypes. These findings, as well as many follow-up studies, including the demonstration that plasma infusions alone are sufficient to exert these effects, have unequivocally demonstrated that factors in the blood are able to communicate information from one or more source tissues to other tissues throughout the body. These could potentially accelerate, delay, or even reverse the rate of aging of other tissues in the body. Indeed, studies of brain endothelial cell aging showed that infusion of aged plasma can accelerate while young plasma can reverse aging as determined by analysis of the transcriptome. These studies highlight the fact that cellular aging does not occur independent of influences that are both local and systemic.

The retina and brain share many neuronal and vasculature characteristics, and potential biomarkers may be present in the retina. Previous studies have analyzed digital fundus photographs and reported a range of retinal vessel alterations in patients with Alzheimer's disease (AD) and mild cognitive impairment (MCI). However, images obtained from this technique can only provide information of retinal arterioles and venules measuring 60-300 μm in diameter. Optical coherence tomography angiography (OCTA) is a recent innovation that allows for further quantification of the retinal microvasculature and visualization of capillaries measuring 5-15 μm in diameter, which may be more representative of the entire microvascular network. Thus, the OCTA may be a potential non-invasive optical imaging tool to determine the presence and role of microvascular dysfunction in AD and cognitive impairment.

While there are a few OCTA studies investigating AD, there have been mixed conclusions. Some researchers reported finding significant reduction in the vessel density (VD) only in the superficial plexus, which complements histology findings and OCT studies since the superficial plexus mainly supplies the inner retinal layer. However, others reported finding changes only in the deep plexus. Studies have also used OCTA to examine participants with MCI, who are at higher risk for dementia and AD, but have drawn conflicting results as well.

To address these gaps, the purpose of the current study is to compare the retinal microvasculature metrics using OCTA, accounting for potential measurement bias and projection artifacts in participants with AD, MCI, and controls. We hypothesize that alterations in OCTA metrics as characterized by sparser vessel density and loss of vessel complexity will occur predominately within the superficial capillary plexus, in AD and to a lesser extent in MCI compared to controls.

24 AD participants, 37 MCI participants, and 29 controls were diagnosed according to internationally accepted criteria. OCTA images of the superficial and deep capillary plexus (SCP, DCP) of the retinal microvasculature were obtained using a commercial OCTA system. The main outcome measures were vessel density (VD) and fractal dimension (FD) in the SCP and DCP within a 2.5-mm ring around the fovea which were compared between groups.

Compared with controls, AD participants showed significantly sparser VD in both plexuses whereas MCI participants only showed reduction at the superficial plexus. In terms of FD, AD and MCI participants exhibited a loss of vessel complexity of the SCP when compared with controls. Our study adds further to the concept that there are possible progressive differences in retinal microvascular alterations between AD and MCI. Taken together with increasing evidence from other research, our current study demonstrates that differences in retinal microvascular changes using OCTA may potentially be used to identify and screen for AD and earlier cognitive phenotypes (i.e., MCI).

A new study adds to evidence that vision changes precede the cognitive decline that occurs in many, but not all, people with Parkinson's. A second new study found that structural and functional connections of brain regions become decoupled throughout the entire brain in people with Parkinson's disease, particularly among people with vision problems. The two studies together show how losses and changes to the brain's wiring underlie the cognitive impairment experienced by many people with Parkinson's disease.

In the first study, researchers studied 77 people with Parkinson's disease and found that simple vision tests predicted who would go on to get dementia after a year and a half. Dementia is a common, debilitating aspect of Parkinson's disease, estimated to affect roughly 50% of people within 10 years of a Parkinson's diagnosis. These longitudinal findings add weight to previous studies that were done at one time point, which had suggested that performance in vision tests was linked to the risk of cognitive decline. Those who went on to develop Parkinson's dementia had white matter damage to some of the long-distance wiring connecting the front and back of the brain, which helps the brain to function as a cohesive whole network.

The second study involved 88 people with Parkinson's disease (33 of whom had visual dysfunction and were thus judged to have a high risk of dementia) and 30 healthy adults as a control group, whose brains were imaged using MRI scans. In the healthy brain, there is a correlation between how strong the structural (physical) connections between two regions are, and how much those two regions are connected functionally. That coupling is not uniform across the brain, as there is some degree of decoupling in the healthy brain, particularly in areas involved in higher-order processing, which might provide the flexibility to enable abstract reasoning. Too much decoupling appears to be linked to poor outcomes.

The researchers found that people with Parkinson's disease exhibited a higher degree of decoupling across the whole brain. Areas at the back of the brain, and less specialised areas, had the most decoupling in Parkinson's patients. Parkinson's patients with visual dysfunction had more decoupling in some, but not all brain regions, particularly in memory-related regions in the temporal lobe.

Epigenetic changes directly contributing to aging and aging-related diseases include the accumulation of histone variants, loss of histones and heterochromatin, and deregulated expression/activity of miRNAs. In addition, histones show aberrant post-translational modifications leading to the imbalance of activating and repressing modifications. Moreover, remodeling complexes act to modulate chromatin accessibility and there is an aberrant expression/activity of miRNAs. Together, these epigenetic deregulations contribute to aging-associated changes in gene transcription and, as a consequence, translation as well as the stabilization or degradation of molecular factors.

While mechanisms underlying aging-related pathologies remain to be elucidated in detail, various studies demonstrate an epigenetic component. In fact, the aforementioned epigenetic modifications were shown to play essential roles in diseases including inflammation, cancer, osteoporosis, neurodegenerative diseases, and diabetes. While the precise mechanisms and connections between several epigenetic changes and human pathologies are still poorly understood, state-of-the-art next generation sequencing methods will allow researchers to address remaining questions.

An improved understanding of epigenetic mechanisms affecting longevity will be deciding crucial step towards the identification of new potential therapeutic targets. In fact, epigenetic drugs are of particular interest to the clinic due to their reversible and transient effect. A limitation of epigenetic studies, however, are the variations among single cells (both on an individual and tissue level), which occur with an even higher frequency in aged organisms. This biologically relevant heterogeneity might be further investigated, understood and potentially deconstructed with the help of new technological approaches like single-cell genomics. Together, characterizing molecular changes in different species during aging using state-of-the-art techniques will provide key insights into the relevance of epigenetics of aging and aging-associated diseases.

Cellular senescence is characterized by an irreversible cell cycle arrest and a pro-inflammatory senescence-associated secretory phenotype (SASP), which is a major contributor to aging and age-related diseases. Clearance of senescent cells has been shown to improve brain function in mouse models of neurodegenerative diseases. However, it is still unknown whether senescent cell clearance alleviates cognitive dysfunction during the aging process.

To investigate this, we first conducted single-nuclei and single-cell RNA-seq in the hippocampus from young and aged mice. We observed an age-dependent increase in p16Ink4a senescent cells, which was more pronounced in microglia and oligodendrocyte progenitor cells and characterized by a SASP. We then aged INK-ATTAC mice, in which p16Ink4a-positive senescent cells can be genetically eliminated upon treatment with the drug AP20187 and treated them either with AP20187 or with the senolytic cocktail Dasatinib and Quercetin. We observed that both strategies resulted in a decrease in p16Ink4a exclusively in the microglial population, resulting in reduced microglial activation and reduced expression of SASP factors.

Importantly, both approaches significantly were observed to improve cognitive function in aged mice. Our data provide proof-of-concept for senolytic interventions' being a potential therapeutic avenue for alleviating age-associated cognitive impairment.

Overexpression of cyclooxygenase-2 (COX-2), a major mediator of inflammation, in the brain produces Alzheimer's disease-like symptoms in mice: age-dependent inflammation and cognitive loss. COX-2 activation is the first step in the production of a lipid called prostaglandin E2 (PGE2), which can bind to one of its receptors, EP2, on immune cells and promote inflammation. To plug up the pathway, researchers have shown that deleting the EP2 receptor in mouse macrophages and brain-specific microglia - the cells normally responsible for detecting and destroying immune invaders and cellular debris - reduces inflammation and increases neuronal survival in response to both a bacterial toxin and a neurotoxin.

In the current study, the researchers wanted to understand how eliminating PGE2 signaling in macrophages could have these effects. They started by comparing macrophages from human blood donors either younger than 35 or older than 65. The cells from older donors made much more PGE2 and had higher abundance of the EP2 receptor than did macrophages from younger donors. When the researchers exposed human macrophages to PGE2, the cells altered their metabolism. Rather than using glucose to make energy, the cells converted it to glycogen and stored it, locking it up where the mitochondria couldn't access it for ATP production. "The result of that is that the cells are basically energy-depleted. They're just fatigued, and they don't work well. They don't phagocytose. They don't clear debris, including misfolded proteins associated with neurodegeneration."

When the scientists treated human macrophages from donors with an average age of about 48 with one of two EP2 receptor inhibitors, glycogen storage decreased, energy production increased, and cells shifted to express anti-inflammatory markers. As in human cells, aged mice also have higher levels of PGE2 in the blood and brain and EP2 receptor levels in macrophages, compared to younger mice. When the researchers knocked down the receptor in macrophages throughout the body in a mouse model of Alzheimer's disease or treated animals with either of two drugs to suppress EP2 function, cells had improved metabolism. The mice's age-associated inflammation also reversed and, with it, age-associated cognitive decline. Treating animals with an EP2 antagonist that couldn't get in the brain and thus only targeted the receptor in peripheral macrophages also led to cognitive improvement in older mice.

Older age is associated with deteriorating health, including escalating risk of diseases such as cancer, and a diminished ability to repair following injury. This rise in age-related diseases/co-morbidities is associated with changes to immune function, including in myeloid cells, and is related to immunosenescence. Immunosenescence reflects age-related changes associated with immune dysfunction and is accompanied by low-grade chronic inflammation or inflammageing. This is characterised by increased levels of circulating pro-inflammatory cytokines such as tumor necrosis factor (TNF), interleukin (IL)-1β and IL-6.

However, in healthy ageing, there is a concomitant age-related escalation in anti-inflammatory cytokines such as transforming growth factor-β1 (TGF-β1) and IL-10, which may overcompensate to regulate the pro-inflammatory state. Key inflammatory cells, macrophages, play a role in cancer development and injury repair in young hosts, and we propose that their role in ageing in these scenarios may be more profound. Imbalanced pro- and anti-inflammatory factors during ageing may also have a significant influence on macrophage function and further impact the severity of age-related diseases in which macrophages are known to play a key role.

In this brief review we summarise studies describing changes to inflammatory function of macrophages (from various tissues and across sexes) during healthy ageing. We also describe age-related diseases and co-morbidities where macrophages are known to play a key role, focused on injury repair processes and cancer, plus comment briefly on strategies to correct for these age-related changes.

Aging is associated with tissue degeneration, aging-related diseases, and an increased susceptibility to infections. These hallmarks of aging have been linked to aging-related changes within somatic stem cell compartments, and primarily investigated in animal models like mice. One of the most extensively studied somatic stem cell-based system is the hematopoietic system.

Hematopoietic stem cells (HSCs) maintain blood homeostasis and show an age-related decline in overall function in mice, which includes an increase in myelopoiesis, accumulation of DNA damage, changes in epigenomic and transcriptional programs, decreased cell polarity and aberrant activity of the small RhoGTPase Cdc42. Although significant progress has been achieved in elucidating mechanisms of aging of murine HSCs, it remains unclear whether these mechanisms can be simply extrapolated to other species, including humans. For these reasons, novel studies into understanding mechanisms of aging of human HSCs are warranted and are a prerequisite to bolster the transition of this knowledge into the clinic.

In this study, we characterize age-related phenotypes of human hematopoietic stem cells (HSCs). We report increased frequencies of HSC, hematopoetic progenitor cells (HPC), and lineage negative cells in the elderly but a decreased frequency of multi-lymphoid progenitors. Aged human HSCs further exhibited a delay in initiating division ex vivo though without changes in their division kinetics. The activity of the small RhoGTPase Cdc42 was elevated in aged human hematopoietic cells and we identified a positive correlation between Cdc42 activity and the frequency of HSCs upon aging.

The frequency of human HSCs polar for polarity proteins was, similar to the mouse, decreased upon aging, while inhibition of Cdc42 activity via the specific pharmacological inhibitor of Cdc42 activity, CASIN, resulted in re-polarisation of aged human HSCs with respect to Cdc42. Elevated activity of Cdc42 in aged HSCs thus contributed to age-related changes in HSCs. Xenotransplantation of human HSCs into immunodeficient mice showed elevated chimerism in recipients of aged compared to young HSCs, indicating a worse function in aged HSCs. Aged HSCs treated with CASIN ex vivo displayed an engraftment profile similar to recipients of young HSCs, however.

Taken together, our work reveals strong evidence for a role of elevated Cdc42 activity in driving aging of human HSCs, and similar to mice, this presents a likely possibility for attenuation of aging in human HSCs.

Researchers have developed a way of combining a bone substitute and drugs to regenerate bone and heal severe fractures in the thigh or shin bone. The study was conducted on rats, but the researchers think that the method in various combinations will soon be commonplace in clinical settings. "The drugs and materials we used in the study for the regeneration of bone are already approved. We simply packaged them in a new combination. Therefore, there are no real obstacles to already using the method in clinical studies for certain major bone defects that are difficult to resolve in patients."

Bones in the human body have a fantastic ability to repair injury, but some defects are so large or complicated that the healing process is delayed or absent. This may be due to the bone having been subjected to a major trauma in connection with a traffic accident for example, or a tumour or infection causing a major bone defect. These cases are currently treated through bone transplantation, usually with bone taken from the patient's own pelvis.

So far, the injectable cocktail successfully mixed by the researchers consists of three different components: an artificial ceramic material, a bioactive bone protein (recombinant BMP-2) and a drug, bisphosphonate, that combats bone resorption. "The bone protein we use has had negative effects in previous studies due to a secondary premature bone resorption, among other things. We have successfully mitigated this effect with the bisphosphonate and, by packaging the drug in a slowly resorbing bone substitute, we can control the speed of release. In the current study with the combination, we achieved a six-fold reduction in the amount of protein compared to previous efforts, while still inducing bone formation. The result was that even fractures with an extensive bone defect could heal without complications. We believe this finding will be of great clinical use in the future."

A large study finds that physical activity does not undo the negative effects of excess body weight on heart health. "One cannot be 'fat but healthy'. This was the first nationwide analysis to show that being regularly active is not likely to eliminate the detrimental health effects of excess body fat. Our findings refute the notion that a physically active lifestyle can completely negate the deleterious effects of overweight and obesity."

The study used data from 527,662 working adults insured by a large occupational risk prevention company in Spain. The average age of participants was 42 years and 32% were women. Participants were categorised as normal weight, overweight, or obese. Additionally, they were grouped by activity level: 1) regularly active, defined as doing the minimum recommended for adults by the World Health Organization (WHO); 2) insufficiently active, some moderate to vigorous physical activity every week but less than the WHO minimum; 3) inactive. Cardiovascular health was determined according to three major risk factors for heart attack and stroke, namely diabetes, high cholesterol, and high blood pressure.

Approximately 42% of participants were normal weight, 41% were overweight, and 18% were obese. The majority were inactive (63.5%), while 12.3% were insufficiently active, and 24.2% were regularly active. Some 30% had high cholesterol, 15% had high blood pressure, and 3% had diabetes. The researchers investigated the associations between each weight category and activity group and the three risk factors. At all weight levels, any activity (whether it met the WHO minimum or not) was linked with a lower likelihood of diabetes, high blood pressure, or high cholesterol compared to no exercise at all. At all weights, the odds of diabetes and hypertension decreased as physical activity rose.

However, overweight and obese participants were at greater cardiovascular risk than their peers with normal weight, irrespective of activity levels. As an example, compared to inactive normal weight individuals, active obese people were approximately twice as likely to have high cholesterol, four times more likely to have diabetes, and five times more likely to have high blood pressure. "Exercise does not seem to compensate for the negative effects of excess weight. This finding was also observed overall in both men and women when they were analysed separately."