All life forms require the element iron as a constituent of their biochemical systems, iron being used in producing ATP in mitochondria, in cytochromes and hemoglobin, and in many other uses. Iron is essential for organismal growth and maintenance, so all life, from bacteria and algae to mammals, have developed the means to collect and store iron from their environments; this centrality of iron for all life suggests that iron may be involved in aging. Most organisms, including humans, have no systematic means of ridding themselves of excess iron. Whether this lack of ways to dispose of excess iron came about due to a relative scarcity of iron, or because the detrimental results from excess iron were relatively rare in an environment in which few organisms died from natural aging, is a question that remains to be answered. Whatever the answer to that may be, most organisms accumulate iron as they age.

A problem that organisms face in the use of iron in biological systems is protecting cells from iron damage. The very property of iron that makes it useful, its ability to accept or donate electrons, also gives it the ability to damage molecules and organelles via the Fenton reaction, in which iron reacts with hydrogen peroxide, leading to the formation of the highly reactive and toxic free radical, hydroxyl.

Most iron in cells is bound to proteins and other molecules that safely store it and prevent it from interacting with other macromolecules. In mammals, ferritin and transferrin are such proteins; hemoglobin is, however, the quantitatively most important iron depot in mammals. In theory, these storage proteins should be enough to protect organelles and macromolecules from iron's reactivity, but in practice another process becomes perhaps more important, and that is iron dysregulation. Storage proteins such as ferritin can themselves be damaged, leading to "leakage" of free iron, which can then react with and damage cellular structures, which in turn can lead to organ damage and the deterioration associated with aging. Whether this damage associated with aging is in fact a cause or consequence of aging of course remains to be determined, but as we shall see, there are several other reasons to think that iron is a driver of aging.

The formation of Revel Pharmaceuticals is a reimagination and expansion of targeting AGE crosslinks using enzymes rather than small molecules as the therapeutic. "Enzymes are biologics, so we can be very precise as we make modifications to repair damaged proteins and break up crosslinks."

"We're quite unique right now, in the aging space - not many companies are focused on the structural, protein side of aging. If you look at the literature and clinical data, it's very clear that damage and crosslinking of collagen and other proteins is a significant contributor to aging. As the structure of the extracellular matrix surrounding cells becomes crosslinked and degraded, proteins begin to aggregate and lose functionality, tissues become stiffer, and the immune system becomes activated leading to low level inflammation. We're looking at the same targets that have been of interest for a long time, but no one's had a good way to correct or repair them. We started out looking at glucosepane, the predominant crosslink in aging human tissue, but there are many other important aging crosslinks and damage products to which we've expanded our scope."

"Our work has led us to five or six interesting targets, which also serves to de-risk our pipeline, so all of our eggs aren't in one basket. What we have now is a suite of enzymes targeting a suite of different damage products." Revel is preparing to move therapeutic enzymes into pilot studies in animal models and human cadaver tissue from biobanks. "If we have 80 year old tissue that comes from a biobank, then the gold standard is really to show that, when we add our enzymes to that very old tissue, we can repair these modifications and correct the damage. Once that critical milestone is met for each enzyme, we will immediately push into animal studies and eventually clinical testing."

The bacteria living in the intestine consist of some 500 to 1000 different species. They make up what is known as the intestinal flora, which plays a key role in digestion and prevents infections. Unlike pathogens that invade from the outside, they are harmless and tolerated by the immune system. The way in which the human immune system manages to maintain this delicate balance in the intestine largely remains unknown. It is known that type A immunoglobulins, referred to as IgA antibodies, play an important role. These natural defense substances are part of the immune system, and recognize an exogenous pathogen very specifically.

A group of researchers have recently been able to show in a mouse model that IgA antibodies specifically limit the fitness of benign bacteria at several levels. This enables the immune system to fine-tune the microbial balance in the intestine. The researchers succeeded in tracking the in-vitro and in-vivo effect in the intestines of germ-free mice with pinpoint accuracy. The antibodies were found to affect the fitness of the bacteria in several ways. The mobility of bacteria was restricted, for example, or they hindered the uptake of sugar building blocks for the metabolism of the bacteria. The effect depended on the surface component that was specifically recognized. "This means that the immune system is apparently able to influence the benign intestinal bacteria through different approaches on a simultaneous basis. Understanding exactly how and where antibodies recognize microorganisms in the intestine will also allow us to develop vaccines against pathogenic organisms on a more targeted basis."

Dimeric IgA secreted across mucous membranes in response to nonpathogenic taxa of the microbiota accounts for most antibody production in mammals. Diverse binding specificities can be detected within the polyclonal mucosal IgA antibody response, but limited monoclonal hybridomas have been studied to relate antigen specificity or polyreactive binding to functional effects on microbial physiology in vivo. Here we use recombinant dimeric monoclonal IgAs (mIgAs) to finely map the intestinal plasma cell response to microbial colonization with a single microorganism in mice. We identify a range of antigen-specific mIgA molecules targeting defined surface and nonsurface membrane antigens.

Secretion of individual dimeric mIgAs targeting different antigens in vivo showed distinct alterations in the function and metabolism of intestinal bacteria, largely through specific binding. Even in cases in which the same microbial antigen is targeted, microbial metabolic alterations were different depending on IgA epitope specificity. By contrast, bacterial surface coating generally reduced motility and limited bile acid toxicity. The overall intestinal IgA response to a single microbe therefore contains parallel components with distinct effects on microbial carbon-source uptake, bacteriophage susceptibility, motility, and membrane integrity.

Senescence is an irreversible proliferation arrest and a key restriction mechanism to prevent the propagation of damaged cells. However, the progressive accumulation of senescent cells with time has been associated with loss of tissue homeostasis, and is known to contribute to the functional impairment of different organs typically seen in ageing. Recently, it has been shown that it also plays an important role in fibrosis and tumour progression, and that it may be involved in cataracts, obesity, diabetes, Alzheimer's and Parkinson's diseases, arthritis, atherosclerosis and many other age-related conditions. This supports the hypothesis that senescence is an antagonistically pleiotropic process, with beneficial effects in the early decades of life of the organism (in development, tissue repair, and as a tumour suppressor mechanism) but detrimental to fitness and survival at later stages, after the percentage of senescent cells in tissues reaches a critical threshold.

Consistent with this view, it has been reported that clearing senescent cells from tissues has a protective effect against cancer and the onset of age-related pathologies. Because of this, great interest has been placed in a recently discovered group of drugs that can preferentially kill senescent cells, collectively known as senolytics, which have been shown to increase healthspan and lifespan of mice with attenuation of age-related dysfunctions like emphysema, hepatic steatosis, lung fibrosis, osteoporosis, osteoarthritis, cardiac regeneration dysfunctions, cognitive memory impairments or Alzheimer disease in different in vivo models. Recently, senolytics, were shown to also decrease the number of senescent cells in humans and alleviate the symptoms of idiopathic pulmonary fibrosis.

In this context, targeted senolytics are emerging as a promising alternative. For instance, it has recently been shown that toxic nanoparticles activated by the presence of β-galactosidase can eliminate senescent cells in vitro and in vivo, confirming the feasibility of the approach. We propose that the senescent surfaceome, the specific profile of membrane proteins differentially upregulated in senescent cells, could be used to this end even more effectively. Using mass spectrometry, we identified a number of markers highly expressed in the plasma membranes of senescent cells in response to the activation of one of the two main pathways of induction of the phenotype (p53/p21 or p16).

We show that an antibody-drug conjugate (ADC) against the marker B2M clears senescent cells by releasing duocarmycin into them, while an isotype control ADC was not toxic for these cells. This effect was dependent on p53 expression and therefore more evident in stress-induced senescence. Non-senescent cells were not affected by either antibody, confirming the specificity of the treatment. Our results provide a proof-of-principle assessment of a novel approach for the specific elimination of senescent cells using a second generation targeted senolytic against proteins of their surfaceome, which could have clinical applications in pathological ageing and associated diseases.

Microglia are the resident innate immune cells of the central nervous system (CNS), and are key players to mediate neuroinflammation, playing critical roles in the recognition and clearance of Aβ in Alzheimer's disease (AD). The activation phenotype of microglia was previously classified by the expression pattern of cytokines in analogy of activated macrophages: the proinflammatory "classical" activation phenotype (M1) and the anti-inflammatory "alternative" activated phenotype (M2). However, this simplistic view of microglial phenotypes does not adequately reflect the complex physiology of microglia.

The progression of neurodegenerative disease induces the loss of microglial homeostatic molecules and functions, leading to chronically progressive neuroinflammation. In addition, recent studies demonstrated that a common disease-associated microglia (DAM) or "neurodegenerative" phenotype, defined by a small set of upregulated genes, was observed in neurodegenerative diseases including AD, amyotrophic lateral sclerosis (ALS), and frontotemporal dementia, and aging. However, it remains unclear whether the loss of homeostatic function in microglia or the DAM phenotype is correlated with the degree of neuronal cell loss, and whether DAM is beneficial or detrimental to neurodegenerative diseases.

In this study, we performed RNA sequencing of microglia isolated from three representative neurodegenerative mouse models, AppNL-G-F/NL-G-F with amyloid pathology, rTg4510 with tauopathy, and SOD1G93A with motor neuron disease. In parallel, gene expression patterns of the human precuneus with early Alzheimer's change (n = 11) and control brain (n = 14) were also analyzed by RNA sequencing.

We found that a substantial reduction of homeostatic microglial genes in rTg4510 and SOD1G93A microglia, whereas DAM genes were uniformly upregulated in all mouse models. The reduction of homeostatic microglial genes was correlated with the degree of neuronal cell loss. In human precuneus with early AD pathology, reduced expression of genes related to microglia- and oligodendrocyte-specific markers was observed, although the expression of DAM genes was not upregulated. Our results implicate a loss of homeostatic microglial function in the progression of AD and other neurodegenerative diseases. Moreover, analyses of human precuneus also suggest loss of microglia and oligodendrocyte functions induced by early amyloid pathology in human.

The establishment of effective therapies for age-associated neurodegenerative diseases such as Alzheimer's disease (AD) is still challenging because pathology accumulates long before there are any clinical signs of disease. Thus, patients are often only diagnosed at an already advanced state of molecular pathology, when causative therapies fail. Therefore, there is an urgent need for molecular biomarkers that are (i) minimally invasive, (ii) can inform about individual disease risk, and (iii) ideally indicate the presence of multiple pathologies. Such biomarkers should eventually be applicable in the context of routine screening approaches with the aim to detect individuals at risk for developing AD that could then be subjected to further diagnostics via more invasive and time-consuming examinations.

We use a novel experimental approach combining the analysis of young and healthy humans with already diagnosed patients as well as animal and cellular disease models to eventually identify a 3-microRNA signature (miR-181a-5p, miR-146a-5p, and miR-148a-3p) that can inform about the risk of cognitive decline when measured in blood. The 3-microRNA signature also informs about relevant patho-mechanisms in the brain, and targeting this signature via RNA therapeutics can ameliorate AD disease phenotypes in animal models.

We suggest that the analysis of this microRNA signature could be used as point-of-care screening approach to detect individuals at risk for developing AD that can then undergo further diagnostics to allow for early and effective intervention. In addition, our data highlight the potential of stratified RNA therapies to treat Alzheimer's disease.

Many dietary patterns, including the Western diet, are associated with reduced lifespan and health span and appear to affect cancer incidence by two major hormonal axes/pathways: (1) the growth hormone-IGF-1; (2) the insulin signaling. Higher protein intake increases the release of growth hormone releasing hormone, and consequently growth hormone release from the pituitary gland and IGF-1 release primarily from the liver. High IGF-1 has been associated with elevated incidence of a number of cancers.

Studies in simple organisms and mice, demonstrate the link between nutrients and particularly protein intake, growth factors, DNA damage, and cancer. The effect of growth factors on DNA damage and cancer is mediated, at least in part, by oxidative stress and damage, but in part also by the inhibition of apoptosis. The reduced activity of growth factors and the lowering of oxidation and DNA damage not only decreases cancer but also extends longevity, since aging is the most important factor promoting cancer. Calorie restriction (CR) is a powerful anti-aging intervention, but it also forces the organism into an extremely low nourishment state, which may not constitute malnourishment in the short-term but which may do so long-term.

Interventions such as intermittent fasting (IF) and periodic fasting (PF) are emerging as alternatives to CR, with some of them being able to minimize side effects and burden while maximizing efficacy. Studies on PF have also pointed to 2 key processes absent or low in CR and IF: (a) a pronounced breakdown process both at the intracellular (autophagy etc) and cellular (apoptosis) levels requiring 2 or more days and associated with a high ketogenic state, (b) a rebuilding/regeneration process involving stem cells and progenitor cells in multiple system and associated with the return from PF to normal feeding (re-feeding).

The fasting mimicking diet (FMD) developed and studied by our laboratories is emerging as a viable and effective intervention in the longevity and cancer prevention fields, since it does not require chronic treatment, it does not cause malnourishment or loss of muscle mass and may be effective when performed only a few times a year for 5 days. In the future years it will be important to continue to test different nutritional interventions with the potential to extend the health span and prevent cancer, with a focus on those that are safe and feasible for long-term use in humans.

People with elevated blood pressure that falls within the normal recommended range are at risk of accelerated brain ageing, according to new research. If we maintain optimal blood pressure our brains will remain younger and healthier as we age. "It's important we introduce lifestyle and diet changes early on in life to prevent our blood pressure from rising too much, rather than waiting for it to become a problem. Compared to a person with a high blood pressure of 135/85, someone with an optimal reading of 110/70 was found to have a brain age that appears more than six months younger by the time they reach middle age."

Researchers examined more than 2,000 brain scans of 686 healthy individuals aged 44 to 76. The blood pressure of the participants was measured up to four times across a 12-year period. The brain scan and blood pressure data was used to determine a person's brain age, which is a measure of brain health. The findings highlight a particular concern for young people aged in their 20s and 30s because it takes time for the effects of increased blood pressure to impact the brain. "By detecting the impact of increased blood pressure on the brain health of people in their 40s and older, we have to assume the effects of elevated blood pressure must build up over many years and could start in their 20s. This means that a young person's brain is already vulnerable."

The research findings show the need for everyone, including young people, to check their blood pressure regularly. "Adults should take the opportunity to check their blood pressure at least once a year, with an aim to ensure that their target blood pressure is closer to 110/70, particularly in younger and middle age groups. If your blood pressure levels are elevated, you should take the opportunity to speak with your GP about ways to reduce your blood pressure, including the modification of lifestyle factors such as diet and physical activity."

As age increases, the elasticity of arterial vessels decreases, and the inner diameter widens due to changes in the mechanical properties of blood vessels and the cardiovascular system. A decrease in elasticity leads to the stiffness of arterial vessels increasing and the reflected wave returning quickly, and abnormalities in proximal aortic diameter are responsible for the abnormal aortic pressure-flow relationship. This phenomenon increases arterial pressure, which elevates the risk of cardiovascular disease (CVD), including hypertension. Therefore, examining these age-related changes in arterial stiffness and appropriate indicators reflecting the stiffness caused by cardiovascular aging are important to prevent risk factors for CVD.

The pulse wave velocity (PWV), one of the representative indicators of arterial stiffness, is the speed at which a blood pressure pulse wave propagates through the arterial system. There is a distance measurement error caused by assuming a straight arterial segment, and in the most frequently used carotid-femoral PWV, the carotid and femoral pulse waves traveling in opposite directions cause overestimation of the PWV. Another measure of arterial stiffness is the augmentation index (AIx), which is the ratio of the height of the peak above the shoulder of the wave to the pulse pressure. The AIx is easier to measure and less time consuming than the PWV; additionally, the AIx enables observation of the reflective properties of the arteries. The AIx increases with age and blood pressure, which has been explained by the fact that wave reflection increases with age.

The sharpness of the pulse wave is a representative characteristic in pulse waveform analysis. Because it is well known that blunter waveforms are generally found in older people, whereas sharper pulse waveforms are found in younger people, pulse sharpness could reflect age-related characteristics, such as vascular aging or arterial stiffness, as well as the AIx. In addition, as the average pulse morphology variability near the peak point of the percussive wave was less than only 2% in a previous study, pulse sharpness could be an index with low variability. However, despite these intuitive considerations of pulse sharpness, few studies have been explored the availability of sharpness as an indicator of vascular aging or arterial stiffness, unlike the AIx. In addition, a formally accepted algorithm for detecting sharpness has not been reported.

The aim of this study was to develop a robust algorithm to quantify pulse sharpness that can complement the limitations of radial augmentation index (rAIx) and explore the role of this quantitative sharpness index in reflecting vascular aging or arterial stiffness. The pulse sharpness index (PSI) was developed by combining the end point angle and virtual height, and 528 radial pulses were analyzed.

Significant sex differences were identified in the rAIx and PSI, and significant age-dependent decreases in the PSI were observed. In addition, the PSI and age were correlated (r = - 0.550) at least as strongly as the rAIx and age (r = 0.532), and the PSI had a significant negative correlation with arterial stiffness (r = - 0.700). Furthermore, the multiple linear regression model for arterial stiffness using the PSI, age, sex and heart rate showed the excellent performance, and the PSI was found to have the greatest influence on arterial stiffness. This study confirmed that the PSI could be a quantitative index of vascular aging and has potential for use in inferring arterial stiffness with an advantage over the rAIx.

Michael Greve thought to himself: It would be stupid to kick the bucket now. He started to look into nutrition, gave up coke, pizza, and red wine, lost 20 kilos, gave up smoking, gained the 20 kilos back, and lost them again. After a total of three years, his body was ready for a life that wouldn't have to be boring for decades. Greve thought to himself: to kick the bucket now would be even stupider. Then he made the decision that changed his life, and may soon change yours: To not end up as the richest man in the graveyard. Michael Greve decided to take such a serious approach to health that he began to study the field of longevity, the science of extending the healthy human lifespan. He plowed through studies and began to get involved, as actively as only a person with a nine or ten-figure bank account can.

Five years ago, he donated the first ten million to the SENS Research Foundation, an authority on longevity research. In the same year, 2016, Greve founded the Forever Healthy Foundation. Forever Healthy has long been globally active, the language of the foundation is English, and the most recently hired employees are based in Istanbul and New York. From Karlsruhe, Greve and a small team currently manage 14 startups that have emerged from particularly promising research projects. In collaboration with the SENS Research Foundation, he organizes an annual conference, Undoing Aging, at which the industry's renowned scientists and opinion leaders meet.

With his own team, he produces scientific papers that can be thought of as a screenshot of current world knowledge on a topic - each paper based on about 2000 abstracts and 150 studies. He publishes them in a database on his website, freely accessible to anyone at any time, comprehensibly transformed into practical advice, for example things like fisetin and EDTA. He has turned himself into the leading global figure of a new approach to longevity: he talks about rejuvenation, the preservation and restoration of youth. He talks about viewing the process of aging as a treatable disease, not an inescapable fate. All this not with the goal of eternal life, but of prolonging the healthy life span as much as possible. To give you an idea of the avalanche Greve has unleashed in the past five years: One of his 14 startups has reached the point where it can dissolve tumors by injection. Another one can repair broken arteries.

Worldwide around 150,000 people die every day: 50,000 from accidents, violence, wars, things like that. 100,000 from diseases like diabetes, cancer, Alzheimer's, and heart attacks. You could simplify it and say: 100,000 people die every day from the worst disease in the world, namely aging. We humans have lived with this for a few million years, we humans have died with this for a few million years. We have become accustomed to that. But does it have to stay that way? "What we're doing now is getting to the bottom of the whole thing. Where does cancer start, where does Alzheimer's start? Where is the root? And more importantly, what can we do about it? I'm only interested in research that results in action. So in working with our startups and at our conference, we don't talk about model organisms and regulatory stuff. We're not talking about someday. We're talking about human treatments, we're talking about therapy, and we're talking about now."

As senescent cells are highly heterogeneous in both their molecular biology and their physiological function, targeted strategies are needed that ideally preserve senescent cells in beneficial contexts while eliminating effects that are detrimental. Broadly, these therapies can be broken down into the major categories of senomorphic and senolytic drugs, although this classification might be arbitrary as agents with senomorphic effects in one cell type or context may be senolytic in another and vice versa. Senomorphic compounds target pathologic SASP signaling, while senolytics eliminate the underlying senescent cells that release damaging SASP factors. Senomorphics are discussed elsewhere, but in brief senomorphics prevent the production of, antagonize or neutralize SASP components, and usually require continuous administration. We will instead focus on emerging senolytic strategies that address a root cause of senescence pathology, senescent cells, yielding pleiotropic benefits with intermittent administration.

While the first senolytics were developed using a bioinformatically informed approach aimed at disrupting senescent cell anti-apoptotic pathways (SCAPs) and other pro-survival networks, the class has expanded to take advantage of additional senescence features and enhance immune-mediated clearance. Broadly, first-generation agents act by transiently disabling SCAPs, causing those senescent cells with a tissue-damaging SASP to kill themselves. Importantly, while all senolytic strategies may elicit off-target effects or interfere with beneficial populations, these can often be limited as most therapeutics are amenable to intermittent 'hit-and-run' dosing strategies that do not require daily, or even weekly, administration.

Characterization of senescent cells has revealed unique markers that serve as senescence-associated self-antigens. These can be co-opted for immune system-mediated senolytic activity and clearance. A recent study took advantage of this using chimeric antigen receptor (CAR) T cells targeted against the urokinase-type plasminogen activator receptor (uPAR) in a mouse model. uPAR is associated with extracellular matrix remodeling that is upregulated at the cell surface of senescent cells during replicative, oncogene-induced and toxicity-induced senescence. Cytotoxic CAR T cells were able to selectively clear uPAR-expressing senescent cells in vitro and in vivo.

Prototypic senolytic drugs were developed to target SCAP networks. In contrast to a one-drug, one-target approach, SCAP inhibition may interface with several pro-survival signals at once. As a result, these early senolytics typically possess several pharmacologic mechanisms of action that interact synergistically. Prime examples of this are the flavonoid fisetin as well as dasatinib and quecertin (D + Q), which have been utilized and reviewed thoroughly. In brief, although the precise mechanism of action is unknown (as is the case for most agents), the D + Q combination exerts broad spectrum senolytic activity through interference with several pro-survival networks.

Additional aspects of senescent cells are advantageous for directed senolysis. One such feature is their increased lysosomal enzyme activity. This can be leveraged with the use of prodrugs that are cleaved and activated by the lysosomal enzyme SA-β-gal or by loading cytotoxic chemicals into galacto-polymer-coated nanoparticles that can be preferentially released into senescent cells. Further, outside its role as a cellular recycling system, autophagy can lead to activation of cell death pathways when highly activated under persistent stress. Autophagy is inhibited within senescent cells, but senescent cells are primed for cell death following an autophagic push. This is demonstrated by autophagy induction and subsequent senolysis.

Scientists are eager to understand what causes the bone loss of osteoporosis, and to develop new ways to treat and prevent it. Researchers have found an important contributor, a cellular protein called ELMO1. This protein, they found, promotes the activity of the bone-removing osteoclasts. While osteoclasts may seem like 'bad guys' because they remove bone, they are critical for bone health, as they normally remove just enough to stimulate new bone growth. The problem arises when the osteoclasts become too aggressive and remove more bone than the body makes. Then bone density suffers and bones grow weaker.

This excessive bone degradation is likely influenced by genetic factors. They note that many of the genes and proteins linked to ELMO1 have been previously associated with bone disorders and osteoclast function. Encouragingly, the researchers were able to prevent bone loss in lab mice by blocking ELMO1, including in two different models of rheumatoid arthritis (RA). That suggests clinicians may be able to target the protein in people as a way to treat or prevent bone loss caused by osteoporosis and RA.

They note that prior efforts to treat osteoporosis by targeting osteoclasts have had only mixed success, and they offer a potential explanation for why: Osteoclasts not only remove bone but play a role in calling in other cells to do bone replacement. As such, targeting ELMO1 may offer a better option than simply waging war on the osteoclasts. "We used a peptide to target ELMO1 activity and were able to inhibit degradation of the bone matrix in cultured osteoclasts without affecting their numbers. We hope that these new osteoclast regulators identified in our study can be developed into future treatments for conditions of excessive bone loss such as osteoporosis and arthritis."

Scientists have known that microglia play many important roles in the brain. For example, the cells police the natural blood-brain barrier that protects the organ from harmful germs in the bloodstream. Microglia also facilitate the formation of the brain's complex network of blood vessels during development. And they are known to be important in many diseases. In Alzheimer's disease, for example, recent work suggests that the loss of the immune cells is thought to increase harmful plaque buildup in the brain.

Scientists have been unsure, however, what role microglia play in maintaining blood vessels in a normal, healthy brain. The new research reveals that the cells are critical support staff, tending the vessels and even regulating blood flow. The researchers identified microglia associating with the brain's capillaries, determined what the immune cells do there and revealed what controls those interactions. Among the cells' important responsibilities is helping to regulate the diameter of the capillaries and possibly restricting or increasing blood flow as needed.

"We are currently expanding this research into an Alzheimer's disease context in rodents to investigate whether the novel phenomenon is altered in mouse models of the disease and determine whether we could target the mechanisms we uncovered to improve known deficits in blood flow in such a mouse model of Alzheimer's. Our hope is that these findings in the lab could translate into new therapies in the clinic that would improve outcomes for patients."

With advanced age, a reduced skin wound healing ability is associated with the development of so-called chronic nonhealing disorders, such as diabetic ulcers and pressure sores. Skin stem cells, also called keratinocyte stem cells, are responsible for skin regeneration and wound closure through a process called re-epithelialization. "Live-imaging and computer simulation experiments showed that human skin stem cells motility is coupled with their proliferative and regenerative capacity and old stem skin cells have a significantly reduced motility."

To understand the mechanisms behind this reduced motility in old stem cells, researchers compared the wound healing and proliferative ability of skin stem cells derived from young mice (12 weeks old) and aged mice (19-25 months old). The experiments showed that a specific molecule, called EGFR (Epidermal Growth Factor Receptor), drives skin stem cell motility and that EGFR signalling is reduced in old stem cells. EGFR acts by preventing the degradation of a specific type of collagen, COL17A1, which is necessary to hold the layers of the skin together.

Interestingly, COL17A1 coordinates the movement of skin stem cells towards the injury by regulating actin and keratin filament networks in the cells. The researchers found that with age, a decrease in EGFR signalling occurs, leading to lower levels of COL17A1 and skin stem cells with reduced mobility that are less able to re-epithelialize the skin. "Although further investigations are still required, stabilizing COL17A1 by regulating its proteolysis is a promising therapeutic approach for improving the decline in skin regeneration observed with age."

Our another achievement is the plasmapheresis trial, which is pretty well-known in the community. We didn't expect to observe dramatic improvements in biomarkers that we would treat as promising, we just wanted to understand the logistics of the whole plasmapheresis process. Because you need to replace half of your plasma with the saline + albumin solution and this is not a simple and standard procedure. But we managed to calculate how many plasma you need to donate with each visit to the doctor and how many albumin you need to replace and we did this and surprisingly we have found some pretty interesting changes in the biomarkers of this gentleman. We have found, for instance and contrary to our expectations, that cholesterol goes both directions - bad LDL goes down and good HDL goes up, which is pretty interesting. Of course we have only two data points, so we cannot draw too many conclusions from that, but we have started a clinical trial aiming to compare plasmapheresis with albumin and without albumin, because the role of albumin of the whole procedure is an interesting question.

A few smaller things our group has achieved. We have tried various senolytics in our volunteers. Created a lentiviral vector for APO-A1 Milano gene delivery. And also a microbiome replacement experiment, because we have access to samples from soviet cosmonauts (who are usually considered exceptionally healthy, so our hypothesis is that transferring the microbiome could yield interesting health improvements).

Here are several things we are planning to deliver in the upcoming years. We are intrigued by the study showing muscular aging through 15-PGDH, and we want to reproduce it on ourselves. Another target is epigenetic rejuvenation of hematopoietic stem cell function via targeting Cdc42. This type of cell is very reluctant to different approaches in reversing aging (even our extracellular matrix one), so we plan to rejuvenate them and investigate how to maintain the useful environment for these rejuvenated cells. The third thing is targeting elastogenesis. Elastin is now considered to be one of the longest living proteins in our body, elastogenesis is limited to early infancy and then the old synthesized elastin remains in our body, accumulates calcium, is degraded by enzymes and so on, therefore we lose elastin which leads to progressive deterioration of various tissues - blood vessels, skin, lungs, ligaments, muscles, ... All tissues lose their elasticity and that is crucial not only for appearance but also functional health. We can try - and already have some methods - to increase elastin production in vivo.