Open Longevity is organizing research of anti-aging therapies in humans by providing online advisory services. Their ultimate goal is to find and introduce effective methods of radical life extension into clinical practice. Therefore, the tokens are called YEAR. Mikhail Batin, the CEO of Open Longevity, states he is sure that effective ways to delay the onset of aging will be found - it is only a matter of time. He and his colleagues just want to accelerate the research.

The project consists of two parts: clinical trials and online service. Part of the funds raised through ICO will be spent on the first three studies: Longevity Diet-1 (a variant of a fasting mimicking diet); Alzheimer's disease therapy (vitamin B12) and atherosclerosis therapy (sartans + statins). One can even find documents for the first trial in progress, though just in Russian yet. As the trial is planned to be submitted to the NIH's Clinical Trials registry, the documents will be translated into English at some point. All the subsequent studies will later be also funded: life extension projects are expected to be submitted for voting on a general basis, voting will be conducted among all the YEAR token holders.

All clinical trials will be carried out in strict accordance with existing norms. Thus CROs (contract research organizations), laboratories, and clinical institutions that traditionally carry out similar research, will be involved. But the OL team is already talking about making all paperwork more automated. Another part of the funds will be spent on creating an online platform. By uploading biomedical data, users will be able to monitor their health and aging status in dynamics; receive recommendations from specialists and expert system based on AI; and also become volunteers in trials. The service will be accessible to everyone. But payment with YEAR tokens is promised to be more favorable than paying with fiat currencies due to 50% discount.

Open Longevity is a project that initiates, organizes, and guarantees openness of clinical trials of antiaging therapies. Two important components of our project are an online expert system, which interprets users' biomedical information in terms of aging biology, and new infrastructure for antiaging clinical trials. They are closely connected: the data obtained through trials is taken into account in the operations of the expert system, and the funds raised from users are spent on antiaging research.

At the first stage, the aim of which is the development of the platform and launching of the first trials, we will raise funds through our ICO. Our task is to build a self-sufficient system that will provide paid services to individuals but at the same time solve important problems for humanity on a noncommercial basis. We do not plan to protect our therapies with patents - our research results will be publicly available. We endeavor to direct patients' energy toward the fight against aging, and in our experience, our policy of openness attracts projects, funding, scientists, and volunteers to us.

One of the common concerns in the industry is that, once on the market, antiaging medicine will become available only to the elite. The openness of our project is a possible solution to this potential problem. Moreover, publishing final and intermediate results, as well as research protocols and all related materials, will give us the highest level of expertise. All clinical trials will be carried out in strict accordance with existing norms. We will prepare questionnaires, informed-consent forms, permissions of ethical committees, and brochures describing the design of our experiments. We will involve a CRO (contract research organization), laboratories, and clinical institutions that traditionally carry out similar research. We will include patients in a global movement to seek and test potential antiaging therapies that, once proven effective, will immediately become part of their own lives.

Researchers are moving closer to realizing the clinical potential of drugs that have previously been shown to support healthy aging in animals. In a review article aging experts say that, if proven to be effective and safe in humans, these drugs could be "transformative" by preventing or delaying chronic conditions as a group instead of one at a time. The drugs being tested are called senolytic agents, because they target senescent cells. These are cells that have stopped dividing and secrete toxic chemicals that damage adjacent cells. Accumulation of senescent cells, which increases with age, is associated with chronic conditions, including diabetes, cardiovascular disease, most cancers, dementia, arthritis, osteoporosis, and frailty.

In a recent study researchers confirmed that the first senolytic drugs to be discovered effectively clear senescent cells while leaving normal cells unaffected. The study also describes a new screening platform for finding additional senolytic drugs that will more optimally target senescent cells. The platform, together with additional human cell assays, identified and confirmed a new category of senolytic drugs, which are called HSP90 inhibitors. The platform will help researchers quickly identify additional drugs that target aging processes, which he says will be useful as they move closer to clinical intervention. "We've moved rapidly in the last few years, and it's increasingly looking like senolytic drugs, including the recently discovered HSP90 inhibitors, are having an impact on a huge range of diseases. We will need to continue to test whether there are more optimal drugs or drug combinations to broaden the range of senescent cell types targeted."

As senolytic drugs and drug combinations are discovered, researchers then will need to test them in clinical trials. The review article, "The Clinical Potential of Senolytic Drugs," acknowledges the unique challenges of these trials in the field of aging, including the difficulty of testing long-term end points, such as life span and health span - the healthy, productive years of life. Outcomes such as effects on median or maximum lifespan cannot be tested feasibly in humans. That's why researchers are using new clinical trial paradigms, which include testing the effects of senolytic drugs on co-morbidity, accelerated aging like conditions, diseases with localized accumulation of senescent cells, potentially fatal diseases associated with senescent cell accumulation, age-related loss of physiological resilience, and frailty. The authors also call out a need for additional geriatricians with research training to lead future clinical trials.

Chronological aging is the leading predictor of the major chronic diseases that account for the bulk of morbidity, mortality, and health costs worldwide. Furthermore, age-related chronic diseases, geriatric syndromes, and disabilities tend to cluster within individuals, leading to multimorbidity. These observations support the concept that fundamental aging processes not only cause aging phenotypes, but also predispose to chronic diseases and the geriatric syndromes. Thus, it has been predicted that therapeutically targeting these processes can delay, prevent, or alleviate age-related chronic diseases and disabilities as a group, instead of one at a time-the "geroscience hypothesis."

The biological processes that underlie aging phenotypes and are active at the nidus of most chronic diseases include chronic, low-grade, "sterile" (absence of known pathogens) inflammation; macromolecular and organelle dysfunction (e.g., changes in DNA, such as telomere erosion, unrepaired damage, mutations, polyploidy, proteins - e.g., aggregation, misfolding, autophagy - carbohydrates, lipids, or mitochondria); stem and progenitor cell dysfunction; and accumulation of senescent cells. These four processes are linked; that is, in general, interventions that target one process also attenuate the others. For example, DNA damage causes increased senescent cell burden and mitochondrial and stem or progenitor cell dysfunction. Conversely, reducing senescent cell burden can lead to less inflammation, less macromolecular dysregulation, and enhanced function of stem and progenitor cells.

To remove senescent cells pharmacologically from wild type animals, "senolytic" agents, including small molecules, peptides, and antibodies, are being developed. Since the article describing the first senolytic agents was published in 2015, progress in identifying additional senolytic agents and their effects has been rapid. In that first article, a hypothesis-driven senolytic agent discovery paradigm was implemented. Senescent cells are resistant to apoptosis, despite the SASP factors they release, which should trigger apoptosis. Indeed, pro-apoptotic pathways are up-regulated in senescent cells, yet these cells resist apoptosis. The hypothesis was therefore tested that senescent cells depend on pro-survival pathways to defend against their own pro-apoptotic signaling.

Using bioinformatic approaches based on the ribonucleic acid (RNA) and protein expression profiles of senescent cells, five senescent-cell anti-apoptotic pathways (SCAPs) were identified. That SCAPs are required for senescent cell viability was verified in RNA interference studies, in which levels of key proteins in these pathways were reduced. Through this approach, survival proteins were identified as the Achilles' heel of senescent cells. Knocking down expression of these proteins causes death of senescent but not nonsenescent cells. The SCAPs discovered so far have been used to identify putative senolytic targets.

The first senolytic agents discovered using this hypothesis-driven approach were dasatinib and quercetin. Ten months later, the third senolytic drug, navitoclax, a BCL-2 pro-survival pathway inhibitor, was reported. Since then, a growing number of senolytics have been reported. Yet more senolytics are in development, and additional potential SCAPs are being identified. The SCAPs required for senescent cell resistance to apoptosis vary according to cell type. The Achilles' heels, for example, of senescent human primary adipose progenitors differ from those of a senescent human endothelial cell strain, indicating that agents targeting a single SCAP may not eliminate all types of senescent cells. The senolytics that have been tested across a wide range of senescent cell types have all exhibited a degree of cell type specificity. For example, navitoclax is senolytic in a cell culture-acclimated human umbilical vein endothelial cell strain but is not effective against senescent primary human fat cell progenitors.

Senolytics do not have to be continuously present to exert their effect. Brief disruption of pro-survival pathways is adequate to kill senescent cells. Thus, senolytics can be effective when administered intermittently. For example, dasatinib and quercetin have an elimination half-life of a few hours, yet a single short course alleviates effects of radiation-induced senescent cell creation in vivo for at least 7 months. The frequency of senolytic treatment will depend on rates of senescent cell re-accumulation, which probably varies according to conditions that induce cellular senescence. Advantages of intermittent administration include less opportunity to develop side effects, the feasibility of administering senolytic drugs during periods of relatively good health, and less risk of off-target effects caused by continuous exposure to drugs. Another advantage of senolytics is that cell division-dependent drug resistance is unlikely to occur, because senescent cells do not divide and therefore cannot acquire advantageous mutations, unlike the situation in treating cancers or infectious agents.

The introduction of effective senolytics or other agents that target fundamental aging processes into clinical practice could be transformative. These drugs may be critical to increasing healthspan and delaying, preventing, or alleviating the multiple chronic diseases that account for the bulk of morbidity, mortality, and health costs in developed and developing societies. They could also delay or treat the geriatric syndromes, including sarcopenia, frailty, immobility, and cognitive impairment, as well as age-related loss of physiological resilience, in a way not imaginable until recently. These agents could transform geriatric medicine from being a discipline focused mainly on tertiary or quaternary prevention into one with important primary preventive options centered on a solid science foundation equivalent to, or even better than, that of other medical specialties.

Senolytics might prevent or delay chronic diseases as a group, instead of one at a time in presymptomatic or at-risk individuals. Furthermore, if what can be achieved in preclinical aging animal models can be achieved in humans, it may be feasible to alleviate dysfunction even in frail individuals with multiple comorbidities, a group that until recently was felt to be beyond the point of treatment other than palliative and supportive measures. Although considerable care must be taken, particularly until clinical trials are completed and the potential adverse effects of senolytic drugs are understood fully, it is conceivable that the rapidly emerging repertoire of senolytic agents might transform medicine as we know it.

In a study on middle-aged fruit flies, researchers substantially improved the animals' health while significantly slowing their aging. They believe the technique could eventually lead to a way to delay the onset of age-related diseases in humans. The approach focuses on mitochondria, the tiny power generators within cells that control the cells' growth and determine when they live and die. Mitochondria often become damaged with age, and as people grow older, those damaged mitochondria tend to accumulate in the brain, muscles and other organs. When cells can't eliminate the damaged mitochondria, those mitochondria can become toxic and contribute to a wide range of age-related diseases. Researchers found that as fruit flies reach middle age - about one month into their two-month lifespan - their mitochondria change from their original small, round shape. "We think the fact that the mitochondria become larger and elongated impairs the cell's ability to clear the damaged mitochondria. And our research suggests dysfunctional mitochondria accumulate with age, rather than being discarded."

The scientists removed the damaged mitochondria by breaking up enlarged mitochondria into smaller pieces - and that when they did, the flies became more active and more energetic and had more endurance. Following the treatment, female flies lived 20 percent longer than their typical lifespan, while males lived 12 percent longer, on average. The research highlights the importance of a protein called Drp1 in aging. At least in flies and mice, levels of Drp1 decline with age. To break apart the flies' mitochondria, researchers increased their levels of Drp1. This enabled the flies to discard the smaller, damaged mitochondria, leaving only healthy mitochondria. Drp1 levels were increased for one week starting when the flies were 30 days old.

Researchers further showed that the autophagy-related gene Atg1 also plays an essential role in turning back the clock on cellular aging. They did this by "turning off" the gene, rendering the flies' cells unable to eliminate the damaged mitochondria via autophagy. This proved that Atg1 is required to reap the procedure's anti-aging effects: While Drp1 breaks up enlarged mitochondria, the Atg1 gene is needed to dispose of the damaged ones. "We actually delayed age-related health decline. And seven days of intervention was sufficient to prolong their lives and enhance their health." One specific health problem the treatment addressed was the onset of leaky intestines, which previous research found commonly occurs about a week before fruit flies die. Subsequent research in other laboratories has determined that an increase in intestines' permeability is a hallmark of aging in worms, mice and monkeys. In this study, the condition was delayed after flies were given more Drp1.

In another part of the experiment, also involving middle-aged fruit flies, the scientists turned off a protein called Mfn that enables mitochondria to fuse together into larger pieces. Doing so also extended the flies' lives and improved their health. "You can either break up the mitochondria with Drp1 or prevent them from fusing by inactivating Mfn. Both have the same effect: making the mitochondria smaller and extending lifespan."

Mitochondrial dysfunction is a key hallmark of aging and has been linked to numerous age-onset pathologies. Therefore, identifying interventions that could improve mitochondrial homeostasis when targeted to aged animals would be highly desirable toward the goal of prolonging healthspan. A growing body of data support the idea that autophagy has an important anti-aging role. However, the relevant autophagic cargo in the context of aging remains elusive. Mitochondrial autophagy (mitophagy) is a type of cargo-specific autophagy, which mediates the removal of dysfunctional mitochondria. Recent studies in mammals, including humans, have reported an age-related decline in mitophagy. Moreover, impairment of mitophagy recapitulates the age-related accumulation of mitochondria in Caenorhabditis elegans. These findings suggest that the mitophagy pathway may represent a therapeutic target to counteract aging. However, a major unanswered question remains: why does mitophagy decline in aged animals?

Mitochondrial dynamics (fission and fusion) and mitophagy are closely related. Mitofusin (Mfn) proteins mediate fusion of the mitochondrial outer membrane, while mitochondrial fission, conversely, requires Dynamin-related protein 1 (Drp1). Several studies indicate that an important event preceding mitophagy is the Parkin-mediated turnover of Mfn leading to a shift in the balance of mitochondrial dynamics toward decreased fusion/increased fission. In yeast, the mitochondrial fission protein, Dnm1, homologous to Drp1, is required for certain forms of mitophagy. Together, these findings support the model that mitochondrial fission can promote the segregation of damaged mitochondria and facilitate their clearance by mitophagy. Critically, however, the interplay between mitochondrial dynamics and mitophagy during aging remains poorly understood, and the question of whether an increase in mitochondrial fission alone is sufficient to prolong lifespan and/or improve mitochondrial function in an aged animal has not been addressed.

Here, we show that inducing Drp1-mediated mitochondrial fission, in midlife, increases lifespan and improves multiple markers of health in aged Drosophila. Remarkably, we show that a transient induction of Drp1, for 7 days, in midlife is sufficient to prolong lifespan. Studying aging flight muscle, we find that a midlife shift toward a more elongated, less circular mitochondrial morphology is linked to the accumulation of dysfunctional mitochondria. Short-term, midlife Drp1 induction restores mitochondrial morphology to a youthful state, improves mitochondrial respiratory function and reduces mitochondrial reactive oxygen species (ROS) levels. Importantly, midlife Drp1 induction facilitates mitophagy and improves proteostasis in aged flies. Finally, we show that disruption of Atg1, a core autophagy gene, inhibits the anti-aging, prolongevity effects of midlife Drp1 induction. Our findings indicate that transient, midlife interventions that promote mitochondrial fission could delay the onset of frailty and mortality in aging mammals.

Eating a ketogenic diet - which is high fat, low protein, and low carbohydrates - ramps up the production of the ketone body beta-hydroxybutyrate acid (BHB). While small studies in humans with cognitive impairment have suggested that BHB could improve memory, this is the first study in aging mammals which details the positive effects of BHB on memory and lifespan. "We're looking for drug targets. The ultimate goal is to find a way for humans to benefit from BHBs without having to go on a restrictive diet."

Reserchers carefully designed three diets that were matched in every way except fat and carbohydrate content: a normal high-carbohydrate diet, a zero-carbohydrate ketogenic diet, and a high-fat, low-carbohydrate diet that was not ketogenic. Mice were fed the ketogenic diet intermittently to prevent them from becoming obese, starting at one year old - middle age for mice. The ketogenic diet-fed mice had a lower risk of dying as they aged from one to two years old, although their maximum lifespan was unchanged. Another group of mice underwent memory testing at both middle age (one year old) and old age (two years old). Mice that had been eating a ketogenic diet performed at least as well on memory tests at old age as they did at middle age, while mice eating the normal diet showed an expected age-associated decline. Mice who ate the ketogenic diet also explored more, and their improved memory was confirmed with another test a few months later.

"We were careful to have all of the mice eating a normal diet during the actual memory testing which suggests the effects of the ketogenic diet were lasting. Something changed in the brains of these mice to make them more resilient to the effects of age. Determining what this is, is the next step in the work. Looking at gene expression, the ketogenic diet suppressed the longevity-related TOR pathway and insulin signaling and up-regulated the fasting-related transcription factor PPAR-alpha, a master regulator that helps the body more efficiently metabolize fat. Exercise also creates ketone bodies - that may be one of the mechanisms why it shows such protective effects on brain function and on healthspan and lifespan."

BHB is a normal human metabolite that is synthesized in the liver from fat, and then circulates throughout the body as a glucose-sparing energy source. It is intrinsically produced during states such as intermittent fasting and dietary restriction (DR) that result in extended longevity, cognitive protection, cancer reduction, and immune rejuvenation. Recent work has elucidated an array of signaling functions of BHB that suggest that BHB might itself regulate inflammation and gene expression, with implications for health and longevity.

A ketogenic diet is one means to deliver high levels of BHB for a prolonged time outside of a fasting or exercise context. Ketogenic diets generally contain little or no carbohydrate and stimulate endogenous ketogenesis. We sought to test whether a ketogenic diet carefully matched to comparison diets could enhance the longevity and healthspan of normal mice, and to elucidate potential molecular mechanisms of such effects.

We show that long-term exposure to a ketogenic diet, fed every other week starting in middle age, reduces midlife mortality and preserves memory in aging C57BL/6 male mice. Similar feeding of a high-fat, low-carbohydrate non-ketogenic diet appeared to have an intermediate effect on mortality, but survival of this group could not be definitely distinguished from either the control or ketogenic diet groups. These results might be interpreted in the broader context of the health effects of DR and of segmental DR mimetics such as metformin and rapamycin, and suggest that one or more aspects of a ketogenic diet may similarly act as a segmental DR mimetic.

Tissue fibrosis is a major cause of human morbidity and mortality worldwide. TGF-β1 signaling is a well-known driver of collagen expression and tissue accumulation important to wound repair. Exaggerated TGF-β1 signaling is also strongly implicated in numerous fibrotic diseases, including those involving liver, heart, and lung. For example, approximately 80% of the upregulated genes in lungs of patients with idiopathic pulmonary fibrosis are reported to be direct or indirect TGF-β1 target genes. Pathological collagen accumulation, and its promoting effects on tissue stiffness, are also strongly implicated in cancer progression. TGF-β1 signaling is both an initiator and a driver of tissue stiffness because accumulation of collagen and other matrix proteins promotes integrin-dependent latent TGF-β1 activation and further extracellular matrix deposition. Enhanced stiffness is thought to promote tumor cell β1 integrin activation, leading to more invasive tumor phenotypes and metastasis, consistent with the strong correlation of TGF-β1 signaling with poor cancer prognosis. For these and other reasons there has been much interest in TGF-β1 signaling as a therapeutic target.

Although attractive as a target, the critical roles of TGF-β1 in suppressing inflammation and epithelial proliferation give pause to the idea of global inhibition of TGF-β1 signaling. Indeed, systemic inhibition of TGF-β1 can lead to the development of squamous skin tumors and autoreactive immunity. In addition, chronic administration of several small-molecule inhibitors of TGF-β1 receptor (TβR) kinases has led to enhanced skin and colonic inflammation and abnormalities in cardiac valves. To minimize adverse consequences, an approach of blocking TGF-β1 activation in specific cell types using the unique pathway of αvβ6-dependent latent TGF-β1 activation has developed and is currently in clinical trial. But this integrin is primarily expressed in epithelia of lung, kidney, and skin. In an attempt to develop a more circumscribed inhibitor of TGF-β1 signaling centered on suppression of collagen accumulation, we undertook a high-throughput, image-based phenotypic screen of small molecules that could block TGF-β1-induced epithelial-mesenchymal transition (EMT) in vitro but not directly inhibit TβRI kinase itself.

We identified trihydroxyphenolic compounds as potent blockers of TGF-β1 responses. Remarkably, the functional effects of trihydroxyphenolics required the presence of active lysyl oxidase-like 2 (LOXL2), thereby limiting effects to fibroblasts or cancer cells, the major LOXL2 producers. This selectivity likely avoids the toxicities of long term general TGF-β1 inhibition in chronic disease processes such as fibrosis and cancer progression. Indeed, we have observed no adverse events in mice on the trihydroxyphenolic-rich diet for at least 6 months, including the absence of skin inflammation and discernible lesions in cardiac valves.

Mechanistic studies revealed that trihydroxyphenolics induce auto-oxidation of a LOXL2/3-specific lysine (K731) in a time-dependent reaction that irreversibly inhibits LOXL2 and converts the trihydrophenolic to a previously undescribed metabolite that directly inhibits TβRI kinase. Combined inhibition of LOXL2 and TβRI activities by trihydrophenolics resulted in potent blockade of pathological collagen accumulation in vivo without the toxicities associated with global inhibitors. These findings elucidate a therapeutic approach to attenuate fibrosis and the disease-promoting effects of tissue stiffness by specifically targeting TβRI kinase in LOXL2-expressing cells.

Mortality biomarkers are of great clinical and research interest. General clinical applications include identifying high-risk patient groups, prognosticating for individual patients, and helping healthcare providers decide among treatment options. Examples of very well-studied mortality biomarkers include blood pressure, cholesterol, and waist circumference, which have well-established relationships with mortality in various populations documented in dozens of studies, some with thousands or millions of participants. These traditional biomarkers have been joined in more recent years by many biomarkers utilizing modern assays, for example genome-wide methylation levels, cell-free DNA concentration, and leukocyte telomere length.

Biomarkers of human mortality are also centrally important to research on human aging, due largely to the long potential duration of prospective studies on human lifespan. This can be a tremendous obstacle both in terms of resources (i.e. money to support such lengthy trials) and delayed progress (i.e. each research result could take decades to obtain). Mortality biomarkers have solved similar problems in the past by providing surrogate endpoints for crucial clinical outcomes, facilitating studies that might otherwise have been prohibitively expensive or time consuming. Blood pressure and cholesterol are two of many markers that have played this role in the past, by facilitating cardiovascular research aimed at reducing morbidity and mortality. Such biomarkers have also gained clinical importance as surrogate markers in clinical practice, where treatments are often initiated with the explicit goal of changing a patient's biomarker value. While this approach has important potential drawbacks, it is certainly more practical for a patient to track how a new intervention affects her blood pressure or serum cholesterol, rather than how it affects her lifespan, which is unknown until death.

Abundant research on mortality biomarkers has resulted in numerous associations documented across hundreds of publications, generating an unwieldy collection of data that can be difficult for researchers or clinicians to interpret or use effectively. There have been no recent attempts to collate this data nor, to our knowledge, to provide tools for locating, organizing, or comparing data from relevant studies. In the present article, we describe an effort to facilitate a more comprehensive and effective approach to evaluating the literature in this area. We present MortalityPredictors.org, a manually curated, publicly accessible database housing published, statistically-significant relationships in humans between biomarkers and all-cause mortality in population-based or generally healthy samples. To our knowledge, this is the first publicly available resource to collect such information, and we hope it will encourage: 1) the allocation of resources to mortality biomarkers with the greatest potential for accurately predicting human all-cause mortality, 2) efforts to construct multi-biomarker models to further improve such accuracy, and 3) research on human aging and therapies that aim to slow aging or otherwise reduce mortality.

The search for robust, reliable and valid biomarkers of the ageing process is a key goal for gerontological science. Such tools should enable the quantification of individual differences in underlying biological ageing. This could have great utility for mapping personalised ageing trajectories, for predicting risk of future age-related deterioration and disease and for evaluating potential treatments aimed at improving healthspan or even slowing ageing itself. Given the multi-faceted nature of biological ageing, numerous potential candidate biomarkers have been proposed. These can be anthropometric, physiological or blood-based; indexing immune function, epigenetic signatures, gene expression profiles, physical capacity or body composition. To improve on individual predictors of biological age, panels combining multiple markers have also been proposed. While many of these approaches are highly promising, the results have yet to be translated into clinical practice.

The criteria most commonly used for assessing the appropriateness of ageing biomarkers is how strongly they correlate with chronological age in healthy people. In addition, thanks to the increasing use of machine learning, the accuracy with which chronological age can be predicted using multivariate biological data is also a useful indicator of potential biomarker value. Aligned with this, an independent line of research has emerged from the field of neuroscience. Using neuroimaging data, principally magnetic resonance imaging (MRI) brain scans, chronological age can be predicted accurately in a machine-learning framework. This neuroimaging-derived brain-age model is based on data from over 2000 healthy adults and shows excellent test-retest reliability. This presents the intriguing possibility that in-vivo measurements of brain volume could be used as an alternative ageing biomarker.

It is well-known that ageing affects the brain, both in terms of outward behavioural changes and cognitive decline, alongside alterations to the brain's biophysical structure and cellular and molecular functioning. Using measures of brain volume derived from T1-weighted structural MRI, assumed to reflect grey and white matter atrophy, high levels of age prediction accuracy have been consistently achieved. For example, our work found a mean/median absolute error of age prediction of 4.2/3.4 years, with a correlation between age and brain-predicted age of r = 0.96. This is comparable to or better than leading biological age prediction models, for example using DNA methylation status (r = 0.96, median absolute error = 3.6 years) or a panel of blood chemistry markers (r = 0.91, mean absolute error = 5.6 years).

Given the published data on neuroimaging-derived brain-age, it is worth considering its qualification against a set of consensus ageing biomarker criteria. Paraphrasing from the American Federation for Aging Research recommendations, an ageing biomarker must: 1) Predict the rate of ageing (i.e., estimate where a person is in their total life span); 2) Measure a basic process that underlies ageing, not the effects of disease; 3) Be able to be tested repeatedly without causing harm; 4) Work in humans and laboratory animals. Based on the above evidence regarding prediction of survival, neuroimaging-derived brain-age meets criteria #1. Given the accuracy of age prediction and the fact that brain atrophy occurs in the context of non-pathological ageing, this satisfies criteria #2. As a non-invasive imaging technique, T1-weighted MRI meets criteria #3. Finally, the accuracy of this technique in non-human primates has been recently reported, suggesting that it appropriately meets criteria #4.

While perhaps the major caveat regarding the use of neuroimaging in this context is the cost and potential logistics, projects like the UK Biobank imaging study show that collecting neuroimaging data on an extremely large scale are becoming increasingly feasible. It is timely for a marriage of neuroscience and biogerontology, and approaches that combine the most complementary information on the ageing human body will have the greatest utility in developing effective ageing biomarkers.

Lung transplantation - the only definitive treatment for patients with end-stage lung disease - remains limited by a severe shortage of donor organs such that only 20% of patients waiting for a donor lung undergo transplantation. Strategies aimed at increasing the number of transplantable lungs would have an immediate and profound impact. Tissue engineering strategies are currently under development to regenerate or replace injured lungs. Because of the extreme complexity of the lung, with its hierarchical three-dimensional architecture, diverse cellular composition, highly specialized extracellular matrix (ECM), and region-specific structure and function, bioengineering a functional lung is still an elusive goal. The lungs bioengineered by full decellularization and recellularization have shown a limited and temporary function, largely due to blood clotting and pulmonary edema, which have led to lung failure within a few hours following transplantation. To date, whole-organ engineering methods using lung grafts with denuded vascular networks have failed to produce functional grafts.

Given the essential need for intact and functional pulmonary vasculature, we developed an airway-specific approach to removing the pulmonary epithelium while preserving the surrounding cells, matrix, basement membrane, and vasculature. Previously established methods for decellularization of the entire organ were designed to remove both the epithelium and endothelium and could only be applied ex vivo. This study developed the first procedure for the removal of epithelium from the lung airway with the full preservation of vascular epithelium, which could be applied in vivo to treat diseases of lung epithelium. Whole lung scaffolds with an intact vascular network may also allow for recellularization using patient-specific cells and bioengineering of chimeric lungs for transplantation. In addition to the clinical potential, lung scaffolds lacking an intact epithelial layer but with functional vascular and interstitial compartments may also serve as a valuable physiological model for investigating (i) lung development, (ii) the etiology and pathogenesis of lung diseases involving pulmonary epithelium, (iii) acute lung injury and repair, and (iv) stem cell therapies.

Lung decellularization has resulted in substantial advances in lung bioengineering and the ability to create scaffolds for tissue engineering applications. We believe that our methodology can address some of the challenges that have slowed the progress in lung bioengineering by (i) preserving the vascular endothelium throughout the lung (from large vessels to capillaries) and (ii) targeting the removal of airway epithelium while maintaining structural and cellular components essential for lung repair. In summary, the creation of de-epithelialized whole lungs with functional vasculature may open new frontiers in lung bioengineering and regenerative medicine. Additionally, de-epithelialization could be applied to other organs with dual flow, such as the liver or kidney.

The composition and functionality of complex and rich community of microbes living on the surfaces and cavities of the mammal's body, i.e. microbiota, is well known to be crucial for the health maintenance of the host. An extremely rich and diverse microbial ecosystem inhabits the gastrointestinal tract collectively named as gut microbiota. Studies on humans have demonstrated that the gut microbiota strongly impacts on the prevention of disorders and pathologies, such as obesity and metabolic syndrome, cardiovascular diseases, inflammatory bowel diseases, as well as several types of cancer. The gut microbiota can indeed influence the education and homeostasis of the immune system and metabolism, as well as brain functionality, with as yet unknown long-term effects on human health and lifespan.

The impact of the gut microbiota on human health is a topic of huge interest for the scientific community, as demonstrated by the ever-increasing amount of studies on the microbiological peculiarities of the human gut ecosystem within the context of different lifestyles, genetic backgrounds, or pathologies. It is a matter of fact that, by preserving the biological homeostasis of the human host, the gut microbiota has a role of primary importance in supporting human longevity. However, only few hypotheses on the mechanisms involved have been advanced. Longevity is a tricky trait to be studied in humans, because it is a rare event, with an incredible amount of confounding genetic, lifestyle, and clinical variables, both past and present. Still, the microbiota of human populations with extraordinary longevity rate is being investigated across geographical zones and interesting hypotheses on the role of the microbiome in health-maintenance during aging are being advanced.

In this scenario, the naked mole-rat might represent an extremely interesting model to study health and longevity, since, like for human beings, in naked mole rat the selection against aging is strongly reduced. This eusocial, subterranean mouse-sized mammal occupies underground mazes of sealed tunnels and lives a very long life in large colonies with only one breeding queen and few breeding males. The naked mole-rat shows few age-related degenerative changes, displays an elevated tolerance to oxidative stress, and its fibroblasts have shown resistance to heavy metals, DNA damaging agents, chemotherapeutics and other poisonous chemicals. Moreover, this mammals show remarkably small susceptibility to both spontaneous cancer and induced tumorigenesis. These features of the naked mole-rat are maintained throughout their long lifespan, making this rodent a putative animal example of impressively prolonged "healthspan".

Moreover, the within-colony low genetic diversity (possibly due to the high inbreeding rate), the climatologically stable underground habitats, and the constant diet (mainly tubers and other underground plant storage organs), make the naked mole-rat a unique model for studying the microbiota-host interaction, focusing on the ability of the gut microbes to contribute to health maintenance during aging. Here, we characterized the gut microbiota of the naked mole-rat by next generation sequencing, aiming at understanding of how the rodent´s gut microbiota profile aligns with human microbiome and that of other mammals.

We found that the naked mole-rat possesses a unique gut microbiome composition, which is the result of the host phylogeny and its peculiar ecology. This microbiome layout has many compositional and functional peculiarities - such as the propensity for an oxidative metabolism, an enhanced capacity to produce short-chain fatty acids and mono- and disaccharides, as well as the peculiar structure within Bacteroidetes, the high load and diversity of Spirochetaceae and the presence of Mogibacteriaceae - some of which are shared with gut microbial ecosystems considered as models of healthy aging, as well as metabolic and immune homeostasis. This might suggest a possible role of the gut microbiota as a universal contributor to mammalian health, which goes beyond the host phylogeny and ecology constrains, supporting health and longevity of the mammalian host.

Worldwide, the number of patients with heart disease is increasing as populations of elderly people expand. Of the heart diseases, cardiovascular disease (CVD) and heart failure (HF) are associated with adverse health outcomes that decrease a patient's well-being and productivity. Prevention of these conditions is desirable to promote healthy aging and improve patients' lifestyle. The pathologic basis of CVD is atherosclerosis caused by ectopic accumulation of cholesterol in vessel walls; thus advent of therapies aimed at reducing low-density lipoprotein (LDL)-cholesterol levels has succeeded in decreasing the number of CVD events. However, these events continue to occur, even in patients whose LDL-cholesterol levels have been lowered, indicating that the pathologies underlying CVD are highly complex.

Many of our previous studies have revealed that the expression and secretion of angiopoietin-like 2 (ANGPTL2) significantly increase in cells stressed by pathophysiologic stimuli such as hypoxia, reactive oxidative species, and pressure overload. ANGPTL2 expression also increases in cells undergoing senescence, suggesting that ANGPTL2 is a SASP factor. Moreover, excess ANGPTL2 signaling is pro-inflammatory in pathologic states and contributes to the development of aging-associated diseases such as CVD. Thus, to understand the mechanisms underlying these conditions, we focus our discussion here on the role of ANGPTL2 in CVD.

Obesity and associated metabolic diseases predispose individuals to coronary artery disease (CAD), the major common form of CVD. In terms of the mechanisms linking these conditions, accumulating evidence suggests that inflammatory changes in perivascular fat, which is distributed ubiquitously around arteries throughout the body, may have a direct role in promoting the pathogenesis of vascular diseases accelerated by obesity. Interestingly, in obesity, chronic inflammation occurs in both visceral and perivascular adipose tissues. In obese mice, the expression of ANGPTL2 is increased in perivascular adipose tissues surrounding the femoral artery at levels equivalent to those seen in visceral adipose tissues. In mice, we have undertaken adipose tissue transplantation experiments that show that adipose tissue-secreted ANGPTL2 accelerates vascular inflammation, pathologic vascular tissue remodeling and subsequent CVD development.

Moreover, atherosclerosis progression, including plaque instability, is associated with chronic vessel wall inflammation and is a risk factor for major CAD events. Therefore, therapies designed to inhibit chronic inflammation in vessel walls should slow atherosclerosis progression. Relevant to this, ANGPTL2 is abundantly expressed in vascular endothelial cells of CAD patients. ANGPTL2 expression in endothelial cells also significantly increases in subjects predisposed to atherosclerotic disease brought on by obesity or metabolic disturbances. As expected, increases in endothelial cell-derived ANGPTL2 expression in mice promote vascular inflammation and subsequent endothelial cell dysfunction and atherosclerosis development. Vascular inflammation, which underlies atherosclerotic disease, emerges from the interplay of different cell types, including endothelial cells, smooth muscle cells, and perivascular adipocytes as resident cells, and macrophages as infiltrating cells. Macrophage-secreted ANGPTL2 also accelerates atherosclerotic disease in mice. Thus, ANGPTL2-induced chronic inflammation predisposes individuals to atherosclerotic disease and to CAD development.

Cellular senescence is defined as cell cycle arrest as a means to counteract DNA damage induced by aging and various stressors. Accumulation of senescent cells in various tissues accelerates aging and disease development. A recent report using a transgenic approach in mice demonstrated that clearance of senescent cells delays several age-associated disorders, suggesting that senescent cells promote these conditions. Interestingly, it has been reported that endothelial cells derived from smokers and exhibiting oxidative stress-induced premature senescence show significantly increased ANGPTL2 expression. Moreover, senescent fibroblasts from patients with Werner syndrome (adult progeria) show abundant ANGPTL2 expression and increased expression of other SASP factors. We have also reported that ANGPTL2 expression significantly increases in the hearts of aged compared with young mice. Thus, ANGPTL2 may function as a senescence-associated secretory phenotype in several senescent cell types. If so, markedly increased circulating ANGPTL2 levels seen in patients with chronic aging-related diseases may reflect the accumulation of senescent cells in their organs.

Undoing Aging 2018 is focused on the cellular and molecular repair of age-related damage as the basis of therapies to bring aging under full medical control. The conference, a joint effort of SENS Research Foundation and Forever Healthy Foundation, provides a platform for the existing scientific community that already works on damage repair and, at the same time, offers interested scientists and students a first-hand understanding of the current state of this exciting new field of biomedical research.

Speakers will include leading researchers from around the world focused on topics including stem cells, senescent cells, immunotherapies, biomarkers and drug discovery. Aubrey de Grey, Chief Science Officer of the SENS Research Foundation, will be the scientific organizer for the conference. Undoing Aging 2018 is not only open to the scientific community but also welcomes all interested members of the broader Life Extension movement. The conference will also feature a student poster session showing the work of innovative undergraduate and graduate students in the field of damage repair.

"With the 2018 Undoing Aging Conference, SENS Research Foundation (SRF) resumes its series of conferences previously based in Cambridge. As we did from 2003 to 2013, we will host a scientific conference that will demonstrate the enormous strides currently being made in genuine rejuvenation biotechnologies. The lesson will be clear - the community is broad and deep, and its members see the potential for genuinely comprehensive approaches to the prevention of age-related disease. We're especially pleased that our partnership with Forever Healthy will bring this conference to the heart of the Berlin life sciences community for the first time."

"Forever Healthy is already a vanguard supporter of SRF research programs and rejuvenation biotechnology start-ups. We are now very excited to work with SRF on Undoing Aging 2018, the first conference for our organization. Forever Healthy has two key goals for this conference: To support the remarkable scientific community already working on repair of age related damage and to create an unique opportunity for the broader scientific world to experience that the possibility of bringing aging under complete, genuine medical control is realistic, achievable, and, indeed, beginning to happen."

Previous research has shown the benefit of statins for reducing high cholesterol and coronary heart disease risk amongst different patient populations. However, until now there has been no conclusive evidence from trials for current guidelines on statin usage for people with very high levels of low density lipoprotein (LDL) cholesterol (above 190mg/dL) and no established heart disease. After studying mortality over a 20-year period, researchers showed that 40mg daily of pravastatin, a relatively weak type of statin, reduced deaths from heart disease in participants by more than a quarter.

"For the first time, we show that statins reduce the risk of death in this specific group of people who appear largely healthy except for very high LDL levels. This legitimises current guidelines which recommend treating this population with statins." In addition, the findings challenge current approaches on treating younger patients with LDL elevations with a 'watch and wait' approach. Instead, even those with slightly elevated cholesterol are at higher long term risk of heart disease, and that the accumulation of modest LDL reductions over time will translate into large mortality benefits. "Our findings suggest that we should consider prescribing statins more readily for those with elevated cholesterol levels above 155 mg/dl and who also appear otherwise healthy."

This research follows on from a five-year 1995 study in which researchers observed the long-term effects of statins on patients involved in the West of Scotland Coronary Prevention Study (WOSCOPS) trial. The researchers took into account the original five-year study and followed the patients for a further 15 years. The WOSCOPS study provided the first conclusive evidence that treating high LDL in men with pravastatin for five years significantly reduces the risk of heart attack or death from heart disease compared with placebo. Statins were subsequently established as the standard treatment for primary prevention in people with elevated cholesterol levels.

Now, researchers have completed analyses of the 15-year follow up of 5,529 men, including 2,560 with LDL cholesterol above 190 mg/dL of the original 6,595, chosen because they had no evidence of heart disease at the beginning of the present study. Participants were aged 45-64 years. During the five-year initial trial they were given pravastatin or placebo. Once the trial ended the participants returned to their primary care physicians, and an additional 15-year period of follow-up ensued. The 5,529 men were split into two groups: those with 'elevated' LDL (between 155 and 190mg/dL) and those with 'very high' LDL (above 190mg/dL). The standard 'ideal' level of LDL for high risk patients is below 100mg/dL, but this varies depending on individual risk factors.

The researchers found that giving pravastatin to men with 'very high' LDL reduced twenty year mortality rates by 18 per cent. Statins also reduced the overall risk of death by coronary heart disease by 28 per cent, and reduced the risk of death by other cardiovascular disease by 25 per cent among those with very high LDL cholesterol. The 15-year follow up also meant the researchers could compare patients' original predicted risk of heart disease with actual observed risk. According to the risk equations for cardiovascular disease, 67 per cent of patients included in the WOSCOPS trial with LDL above 190mg/dL would have less than a 7.5 per cent risk of heart disease by year ten, and thus would not have been treated with statins based on that risk. However, the present study shows that in fact, this group actually had a 7.5 per cent risk by year five, meaning their ten year risk was 15 per cent. Following statin therapy, this group's ten year risk was reduced compared with those that were given placebo during the trial.

For about one hundred years it has been known that nutrient restriction and moderate stress can significantly prolong life. Researchers have now discovered how the transcription factor Gcn4, a protein that regulates the expression of many genes, extends the life of baker's yeast Saccharomyces cerevisiae. In various stress situations, the cells stimulate Gcn4 production which leads to reduced biosynthesis of new proteins and increased yeast lifespan.

It has long been known that protein synthesis - also known as translation - plays an important role in aging. Inhibition of protein synthesis, caused for example by reduced nutrient intake, can have a positive effect on the life expectancy of diverse organisms such as yeast, flies, worms, or fish. Reducing the ribosomes, the protein factories of the cell, can also considerably extend the lifespan of yeast cells. What these cellular stresses have in common is that they activate the production of Gcn4. However, how this protein promotes longevity has remained unclear.

The team exposed yeast cells to different stress conditions, measured their lifespan, protein synthesis rates and Gcn4 expression. "We observed that the level of the Gcn4 protein was positively correlated with the longevity of yeast cells. However, we wanted to understand why. We have now shown for the first time that it is the transcriptional suppression of genes that are important for cellular protein synthesis by Gcn4 that seems to account for its lifespan extension effect. As the translation machinery is limiting, the energy-intensive production of new proteins is overall dampened." From the yeast cell's point of view, this is an advantage: This enables them to live about 40 percent longer than usual.

The transcription factor Gcn4 is conserved in over 50 different organisms, including mammals, and it likely play a significant role in the aging of these organisms as well. The researchers will now investigate whether the mammalian homolog similarly slows aging and extends lifespan by regulating protein synthesis genes in response to nutrients and stress.

Parkinson's disease (PD) is the second most common neurodegenerative disorder, primarily caused by the death of dopamine-containing neurons in the substantia nigra, a region of the brain involved in motor control. While people naturally lose dopamine neurons as they age, patients with PD lose a much larger number of these neurons and the remaining cells are no longer able to compensate. Understanding how and why these neurons die is an important step in identifying treatments. While previous research indicated that the cellular mechanism behind the cell death involved the mitochondria and lysosomes, how these two pathways converge in dopamine neurons to cause cell death remained unknown up until now.

Using human neurons from Parkinson's patients, researchers identified a toxic cascade of mitochondrial and lysosomal dysfunction initiated by an accumulation of oxidized dopamine and a protein called alpha-synuclein. Specifically, the current study demonstrated that an accumulation of oxidized dopamine depressed the activity of lysosomal glucocerebrosidase (GCase), an enzyme implicated in PD. That depression in turn weakened overall lysosomal function and contributed to degeneration of neurons. The accretion of oxidized dopamine didn't just interfere with lysosomes, however. Researchers discovered that the dopamine also damaged the neurons' mitochondria by increasing mitochondrial oxidative stress. These dysfunctional mitochondria led to increased oxidized dopamine levels, creating a vicious cycle.

"The mitochondrial and lysosomal pathways are two critical pathways in disease development. Combined with the alpha-synuclein accumulation, this study links the major pathological features of PD. One of the key strategies that worked in our experiments is to treat dopamine neurons early in the toxic cascade with specific antioxidants that improve mitochondrial oxidative stress and lower oxidized dopamine. With this approach, we found that we can attenuate or prevent the downstream toxic effects in human dopaminergic neurons." Interestingly, when compared to human cellular models, mouse models of PD did not demonstrate the same toxic cascade. The researchers showed this is due to differences in metabolism of dopamine between species, and underscored the importance of studying human neurons to discover new targets for drug development.

Researchers have recently proposed a novel role for biofilms - colonies of bacteria that adhere to surfaces and are largely resistant to immune attack or antibiotics - in eczema. It was suggested that because biofilms block skin ducts and trigger innate immune responses, they may cause the stubborn skin condition. Other recent work shows that Lyme spirochetes form biofilms, which led the researchers to wonder if biofilms might also play a role in Alzheimer's disease. When they stained for biofilms in brains from deceased Alzheimer's patients, he found them in the same hippocampal locations as amyloid plaques.

Spirochetes, common members of the oral microbiome, belong to a small set of microbes that cross the blood-brain barrier when they're circulating in the blood, as they are during active Lyme infections or after oral surgery. However, the bacteria are so slow to divide that it can take decades to grow a biofilm. This time line is consistent with Alzheimer's being a disease of old age, researchers reasons, and is corroborated by syphilis cases in which the neuroinvasive effects of spirochetes might appear as long as 50 years after primary infection.

Work on biofilms contributes to the revival of a long-standing hypothesis concerning the development of Alzheimer's. For 30 years, a handful of researchers have been pursuing the idea that pathogenic microbes may serve as triggers for the disease's neuropathology. Most came across the connection serendipitously, and some have made it their life's work, in spite of scathing criticism and related challenges in attracting funding and publishing results.

The Alzheimer's field seems primed for a fresh look at a theory that might account for the disease's pathogenesis. Researchers still cannot say with confidence which features of the disease, such as neuroinflammation, tau tangles, and amyloid plaques, are involved in disease progression and thus would make effective targets for treatment. So far, most drugs that have made it to clinical testing have targeted the amyloid-β peptide, the main component of the amyloid plaques that characterize Alzheimer's brains. The idea is that a build-up of amyloid-β causes the neuropathology and that removing amyloid-β - by decreasing its production, impeding aggregation, or aiding removal of the molecule from the brain - will improve, or at least stall, symptoms of dementia. But so far, researchers have come up empty-handed.

In light of continued failures to develop effective drugs, some researchers think it's high time that more effort and funding go into alternative theories of the disease. "Any hypothesis about Alzheimer's disease must include amyloid plaques, tangles, inflammation - and, I believe, infection." And, slowly but surely, Alzheimer's researchers finally seem to be giving the pathogen hypothesis a good, hard look. There remain more questions than answers at this point in terms of the causative factors in Alzheimer's, however. "The pathology is a mess. The brain has been diseased for a long time by the time we see it. We're looking at the end product and trying to determine how it got that way. Most of the resources in this field are spent on a few biomarkers. All the evidence shows that amyloid is important. But causality and centrality are two different things."