A world-first vaccine which could eliminate or at least reduce the need for surgery and antibiotics for severe gum disease has been validated. A team of dental scientists has been working on a vaccine for chronic periodontitis for the past 15 years. Clinical trials on periodontitis patients could potentially begin in 2018. Moderate to severe periodontitis affects one in three adults and more than 50 per cent of Australians over the age of 65. It is associated with diabetes, heart disease, rheumatoid arthritis, dementia and certain cancers. It is a chronic disease that destroys gum tissue and bone supporting teeth, leading to tooth loss.

The findings represent analysis of the vaccine's effectiveness by collaborating groups. The vaccine targets enzymes produced by the bacterium Porphyromonas gingivalis, to trigger an immune response. This response produces antibodies that neutralise the pathogen's destructive toxins. P. gingivalis is known as a keystone pathogen, which means it has the potential to distort the balance of microorganisms in dental plaque, causing disease. "We currently treat periodontitis with professional cleaning sometimes involving surgery and antibiotic regimes. These methods are helpful, but in many cases the bacterium re-establishes in the dental plaque causing a microbiological imbalance so the disease continues. Periodontitis is widespread and destructive. We hold high hopes for this vaccine to improve quality of life for millions of people."

>From epidemiological surveys moderate to severe forms of periodontitis affect one in three adults and the disease has been linked to an increased risk of cardiovascular diseases, certain cancers, preterm birth, rheumatoid arthritis and dementia related to the regular bacteremia and chronic inflammation associated with the disease. The global prevalence of severe periodontitis has been estimated from 2010 epidemiological data to be 10.5-12.0% and the global economic impact of dental diseases, of which periodontitis is a major component, has been estimated to be 442 billion per year. The conventional therapy for periodontitis involves scaling and root planing to remove plaque microorganisms. Treatment can sometimes involve surgery to improve access and/or to reduce pocket depth and can also include the use of antibiotics and/or antimicrobials. However, treatment outcomes are variable and heavily dependent on patient compliance. Even in patients on a periodontal maintenance program involving regular professional intervention sites continue to progress and teeth are lost.

Although chronic periodontitis is associated with a polymicrobial biofilm, specific bacterial species of the biofilm such as Porphyromonas gingivalis, Treponema denticola and Tannerella forsythia as a complex or consortium have been closely associated with clinical measures of disease. P. gingivalis is found at the base of deep periodontal pockets as microcolony blooms in the superficial layers of subgingival plaque adjacent to the periodontal pocket epithelium, which helps explain the strong association with underlying tissue inflammation and bone resorption at relatively low proportions (10-15%) of the total bacterial cell load in the pocket. Furthermore, it has been shown from studies using the mouse periodontitis model that P. gingivalis is a keystone pathogen, which dysregulates the host immune response to favour the polymicrobial biofilm disrupting homeostasis with the host to cause dysbiosis and disease.

The extracellular Arg- and Lys-specific proteinases 'gingipains' (RgpA/B and Kgp) of P. gingivalis have been implicated as major virulence factors that are critical for colonisation, penetration into host tissue, dysregulation of the immune response, dysbiosis and disease. The gingipains, in particular the Lys-specific proteinase Kgp is essential for P. gingivalis to induce alveolar bone resorption in the mouse periodontitis model. The gingipains have also been found in gingival tissue at sites of severe periodontitis at high concentrations proximal to the subgingival plaque and at lower concentrations at distal sites deeper into the gingival tissue. This has led to the development of a cogent mechanism to explain the keystone role played by P. gingivalis in the development of chronic periodontitis.

The role of P. gingivalis as a keystone pathogen in the initiation and progression of chronic periodontitis suggests that a strategy of targeting the major virulence factors of the bacterium, the gingipains, by vaccination may have utility in the prevention of P. gingivalis-induced periodontitis. Indeed, studies using the gingipains as a prophylactic vaccine that induces a high-titre antibody response in naive animals before superinfection with the pathogen have shown protection against alveolar bone resorption. However, patients with P. gingivalis-associated periodontitis harbour the pathogen at above threshold levels in subgingival plaque and exhibit an inflammatory immune response, hence it is possible that therapeutic vaccination could exacerbate inflammation and bone resorption in these patients. Here we show that therapeutic vaccination with a chimera antigen targeting the gingipains protects against alveolar bone resorption in P. gingivalis-associated experimental periodontitis and that this protection is mediated via a predominant Th2 anti-inflammatory response with the production of gingipain-neutralising IgG1 antibodies.

Results of a new study led offer new evidence for a strong link between angiotensin receptor autoantibodies and increased risk of frailty. The team says a large class of common blood pressure drugs that target the angiotensin receptor, called angiotensin receptor blockers (ARBs), may help patients depending on the levels of the autoantibodies. In healthy individuals, immune cells produce proteins called antibodies that attack foreign invaders to destroy them and clear them out of the system. In contrast, with autoimmune disorders, the immune cells produce autoantibodies that target the body's own tissue. "We discovered that frail older individuals have markedly higher levels of an autoantibody against its own angiotensin system. The angiotensin system is a key hormonal system that regulates blood pressure and fluid balance. The presence of these antibodies in this subset of vulnerable older adults was associated with increased inflammatory burden, and with decline in grip strength, walking speed and increased number of falls."

Individuals with higher levels of autoantibodies were also more likely to suffer from higher blood pressure. The use of ARBs in such individuals correlated with better control of their blood pressure, suggesting a possible personalized medicine approach to high blood pressure treatment in older adults.Some older adults become frail as they age, and this frailty has been associated with chronic inflammation. To examine the relationship between autoantibody levels and frailty, the research team first recruited 255 participants ages 20 to 93 in Baltimore, Maryland. Participants were separated into two categories: 169 younger adults (ages 20 to 69) and 87 older adults (70 and older). The team measured blood levels of autoantibodies and found that older adults had nearly twice the levels of autoantibodies than the younger adults - a median of 7.3 micrograms per milliliter of blood compared to the younger adult group's median level of 3.76. The researchers then used a frailty screening tool to identify frail older adults by measuring grip strength and walking speed, and asking questions about weight loss, fatigue and levels of physical activity. Older adults with high autoantibody levels were 3.9 times more likely to be frail. For every 1 microgram per milliliter of blood increase in autoantibodies, the researchers observed a decrease in hand grip strength of 5.7 pounds. Additionally, every 1 microgram per milliliter of blood increase in autoantibodies increased the odds of falling by 30 percent.

"Building off of our knowledge that these autoantibodies cause chronic inflammation, we decided to look at a class of medications, angiotensin receptor blockers, that block inflammation and are commonly prescribed to lower blood pressure." To examine the effects of autoantibodies levels on ARBs, the team collected 20-year-old data from a second patient population in Chicago and measured patients' previously collected serum for autoantibody levels. The 60 participants were 70 to 90 years old, and half had been treated with ARBs. The researchers observed similar associations between autoantibody levels and decline in grip strength and walking speed in the Chicago population. Furthermore, for every 1 microgram per milliliter increase of autoantibodies, those not receiving ARBs lived 115 days less - approximately shortened life span by 9 percent. Chronic treatment with ARBs attenuated the autoantibodies' association with decline in grip strength and increased mortality.

Agonistic angiotensin II type I receptor autoantibodies (AT1RaAbs) have not been associated with functional measures or risk for adverse health outcomes. AT1RaAbs could be utilized to stratify patient risk and to identify patients who can benefit from angiotensin receptor blocker (ARB) treatment. Demographic and physiologic covariates were measured in a discovery set of community dwelling adults from Baltimore (N=255) and AT1RaAb associations with physical function tests and outcomes assessed. A group from Chicago (N=60) was used for validation of associations and to explore the impact of ARB treatment.

The Baltimore group had 28 subjects with falls, 32 frail subjects and 5 deaths. Higher AT1RaAbs correlated significantly with interleukin-6, systolic blood pressure, body mass index (BMI), weaker grip strength, and slower walking speed. Individuals with high AT1RaAbs were 3.9 times more likely to be at high risk after adjusting for age. Every 1 µg/ml increase in AT1RaAbs increased the odds of falling 30% after adjusting for age, gender, BMI and blood pressure. The Chicago group had 46 subjects with falls and 60 deaths. Serum AT1RaAb levels were significantly correlated with grip strength, walking speed and falls. Every 1 µg/ml increase in AT1RaAbs, decreased time to death by 9% after adjusting for age, gender, BMI and blood pressure. Chronic treatment with ARBs was associated with better control of systolic blood pressure and attenuation of decline in both grip strength and time to death.

Researchers have developed the first artificial red blood cells designed to emulate vital functions of natural red blood cells. If confirmed safe for use in humans, the nanotechnology-based product could represent an innovative alternative to blood transfusions. The artificial cells, called ErythroMer, are designed to be freeze-dried, stored at ambient temperatures, and simply reconstituted with water when needed. Proof-of-concept studies in mice demonstrate that the artificial cells capture oxygen in the lungs and release it to tissues - the main functions of red blood cells - in a pattern that is indistinguishable from that seen in a control group of mice injected with their own blood. In rats, ErythroMer effectively resuscitated animals in shock following acute loss of 40 percent of their blood volume.

The donut-shaped artificial cells are formulated with nanotechnology and are about one-fiftieth the size of human red blood cells. A special lining encodes a control system that links ErythroMer oxygen binding to changes in blood pH, thus enhancing oxygen acquisition in the lungs and then dispensing oxygen in tissues with the greatest need. Tests show ErythroMer matches this vital oxygen binding feature of human red blood cells within 10 percent, a level the researchers say should be sufficient to stabilize a bleeding patient until a blood transfusion can be obtained. So far, tests suggest ErythroMer has overcome key barriers that halted development of previous blood substitutes, including efficacy and blood vessel narrowing. The team's next steps are testing in larger animals, ongoing safety assessment, optimizing pharmacokinetics, and ultimately conducting in-human clinical trials. The researchers are also pursuing methods for scaling up production. If further testing goes well, they estimate ErythroMer could be ready for use within 10-12 years.

4.5 million Americans receive blood transfusions each year, but human blood is limited by its supply and availability. under development, including Perfluorocarbon-Based Oxygen Carriers (PBOC) and Cell-Free Hemoglobin Based Carriers (HBOC), have mostly failed to preserve key physiologic functions of human blood cells. An effective artificial blood substitute will likely create and fulfill market demands for applications including hemorrhagic shock and emergency blood supplies. ErythroMer is a novel blood substitute composed of a patented nanobialys nanoparticle. Existing blood substitutes under development often trap nitric oxide unintentionally and fail to release oxygen in a context-specific manner. ErythroMer has multiple unique advantages by design: (1) Toroidal morphology resembling red blood cells; (2) Physiologic oxygen binding and release; (3) Simple system to inhibit hemoglobin auto-oxidation; (4) Limited nitric oxide sequestration; (5) Amenability to freeze-drying (lyophilization) and reconstitution. As a validation of these advantages, ErythroMer has been shown to demonstrate superior performance than other blood substitutes in a rodent model.

There is need for an artificial oxygen (O2) carrier for use when stored blood is unavailable or undesirable. To date, efforts to develop hemoglobin (Hb) based oxygen carriers (HBOCs) have failed, because of design flaws which do not preserve physiologic interactions of Hb with: O2 (they capture O2 in lungs, but do not release O2 effectively to tissue) and nitric oxide (NO) (they trap NO, causing vasoconstriction). ErythroMer design surmounts these weaknesses by: encapsulating Hb, controlling O2 capture/release with a novel 2,3-DPG shuttle and attenuating NO uptake through shell properties. The ErythroMer prototype has passed rigorous initial ex vivo and in vivo "proof of concept" testing and bench testing, which suggests this design surmounts prior challenges (by HBOCs) in emulating normal RBC physiologic interactions with O2 and NO. In models of major bleeding/anemia, ErythroMer reconstitutes normal hemodynamics and O2 delivery, observed at the system, tissue, and cellular level. ErythroMer potential for extended ambient dry storage has significant implications for portability and use. Next steps include formulation scaling, detailed study of pharmacokinetics, biodistribution and safety, as well as evaluation in large animal models of hemorrhagic shock.

Satellite cells (SC) are adult muscle stem cells located at the periphery of muscle fibers. SCs are accordingly exposed to various signals from within and outside of the fiber, which collectively comprise the specific environment termed the SC niche. Although metabolically inactive and quiescent in resting conditions, SCs quickly become activated in response to a stimulus such as injury or strenuous exercise. These stem cells are indispensable for skeletal muscle regeneration, and despite being present in relatively small numbers (2-5% of total myonuclei), SCs have a vast proliferative and regenerative potential. Proper activation and proliferation, as well as return to quiescence, are all essential to preserving SC number and function. In various pathological contexts, for example, in certain muscular dystrophies or aging, a depletion of SC numbers is linked to impaired regenerative capacity. Importantly, reduced SC numbers and myogenic activity are often caused by alterations of the SC niche. For example, excess fibronectin in the basal lamina in an uninjured state is correlated with a reduced ability of SCs to respond to injury. Age-associated accumulation of extracellular matrix (ECM) components leads to the thickening of the basal lamina, thereby preventing SCs from sensing changes in the environment and resulting in a reduced activation propensity. Inversely, treatment with fibronectin can restore satellite cell activation in old muscle. Moreover, local transient fibronectin secretion by SCs is an important step in the cascade of SC activation and subsequent proliferation, and such a transient increase in fibronectin muscle expression is necessary for successful regeneration.

SC numbers vary by muscle fiber type, with higher counts present in oxidative compared to glycolytic muscle beds. In line with this, endurance exercise increases SC numbers in mice and humans. The peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α) is a major driver of oxidative fiber-type specification, mitochondrial biogenesis, and high endurance capacity. Furthermore, PGC-1α gene expression is induced by exercise and exhibits a preference for slow, oxidative fibers. Finally, muscle-specific overexpression of PGC-1α protects against a variety of muscle-wasting conditions, including fiber atrophy or the pathologies in dystrophic mouse models. Nevertheless, a potential link between PGC-1α, oxidative fibers, exercise, and SCs has not been studied yet. By using a mouse model which specifically overexpresses PGC-1α in adult muscle fibers, we attempted to delineate the aforementioned missing link and assess the importance of indirect effects of PGC-1α on SC phenotype. Here, we show that muscle fiber PGC-1α modulates SC number as well as proliferation and that the latter, at least in part, could be regulated by the altered expression of ECM components, including fibronectin protein levels, in the basal lamina. Increased PGC-1α content in the SC niche therefore results in an accelerated SC response to injury and higher myogenic capacity.

During aging, myofiber size progressively decreases with an accompanying loss of fast twitch myofibers, leading to reduced overall muscle mass and strength that, when severe, results in sarcopenia. Loss of muscle mass and strength is accompanied by increased matrix deposition (fibrosis) and increased fat infiltration. Skeletal muscle regeneration is impaired in aged muscle and associated with cell-intrinsic deficits in satellite cell function; however, satellite cell contribution to sarcopenia has been recently questioned, although a contribution of satellite cell loss to aging-associated fibrosis is supported.

Satellite cells in G0 phase reside within the musculature and are poised to rapidly activate in response to injury. Upon activation, satellite cells re-enter the cell cycle, migrate away from their niche, and proliferate as myoblasts, eventually undergoing terminal differentiation into myocytes that fuse into pre-existing damaged muscle fibers or fuse to one another generating new muscle fibers. During regeneration, a portion of satellite cells returns to its niche, re-enters quiescence, and expresses Pax7 but no other myogenic transcription factors. The transmembrane heparan sulfate proteoglycan syndecan-3, a component of the satellite cell niche, controls satellite cell homeostasis by regulating signaling pathways within the niche. Moreover, members of the Syndecan family regulate cell-cell adhesion and cell-matrix adhesion via interaction with integrins and cadherins. Following a muscle injury, syndecan-3 null (Sdc3-/-) satellite cells fail to replenish the resident pool of quiescent satellite cells within the niche and therefore syndecan-3 appears to regulate satellite cell homeostasis.

We show that syndecan-3 loss alters satellite cell adhesion to the myofiber, altering interactions with the niche and (i) improves muscle regeneration upon repeated acute muscle injuries, (ii) rescues muscle histopathology and function in dystrophic muscle tissue, and (iii) improves muscle aging with a reduction in fibrosis. The lifelong improvement in muscle regeneration observed in Sdc3-/- muscle arises in part by altered satellite cell homeostasis and changes in satellite cell adhesiveness to the myofiber.

Recently it has been demonstrated that senescent cells (cells which have ceased to replicate due to stress or replicative capacity exhaustion) are linked to many age-related diseases. Furthermore, removing senescent cells from mice has been recently shown to drastically increase mouse healthspan, the period of life free of serious diseases. CellAge, together with a leading synthetic biology partner, Synpromics, are poised to develop a technology allowing for the identification and removal of harmful senescent cells. Our breakthrough technology will benefit both the scientific community and the general public.

In short, CellAge is going to develop synthetic promoters which are specific to senescent cells, as promoters that are currently being used to track senescent cells are simply not good enough to be used in therapies. The most prominently used p16 gene promoter has a number of limitations, for example. First, it is involved in cell cycle regulation, which poses a danger in targeting cells which are not diving but not senescent either, such as quiescent stem cells. Second, organism-wide administration of gene therapy might at present be too dangerous. This means senescent cells only in specific organs might need to be targeted and p16 promoter does not provide this level of specificity. Third, the p16 promoter is not active in all senescent cells. Thus, after therapies utilizing this promoter, a proportion of senescent cells would still remain. Moreover, the p16 promoter is relatively large (2.1kb), making it difficult to incorporate in present gene therapy vehicles. Lastly, to achieve the intended therapeutic effect the strength of p16 promoter to drive therapeutic effect might not be high enough.

CellAge will be constructing a synthetic promoter which has a potential to overcome all of the mentioned limitations. A number of gene therapy companies have successfully targeted other types of cells using this technology. With your help, we will be able to use same technology to develop tools and therapies for accurate senescent cell targeting. As our primary mission is to expand the interface between synthetic biology and aging research as well as drive translational research forward, we will offer our senescence reporter assay to academics for free. We predict that in the very near future this assay will be also used as a quality control step in the cell therapy manufacturing process to make cell therapies safer!

How did you folk at CellAge meet? What made you decide that senescent cell clearance was the most needful accomplishment you could work on?

As many worthwhile efforts go, we didn't push CellAge into existence just because we wanted to start a company. I have been following ageing research for very long time and so I was aware what is happening in the field. At the same time, I emerged myself into synthetic biology where I am doing my PhD now. For a while, I have been exposed to these different fields and at some point things just connected. Recent publications on mouse models showed that there is a great promise in removing senescent cells and from my own end, some exciting technological opportunities presented themselves from the synthetic biology side. So CellAge is really a result of many coincidence that led to this project. After I discussed these ideas with more experienced people, some of whom are our advisors now, I came to realize that there is a real opportunity here and we took it!

There are a lot of approaches under development; perhaps you could outline yours and how it differs from those of Oisin, UNITY, and SIWA, among others?

Yes there are multiple companies working towards same or similar goal and I am very happy of their efforts. First and foremost, I am scientists and I lead CellAge as a scientist - we just want to see this technology coming to existence, be it us or someone else who does it. That being said, at this stage it's really hard to see which approach will be best and it's likely (considering examples in oncology field) that combination of therapies will need to be taken (e.g. immunotherapy together with gene therapy or small molecules together with gene therapy). Moreover, some approaches might be more suitable for some applications and some patient groups. So its good we have multiple shots at the same goal to maximize our success chances and not have all the eggs in the same basket. But of course this all only make sense if we have an unique angle and I strongly believe we do! At CellAge, we are focusing on using synthetic biology tools to construct promoters which will be only active in senescent cells. Early on, this will help scientists working on aging research to better identify senescent cells and push field forward faster, and later this might become a key or supportive technology used in the therapies. Lastly and most importantly, I just want to stress out that for me science is key thing here and I do not see other groups working the the field as competition but rather as a potential source of collaboration.

There seems to be a growing contingent who want to treat cellular senescence by tinkering with or shutting down the senescence-associated secretory phenotype (SASP). What is your take on this as an approach versus cell destruction?

I think this is a very potent strategy, which probably is also technically easier to achieve because of regulatory burdens and the fact that small molecules might be more potent in this front. That being said, there might be couple of downsides with this approach and so different approaches, like ours at CellAge, should still be investigated. Firstly, different cells have different SASP and so there might not be a single bullet to cure it all. Secondly, although SASP is one of the key mechanisms how senescent cells harm our body but it's not the only one. Senescent cells can also escape senescence and become cancerous. Lastly, unless you take "SASP inhibitors" for the rest of your life, this will be only temporary solution if cells remain in the tissues. Also, I just would like to add that senescent cell destruction is only a first step for us. Here at CellAge we believe that eventually we will go beyond just killing cells and will be able to repair cells before they become damaged or senescent.

You're looking at crowdfunding; what made you choose this path for the initial development of your work?

Crowdfunding is not the only path we are taking, but it is one we are counting on most. We are also applying for grants and various competitions in addition to this crowdfunding campaign. We believe that for the stage of our company, this is most appropriate path. Importantly, we want to make our tools available to academics free of charge and investors might have a problem with that.

You are clearly energized by the goal of healthy life extension, making the human life span longer. What is your vision for the broader future of SENS-like rejuvenation medicine over the coming decades?

As a scientists I would like to be a bit more skeptic and rather advocate that CellAge is working on healthspan, rather than lifespan extension. I think that although we had glimpses of how lifespan can be expanded in mice, but we are still relatively far from translating that into humans. Instead, CellAge is focusing on age-related diseases and their prevention - a field in which role of senescent cells has much more of scientific proof. I personally am a big fan of SENS and their work. I think they are taking a correct way forward and I would even dare to predict, or hope, that many things they are aiming to achieve will reach the daylight soon enough. For the future, CellAge vision is to construct even more elaborate genetic circuits and gene therapies which will allow to fix cells instead of killing them. We are big believers in using biological logical gates and circuits to construct novel computing processes in the cells in the form of gene therapy.

Neurological dysfunction is the basis of numerous human diseases. Affected tissues often contain insoluble aggregates of proteins that display altered conformations, a feature believed to contribute to an estimated 50 distinct human diseases. Neurodegenerative amyloid disorders, including Alzheimer's, Huntington's, and Parkinson's diseases (PD), are each associated with a distinct amyloid protein. PD is a multifactorial disorder that has a strong environmental component, as less than 10% of cases are hereditary. Aggregation of α-synuclein (αSyn) is thought to be pathogenic in a family of diseases termed synucleinopathies, which includes PD, multiple system atrophy, and Lewy body disease. αSyn aggregation is a stepwise process, leading to oligomeric species and intransient fibrils that accumulate within neurons. Dopaminergic neurons of the substantia nigra pars compacta (SNpc) appear particularly vulnerable to effects of αSyn aggregates.

Although neurological diseases have been historically studied within the central nervous system (CNS), peripheral influences have been implicated in the onset and/or progression of diseases that impact the brain. Indeed, emerging data suggest bidirectional communication between the gut and the brain. Gastrointestinal (GI) physiology and motility are influenced by signals arising both locally within the gut and from the CNS. Neurotransmitters, immune signaling, hormones, and neuropeptides produced within the gut may, in turn, impact the brain. The human body is permanently colonized by microbes on virtually all environmentally exposed surfaces, the majority of which reside within the GI tract. Increasingly, research is beginning to uncover the profound impacts that the microbiota can have on neurodevelopment and the CNS. Dysbiosis (alterations to the microbial composition) of the human microbiome has been reported in subjects diagnosed with several neurological diseases. For example, fecal and mucosa-associated gut microbes are different between individuals with PD and healthy controls. Yet, how dysbiosis arises and whether this feature contributes to PD pathogenesis remains unknown.

Gut bacteria control the differentiation and function of immune cells in the intestine, periphery, and brain. Intriguingly, subjects with PD exhibit intestinal inflammation, and GI abnormalities such as constipation often precede motor defects by many years. It is posited that aberrant αSyn accumulation initiates in the gut and propagates via the vagus nerve to the brain in a prion-like fashion. This notion is supported by pathophysiologic evidence: αSyn inclusions appear early in the enteric nervous system (ENS) and the glossopharyngeal and vagal nerves. Further, injection of αSyn fibrils into the gut tissue of healthy rodents is sufficient to induce pathology within the vagus nerve and brainstem. However, the notion that αSyn aggregation initiates in the ENS and spreads to the CNS via retrograde transmission remains controversial, and experimental support for a gut microbial connection to PD is lacking.

Based on the common occurrence of GI symptoms in PD, dysbiosis among PD patients, and evidence that the microbiota impacts CNS function, we tested the hypothesis that gut bacteria regulate the hallmark motor deficits and pathophysiology of synucleinopathies. Herein, we report that the microbiota is necessary to promote αSyn pathology, neuroinflammation, and characteristic motor features in a validated mouse model. We identify specific microbial metabolites, short-chain fatty acids, that are sufficient to promote disease symptoms. Remarkably, fecal microbes from PD patients impair motor function significantly more than microbiota from healthy controls when transplanted into mice. Together, these results suggest that gut microbes may play a critical and functional role in the pathogenesis of synucleinopathies such as PD.

In the 21st century, almost everything that kills people, except for accidents and other unintentional causes of death, has been classified as a disease. Aging kills, so it's past time to declare it a disease too and seek cures for it. In 2015, a group of European gerontologists persuasively argued for doing just that. They rejected the common fatalistic notion that aging "constitutes a natural and universal process, while diseases are seen as deviations from the normal state." A century ago osteoporosis, rheumatoid arthritis, high blood pressure, and senility were considered part of normal aging, but now they are classified as diseases and treated. "There is no disputing the fact that aging is a 'harmful abnormality of bodily structure and function,'" they note. "What is becoming increasingly clear is that aging also has specific causes, each of which can be reduced to a cellular and molecular level, and recognizable signs and symptoms."

So why do people age and die? Basically, because of bad chemistry. People get cancer when chemical signals go haywire enabling tumors to grow. Heart attacks and strokes occur when chemical garbage accumulates in arteries and chemical glitches no longer prevent blood cells from agglomerating into dangerous clumps. The proliferation of chemical errors inside our bodies' cells eventually causes them to shut down and emit inflammatory chemicals that damage still healthy cells. Infectious diseases are essentially invasions of bad chemicals that arouse the chemicals comprising our immune systems to try and (too often) fail to destroy them.

Also in 2015, another group of European researchers pointed out that we've been identifying a lot of biomarkers for detecting the bad chemical changes in tissues and cells before they produce symptoms associated with aging. Such biomarkers enable pharmaceutical companies and physicians to discover and deploy treatments that correct cellular and molecular malfunctions and nudge our bodies' chemistry back toward optimal functioning. As a benchmark, the researchers propose the adoption of an "ideal norm" of health against which to measure anti-aging therapies. "One approach to address this challenge is to assume an 'ideal' disease-free physiological state at a certain age, for example, 25 years of age, and develop a set of interventions to keep the patients as close to that state as possible," they suggest. Most people's body chemistry is at its best when they are in their mid-twenties. In fact, Americans between ages 15 and 24 are nearly 500 times less likely to die of heart disease, 100 times less likely to die of cancer, and 230 times less likely die of influenza and pneumonia than people over the age of 65 years. For lots of us who are past our twenties, television talk show host Dick Cavett summed it up well: "I don't feel old. I feel like a young man that has something wrong with him."

The 24 patients had undergone most standard therapies available to them and yet their chronic lymphocytic leukemia had come back strong. Almost all of them had been treated with a newly approved, targeted drug called ibrutinib; data from other studies show that most patients whose disease progresses after ibrutinib treatment do not survive long. The majority of the 24 had chromosomal markers in their leukemia cells that serve as predictors of a bad response to most standard therapies. But most of these patients, who were enrolled in a small, early-phase trial, saw their advanced tumors shrink or even disappear after an infusion of genetically engineered immune cells.

In the trial, participants' disease-fighting T cells were removed from their blood and genetically engineered to produce an artificial receptor, called a CAR, or chimeric antigen receptor, that empowered them to recognize and destroy cancer cells bearing a target molecule called CD19. After patients received chemotherapy, the CAR T cells were infused back into their bloodstream to kill their CD19-positive cancers. While all 24 patients with chronic lymphocytic leukemia, or CLL, received the experimental therapy, researchers focused in his presentation on the results in a subgroup of 19 patients who received particular chemotherapy regimens and doses of CAR T cells the researchers now prefer, based on recent data in other groups of patients on the trial. Fourteen of 19 experienced a partial or complete regression of their disease in their lymph nodes. And of the 17 who had leukemia in their bone marrow when they enrolled on the trial, the marrow became cancer-free in 15 after they received CAR T cells. "It's very pleasing to see patients with refractory disease respond like this. We had seen very good responses to the same CAR T-cell therapy in acute lymphoblastic leukemia and non-Hodgkin lymphoma, so we hoped responses would be good in CLL too."

Follow-up with CLL participants is ongoing. As per U.S. Food and Drug Administration requirements for experimental gene therapies, the research team will track patient outcomes for at least 15 years. Researchers reported that the CLL patients with the highest number of CAR T cells in their blood after infusion were most often the patients who had had the greatest extent of cancer in their marrow, blood and lymph nodes at the time of infusion. Those with more CAR T cells were also most likely to have their disease disappear from the bone marrow after the cells entered their bodies. Side effects included high fevers, due to activation of CAR T cells, and neurologic symptoms. Although one patient died from severe toxicity, the side effects experienced by other patients in the study were temporary. The researchers also reported biomarkers they had identified in patients' blood from the day after CAR T-cell infusion that were associated with the later development of the most severe toxicities. They hope these markers could eventually become the cornerstone of tests to predict and mitigate the most serious side effects of CAR T-cell infusion. "If you can find biomarkers within a day of CAR T-cell infusion, which we have, you can then look at future cohorts of patients to work out whether early intervention can help prevent toxicity."

Ever since researchers connected the shortening of telomeres - the protective structures on the ends of chromosomes - to aging and disease, the race has been on to understand the factors that govern telomere length. Now, scientists have found that a balance of elongation and trimming in stem cells results in telomeres that are, as Goldilocks would say, not too short and not too long, but just right. "This work shows that the optimal length for telomeres is a carefully regulated range between two extremes. It was known that very short telomeres cause harm to a cell. But what was totally unexpected was our finding that damage also occurs when telomeres are very long."

Telomeres are repetitive stretches of DNA at the ends of each chromosome whose length can be increased by an enzyme called telomerase. Our cellular machinery results in a little bit of the telomere becoming lopped off each time cells replicate their DNA and divide. As telomeres shorten over time, the chromosomes themselves become vulnerable to damage. Eventually the cells die. The exception is stem cells, which use telomerase to rebuild their telomeres, allowing them to retain their ability to divide, and to develop ("differentiate") into virtually any cell type for the specific tissue or organ, be it skin, heart, liver or muscle - a quality known as pluripotency. These qualities make stem cells promising tools for regenerative therapies to combat age-related cellular damage and disease. "In our experiments, limiting telomere length compromised pluripotency, and even resulted in stem cell death. So then we wanted to know if increasing telomere length increased pluripotent capacity. Surprisingly, we found that over-elongated telomeres are more fragile and accumulate DNA damage."

The reasearchers began by investigating telomere maintenance in laboratory-cultured lines of human embryonic stem cells (ESCs). Using molecular techniques, they varied telomerase activity. Perhaps not surprisingly, cells with too little telomerase had very short telomeres and eventually the cells died. Conversely, cells with augmented levels of telomerase had very long telomeres. But instead of these cells thriving, their telomeres developed instabilities. "We were surprised to find that forcing cells to generate really long telomeres caused telomeric fragility, which can lead to initiation of cancer. These experiments question the generally accepted notion that artificially increasing telomeres could lengthen life or improve the health of an organism."

The team observed that very long telomeres activated trimming mechanisms controlled by a pair of proteins called XRCC3 and Nbs1. The lab's experiments show that reduced expression of these proteins in ESCs prevented telomere trimming, confirming that XRCC3 and Nbs1 are indeed responsible for that task. Next, the team looked at induced pluripotent stem cells (iPSCs), which are differentiated cells (e.g., skin cells) that are reprogrammed back to a stem cell-like state. iPSCs - because they can be genetically matched to donors and are easily obtainable - are common and crucial tools for potential stem cell therapies. The researchers discovered that iPSCs contain markers of telomere trimming, making their presence a useful gauge of how successfully a cell has been reprogrammed. "Stem cell reprogramming is a major scientific breakthrough, but the methods are still being perfected. Understanding how telomere length is regulated is an important step toward realizing the promise of stem cell therapies and regenerative medicine."

Researchers have linked the function of a core component of cells' machinery - which cuts and rejoins RNA molecules in a process known as "RNA splicing" - with longevity in the roundworm. The finding sheds light on the biological role of splicing in lifespan and suggests that manipulating specific splicing factors in humans might help promote healthy aging. "What kills neurons in Alzheimer's is certainly different from what causes cardiovascular disease, but the shared underlying risk factor for these illnesses is really age itself. So one of the big questions is: Is there a unifying theme that unfolds molecularly within various organ systems and allows these diseases to take hold?"

Due to advances in public health, life expectancy has dramatically increased worldwide over the last century. Although people are generally living longer lives, they are not necessarily living healthier lives, particularly in their last decades. Age-related diseases such as cancer, heart disease, and neurodegenerative disease are now among the leading global health burdens - a problem that will likely only worsen. In order for bodies - and cells - to maintain youthfulness, they must also maintain proper homeostasis. At the cellular level, that means keeping the flow of biological information, from genes to RNA to proteins, running smoothly and with the right balance. While a considerable amount is known about how dysfunction at the two ends of this process - genes and proteins - can accelerate aging, strikingly little is known about how the middle part, which includes RNA splicing, influences aging. Splicing enables one gene to generate multiple proteins that can act in different ways and in disparate parts of the body. "Although we know that specific splicing defects can lead to disease, we were really intrigued about de-regulation of RNA splicing as a driver of the aging process itself, because practically nothing is known about that. Put simply, splicing is a way for organisms to generate complexity from a relatively limited number of genes."

Researchers designed a series of experiments in the roundworm Caenorhabditis elegans to probe the potential connections between splicing and aging. "C. elegans is a great tool to study aging in because the worms only live for about three weeks, yet during that time they can show clear signs of age. For example, they lose muscle mass and experience declines in fertility as well as immune function." Notably, the worms' cells are transparent, so researchers harnessed fluorescent genetic tools to visualize the splicing of a single gene in real-time throughout the aging process. Not only did the scientists observe variability on a population level - after five days, some worms showed a youthful pattern of splicing while others exhibited one indicative of premature aging - but they could also use these differences in splicing (reflected fluorescently) to predict individual worms' lifespans prior to any overt signs of old age.

Interestingly, when the team looked at worms treated in ways that increase lifespan (through a technique known as dietary restriction), they found that the youthful splicing pattern was maintained throughout the worms' lives. Importantly, the phenomenon is not restricted to just one gene, but affects genes across the C. elegans genome. The finding suggests that splicing could play a broad role in the aging process, both in worms as well as humans. As they dug more deeply into the molecular links between splicing and aging, researchers zeroed in on one particular component of the splicing apparatus in worms, called splicing factor 1 (SFA-1) - a factor also present in humans. In a series of experiments, the researchers demonstrate that this factor plays a key role in pathways related to aging. SFA-1 is specifically required for lifespan extension by dietary restriction and by modulation of the TORC1 pathway components AMPK, RAGA-1 and RSKS-1/S6 kinase. Remarkably, when SFA-1 is present at abnormally high levels, it is sufficient on its own to extend lifespan.

Aging and wrong lifestyle choices, including inadequate dietary patterns, increase the risk of developing several diseases such as obesity and its-related chronic degenerative diseases. Interestingly, the aging program can be accelerated by obesity. It is thus likely that obesity reduces life- and health span and plays a predominant role in the onset of age-related diseases. In fact, the prevalence of obesity is globally increasing in populations and has become a burden for healthcare systems. Several studies suggest that dietary restriction (DR) regimens (e.g. intermittent fasting, calorie restriction, low calorie diet) reverse obesity and improve health in human by promoting the same molecular and metabolic adaptations that have been shown in animal models of longevity. In particular, DR in humans ameliorates several metabolic and hormonal factors that are implicated in the pathogenesis of an array of age-associated chronic metabolic diseases.

At present it is difficult to evaluate the effectiveness of DR on lifespan in humans, so that several works proposed predictive non-invasive biomarkers to evaluate the geroprotective role of DR. However, a miscellaneous of biomarkers is investigated in human intervention studies limiting the statistical robustness of the data. Whether a "biomarker-based" approach could be suitable for evaluating the effectiveness of DR still remains a matter of debate. Precision medicine is a medical model that proposes the customization of healthcare, with the identification of predictors that can help to find the effectiveness of health-promoting dietary interventions. Biomarkers represent potentially predictive tools for precision medicine but, although affordable 'omics'-based technology has enabled faster identification of putative biomarkers, their validation is still hindered by low statistical power as well as limited reproducibility of results. Herein, through meta-analysis we have evaluated the effect size of DR regimens on adipose mass and well-recognized biomarkers of healthy aging.

Herein we included all studies evaluating the impact of DR on several healthy-associated markers in human including adipose mass. Increased visceral adiposity leads to chronic inflammation, which is often associated with a number of comorbidities (e.g. hyperinsulinemia, hypertension, insulin resistance, glucose intolerance) and reduced life expectancy. Through this meta-analysis approach, we confirmed the capacity of DR to reduce total and visceral adipose mass and, interestingly, we observed a more effective visceral adipose mass reduction after DR regimens. These findings suggest that to obtain a more effective adipose mass loss, 20% in calorie reduction could be an elective strategy. Central or visceral adiposity perturbs systemic inflammation in animal models and human and relatively to this, the healthy effects of DR could be mediated by visceral adiposity reduction. Indeed, DR significantly diminished the markers of inflammation, highlighting the central role of DR-mediated adipose tissue remodelling in improving inflammatory profile in human. Furthermore, DR also increased adiponectin/leptin ratio, which is commonly associated with ameliorated insulin sensitivity in human. In line with this effect, we demonstrated that DR was successful in reducing insulin, IGF-1 and HOMA index.

Chronological age, defined as the time elapsed since birth, fails to be an accurate indicator of the rate of the aging process. This is due to the heterogeneity that aging shows in the diverse members of a population. This phenomenon led to the concept of "biological age", which estimates how well an individual functions in comparison with others of the same chronological age. Given that biological age is a better indicator than chronological age of the health, remaining healthy life span, and active life expectancy of each subject, its determination is very relevant. However, despite its simple definition, quantification of the biological age is a difficult task. Many studies have been carried out trying to obtain the most appropriate parameters for determining biological age and have been mainly focused on both physiological (respiratory function, systolic arterial tension) as well as on biochemical (albumin, cholesterol) markers. Moreover, other markers such as genetic (telomere length) or epigenetic (DNA methylation) have also been proposed. Nevertheless, despite different sets of markers being proposed in these studies, none of them have been validated. Therefore, the subject is still incomplete and more research should be carried out.

Most work on biological age has not included parameters of the immune system, which is a homeostatic system that contributes to the appropriate function of the organism. It is well known that with aging there is an increased susceptibility to infectious diseases, autoimmune processes and cancer, which indicates the presence of a less competent immune system, exerting a great influence on age-related morbidity and mortality. Since it has been demonstrated that the functioning of the immune system is an excellent marker of health and given that several age-related changes in immune functions have been linked to longevity whereas others have been shown to be predictive of mortality, the aim of the present study was to determine if some immune functions could be useful as markers of biological age and therefore as predictors of longevity.

In order to validate a potential set of parameters as markers of biological age, it is necessary to confirm that the levels shown in particular subjects reveal their real health and senescent conditions and, consequently, their rate of aging. This has to be demonstrated by meeting two requirements. The first is that if an adult individual shows values characteristic of a chronologically old individual, he or she should die prematurely. The second is that a long-lived individual, known to have experienced healthy aging, should have a value of these biomarkers similar to that of an adult. The first requisite can only be confirmed in experimental animals, given that it is a difficult task to follow-up human subjects throughout the whole aging process due to their long life span. Thus, mice were chosen for our study, which show a mean longevity of about 2 years. The second requirement can be confirmed in both human centenarians and experimental animals such as extremely long-lived mice.

Among all the possible functions of immune cells, we have focused on the ones that are the most relevant in the immune response and are known to experience an age-related decrease. In phagocytes, their ability to migrate towards the focus of infection (chemotaxis) and their capacity to ingest foreign particles (phagocytosis); in natural killer (NK) cells, their capacity to destroy tumoral cells and in lymphocytes, their ability to migrate towards the site of antigen recognition (chemotaxis) and to proliferate in response to mitogens (lymphoproliferation). Thus, in order to validate the above mentioned immune functions as markers of biological age and predictors of longevity, these functions were studied in leukocytes isolated from peripheral blood of human subjects in a cross-sectional study, from their 30s until their 100s. In addition, the same functions were analyzed in leukocytes obtained from peritoneum of mice without killing them, enabling a longitudinal study to be performed, starting at the adult age and following each animal until its death. Neutrophil chemotaxis and phagocytosis, as well as the activity of NK cells, lymphocyte chemotaxis and proliferative response showed lower values in old individuals in comparison to those in adults. Considering the state of these functions in subjects which reach a high longevity, and consequently have attained successful aging, both humans and mice showed more similar values to those observed at adult age than to those at old age.

Hematopoiesis is an active, continuous process involving the production and consumption of mature blood cells that constitute the hemato-lymphoid system. All blood cells arise from a small population of hematopoietic stem cells (HSCs) in the bone marrow (BM) that have two unique properties: self-renewing capacity, the ability to generate themselves, and multi-lineage differentiation capacity, the ability to produce all blood cell types. Since, in the steady state, most adult HSCs are in the G0 phase of the cell cycle, i.e., they are quiescent and are estimated to turnover slowly on a monthly time scale, daily hematopoietic production is mainly sustained by highly proliferative downstream hematopoietic progenitor cells (HPCs).

Aging of the hematopoietic system is represented by functional declines in both the adaptive and the innate immune system, an immunosenescence that leads to high susceptibility to infections, low efficacy of vaccinations, and increased vulnerability to the development of autoimmunity and hematologic malignancies. It has been show that (a) B cell production decreases significantly with advancing age, i.e., the naïve B cell pool diminishes, while the memory B cell pool expands. Diversity of the B cell repertoire also decreases in association with lowered antibody affinity and impaired class switching. B cells are prone to produce auto-antibodies increasing the incidence of spontaneous autoimmunity; (b) de novo T cell production also declines with aging partially due to thymic involution. CD8+ T cells undergo oligoclonal expansion and their repertoire is skewed toward previously encountered antigens, as niches for naïve T cells in peripheral lymphoid tissues become occupied by terminally differentiated cells; (c) NK cells show diminished cytotoxicity and cytokine secretion; (d) although myeloid cells increase in number, their functionality is decreased, e.g., neutrophils migrate less in response to stimuli, and macrophages have reduced phagocytic activity and decreased oxidative burst; and (e) erythropoiesis also declines in elderly people causing frequent anemia, while the thrombocytic lineage has not, to date, been reported to be significantly affected by aging.

There are similarities between hematopoietic alterations during inflammation and those that occur with aging. In response to aging and bacterial infection, myelopoiesis becomes dominant over lymphopoiesis in relation to immunosenescence. Most notably, B-lymphopoiesis is impaired due to a decreased level of E47, a transcription factor essential for B cell development, in aged mice. The aging-associated myeloid dominance and/or adipogenesis in BM might be triggered by increased basal levels of pro-inflammatory cytokines even in the absence of infection. Indeed, levels of circulating pro-inflammatory cytokines, such as IL-6, TNF-α, IL-1Rα, and C-reactive protein, are reportedly upregulated in healthy elderly populations. These observations allow us to hypothesize that "inflammaging" represents a subclinical grade of chronic inflammation possibly contributing to the initiation and/or acceleration of hematopoietic aging.

Since numerous inflammatory factors are increased in aged hematopoietic tissues, and inflammation- and aging-associated hematopoietic changes share common cellular and molecular alterations, it is reasonable to speculate that low-grade inflammation might be involved in hematopoietic aging with reduced fitness of both adaptive and innate immune cells. Given that some hematopoietic phenotypes during inflammation and aging arise from functional alterations in HSCs and progenitor cells (HSPCs), it would be worthwhile to elucidate the underlying common mechanisms. Future research could yield meaningful insights into cell-intrinsic changes in HSPC quantity and quality, e.g., how aspects of HSPC population dynamics such as functional heterogeneity and population size change, whether all subsets of HSCs with a distinct lineage output respond equally to inflammatory stimuli or only the minor fraction is responsive, how the self-renewal and differentiation capacities of HSC are altered on a per-cell basis, and molecular changes in cellular signaling, such as alterations in cellular metabolism, transcriptional networks, epigenetic modifications, and genomic instability. It is also essential to understand to what extent inflammaging-associated cell-extrinsic factors influence HSPC biology, including signals derived from the BM niche, tissue damage/repair, infection, obesity, or the microbiome. In addition, the fundamental task that remains is identification of the factors initially triggering the process of hematopoietic inflammaging. Inflammation- or aging-related external stimuli appear to force quiescent HSCs to proliferate and impair their self-renewal and differentiation capacities, as suggested by evidence that HSC cycling in response to chemotherapy administration or hematopoietic stress accelerates the manifestation of aging phenotypes. These data suggest that the central features of HSCs aging might be attributable to accumulation of a proliferative history that is closely associated with perturbed self-renewal and differentiation.

Inflammation and aging have thus far been seen as two independent pathophysiological processes. However, a growing body of evidence has highlighted biological changes in hematopoiesis and HSCs that are common to both inflammation and aging. Thus, it is likely that sustained inflammatory stimuli contribute to hematopoietic aging and possibly leukemogenesis, supporting the inflammaging concept. Since inflammation and aging might both be involved in increased risk for leukemogenesis, eliminating unwanted inflammaging factors is a potential approach to preserving both HSC and immune functions, and thereby preventing a functional decline in hematopoiesis and the emergence of malignant clones. Future investigation is required to better characterize hematopoietic inflammaging processes at the tissue, cellular, and molecular levels.

Cardiovascular diseases (CVD) are the leading cause of death in developed societies. The risk of CVD increases progressively with advancing age, such that greater than 90% of deaths from CVD occur in people over the age of 55. Although the mechanisms underlying the age-related increase in CVD risk have not been fully elucidated, strong evidence indicates that the development of arterial dysfunction is a key factor. An important manifestation of arterial dysfunction is vascular endothelial dysfunction, characterized by a decline in endothelium-dependent dilation (EDD).

A major mechanism underlying the development of age-related endothelial dysfunction is oxidative stress, characterized by excessive production of reactive oxygen species (ROS) relative to endogenous antioxidant defense capacity. Oxidative stress can disrupt many aspects of arterial function, including reducing the bioavailability of the vasodilatory and vasoprotective molecule nitric oxide (NO), resulting in impaired EDD. A key source of arterial oxidative stress is excessive production of mitochondrial reactive oxygen species (mtROS). Whereas healthy mitochondria are critical mediators of arterial homeostasis and produce physiological levels of mtROS vital for cell signaling, declines in mitochondrial health are characterized by excessive mtROS production. We have recently shown that excess arterial mtROS production is a major contributor to tonic arterial oxidative stress-mediated suppression of EDD with primary aging in mice. Emerging evidence suggests that, in addition to baseline deficits in vascular function, aging may also be accompanied by reduced arterial resilience, i.e., the ability to withstand stress. Because human aging occurs in the presence of numerous stressors, it is important to understand how aging alters arterial resilience and to identify potential interventions that may improve the ability of arteries to withstand these challenges.

Mitochondria are critical components of the cellular stress response and interact with and regulate other stress response mediators, including antioxidant enzymes and heat shock proteins (Hsp). Thus, mitochondrial dysregulation has the potential to impact major upstream mechanisms, such as oxidative stress, that mediate vascular function. However, it is unknown whether age-related declines in arterial mitochondrial health contribute to decreased resilience in the presence of acute stressors. Aerobic exercise is a powerful intervention that improves baseline endothelial function in the setting of aging. It is well known that aerobic exercise improves mitochondrial biogenesis and homeostasis in non-vascular tissues, and recent work suggests that exercise can also improve markers of arterial mitochondrial content and health in healthy animals, but the effects of aerobic exercise on arterial mitochondria with primary aging are unclear. We tested the hypothesis that aging would be associated with impaired arterial resilience to acute stress and reduced arterial mitochondrial health in mice, and that voluntary aerobic exercise initiated in late-life (10 weeks of voluntary wheel running) would increase resilience and improve mitochondrial health in aging arteries.

In line with a recent study in our laboratory, we observed that age-related vascular endothelial dysfunction is accompanied by elevated arterial mitochondrial superoxide production. Importantly, we show here that voluntary aerobic exercise normalized mitochondrial superoxide production in arteries of old mice, suggesting that exercise-induced reductions in arterial mitochondrial oxidative stress may contribute to improvements in vascular endothelial function. Our findings further extend previous work by demonstrating that, in addition to restoring baseline vascular endothelial function, voluntary aerobic exercise improves arterial resilience to acute stressors in old mice. Consistent with our previous report, we observed that acute treatment with rotenone, a mitochondrial Complex I inhibitor that can also induce mitochondrial superoxide production, impairs carotid artery endothelial function in old mice to a greater degree than arteries from young mice, indicating that aging arteries are more vulnerable to a mitochondria-specific challenge. In the present study, we show that voluntary aerobic exercise completely restores the ability of aged arteries to withstand this acute mitochondrial stress.

Researchers have developed the GeroScope algorithm to identify geroprotectors - substances that extend healthy life. Hundreds of compounds were screened for geroprotective activity using computer simulations, and laboratory experiments were conducted on the ten substances that were identified using this algorithm. Decades of hard work by highly-competent research teams and millions are spent on the process of developing new drugs. And the screening and development process of geroprotectors, interventions intended to combat aging, a complex multifactorial biological process affecting every cell in the human body, is even more tedious. Computer modeling techniques may significantly reduce the time and cost of development. "The aging of the population is a global problem. Developing effective approaches for creating geroprotectors and validating them for use in the human body is one of the most important challenges for biomedicine. We have proposed a possible approach that brings us one step closer to solving this problem."

For several years the group studied cancer-related processes and relied on the Oncofinder, an algorithm designed to study and analyze the activation values of molecular pathways by comparing gene expression in cancerous and normal healthy cells, and also comparing tissue samples of different patients. The researchers applied a similar approach to develop GeroScope, which is able to compare changes in the cells of young and old patients and search for drugs with minimal side effects that compensate for these changes. To do this, the scientists analyzed transcriptomic data in "young" (donors aged between 15 and 30 years) and "old" (donors over the age of 60) samples from many human tissue types. This data was used for advanced computer modeling to identify and re-construct the molecular pathways associated with aging. Molecular pathways are a sequence of reactions that lead to changes in a cell. The most common molecular pathways are involved in metabolism and signal transduction. GeroScope modeled molecular pathways and analyzed cell reactions to various substances. Having chosen 70 compounds from the database of geroprotective drugs, the scientists used the new algorithm to identify 10 substances that could have geroprotector properties in accordance with the model.

The predictions made by the computer model were confirmed in cell cultures of human fibroblasts for several substances. Some of these drugs are already actively sold as dietary supplements individually. Further analysis of the pathway-level effects of many of these compounds provided insights into the possible combinations providing maximal cumulative effects and minimizing the possible adverse effects. "For computer modeling this is a very good result. In the pharmaceutical industry, 92% of drugs that are tested on animals fail during clinical trials in humans. The ability to simulate biological effects with such a high level of accuracy in silico is a real breakthrough. We hope that some of these drugs will soon be tested on people using biologically-relevant biomarkers of aging."