In the study, investigators injected cardiosphere-derived cells, a specific type of stem cell known as CDCs, from newborn laboratory rats into the hearts of rats with an average age of 22 months, which is considered aged. Other laboratory rats from the same age group were assigned to receive placebo treatment, saline injections instead of stem cells. Both groups of aged rats were compared to a group of young rats with an average age of 4 months. Baseline heart function was measured in all rats, using echocardiograms, treadmill stress tests, and blood analysis. The older rats underwent an additional round of testing one month after receiving cardiosphere-derived cells that came from young rats.

"The way the cells work to reverse aging is fascinating. They secrete tiny vesicles that are chock-full of signaling molecules such as RNA and proteins. The vesicles from young cells appear to contain all the needed instructions to turn back the clock." Results of those tests show lab rats that received the cardiosphere-derived cells experienced the following: improved heart function; demonstrated longer heart cell telomeres; improved their exercise capacity by an average of approximately 20 percent; and regrew hair faster than rats that didn't receive the cells. "This study didn't measure whether receiving the cardiosphere-derived cells extended lifespans, so we have a lot more work to do. We have much to study, including whether CDCs need to come from a young donor to have the same rejuvenating effects and whether the extracellular vesicles are able to reproduce all the rejuvenating effects we detect with CDCs."

Cardiosphere-derived cell (CDC) therapy has exhibited several favourable effects on heart structure and function in humans and in preclinical models; however, the effects of CDCs on aging have not been evaluated. We compared intra-cardiac injections of neonatal rat CDCs to a control of phosphate-buffered saline, PBS, in 21.8 ± 1.6 month-old rats (mean ± standard deviation; n = 23 total). Ten rats of 4.1 ± 1.5 months of age comprised a young reference group. Blood, echocardiographic, haemodynamic and treadmill stress tests were performed at baseline in all animals, and 1 month after treatment in old animals. Histology and the transcriptome were assessed after terminal phenotyping. For in vitro studies, human heart progenitor cells from older donors, or cardiomyocytes from aged rats were exposed to human CDCs or exosomes secreted by CDCs from paediatric donors.

Transcriptomic analysis revealed that CDCs, but not PBS, recapitulated a youthful pattern of gene expression in the hearts of old animals (85.5% of genes differentially expressed). Telomeres in heart cells were longer in CDC-transplanted animals. Cardiosphere-derived cells attenuated hypertrophy; histology confirmed decreases in cardiomyocyte area and myocardial fibrosis. Cardiosphere-derived cell injection improved diastolic dysfunction compared with baseline, and lowered serum brain natriuretic peptide. In CDC-transplanted old rats, exercise capacity increased ∼20%, body weight decreased ∼30% less, and hair regrowth after shaving was more robust. Serum biomarkers of inflammation (IL-10, IL-1b, and IL-6) improved in the CDC group. In summary, young CDCs secrete exosomes which increase telomerase activity, elongate telomere length, and reduce the number of senescent human heart cells in culture.

Osteoarthritis (OA) is one of the most common causes of pain and disability in adults. There are a host of risk factors for the development of OA that include joint injury, obesity, genetic predisposition, and abnormal joint shape and alignment. However, the factor that has the greatest influence on the incidence and prevalence of OA is age. A major limitation in the management of patients with OA is the lack of any therapy that can slow the progression of the disease. The lack of any intervention that targets the disease process has resulted in a substantial increase in joint replacement surgery. Clearly, a safe, effective and less-expensive treatment that can alter the course of the disease will have a major impact on both quality of life and future health-care expenditures. The obvious question is how do we slow or stop the progression of joint damage and improve symptoms in individuals with OA.

OA is a slowly progressive disease of synovial joints characterized pathologically by focal destruction of the articular cartilage, a hypertrophic response in neighboring bone that results in osteophyte formation and subchondral sclerosis, variable degrees of synovial inflammation, a thickening of the joint capsule, and damage to soft tissue structures including ligaments and, in the knee, the meniscus. The destruction and loss of the articular cartilage is central to the development of OA and most of the research to date on aging mechanisms relevant to OA has focused on changes in the cartilage. It is important to note that joint aging and OA are not one and the same but rather aging changes can make the development of OA more likely to occur. With normal aging the cartilage appears slightly brown due to an accumulation of advanced glycation end-products and is thinner than in young adults but is otherwise smooth and intact. The accumulation of advanced glycation end-products has been found to alter the biomechanical properties of cartilage making it more "brittle" and susceptible to degeneration. In contrast, in joints affected by OA there is marked destruction and loss of the cartilage accompanied by osteophytes and subchondral bone thickening.

The destruction and loss of the articular cartilage in OA is driven by an imbalance in the production and activity of pro-inflammatory and catabolic mediators. The imbalance in catabolic and anabolic signaling results in overproduction of matrix degrading enzymes including the matrix metalloproteinases (MMPs) and aggrecanases. MMP-13 is important because of its ability to degrade type II collagen, the major structural protein in cartilage which provides the tissue's tensile strength, whereas the aggrecanases are notable for their ability to degrade aggrecan, the large proteoglycan that is responsible for the resiliency of cartilage.

Aging processes that promote an imbalance in chondrocyte signaling resulting in increased production of MMPs and aggrecanases would be central to the development and progression of OA. A focus of our research efforts, and others in the field, has been on gaining a better understanding of the basic molecular mechanisms driving this imbalance in signaling. This could be due to cellular senescence and the development of what has been termed the senescence-associated secretory phenotype. The senescence-associated secretory phenotype is characterized by increased production of many of the same cytokines, chemokines, and MMPs found in OA cartilage, suggesting that OA chondrocytes assume a senescent phenotype. More studies are needed to define the underlying mechanisms of chondrocyte senescence and to determine if removal of senescent cells using compounds that have been called "senolytics" would slow the progression of OA and be disease and/or symptom modifying.

Hallmarks of aging have been proposed, such as cellular senescence and telomere attrition, that are believed to represent key mechanisms by which aging contributes to the development of age-related conditions. One of the hallmarks is mitochondrial dysfunction which can promote age-related disorders in part through increased levels of reactive oxygen species (ROS). Age-related mitochondrial dysfunction has been suggested as a contributing factor in the development of OA. To obtain in vivo support for the hypothesis that mitochondrial dysfunction promotes the development of OA through increased levels of ROS, we evaluated the severity of naturally occurring OA in transgenic mice engineered to express human catalase targeted to the mitochondria. These mice have been shown to have reduced markers of oxidative stress with aging, accompanied by a reduction in age-related pathology and increased lifespan. Compared to age-matched wild-type controls, we found that the 18- to 33-month-old male MCAT mice had a modest but significant reduction in the severity of OA changes in knee articular cartilage.

It is thought that elevated levels of ROS, found in oxidative stress conditions, could promote age-related conditions through the disruption of physiologic signaling. In a series of studies, we have shown that oxidative stress occurs with aging in articular cartilage and this promotes an imbalance in catabolic and anabolic signaling that could play a key role in the development of OA. IGF-1 and OP-1 are key cartilage growth factors and we showed a reduced response of human articular chondrocytes to IGF-1 or the combination of IGF-1 and OP-1, resulting in reduced matrix gene expression and matrix protein synthesis. The reduced response to these growth factors appears to be due to altered cell signaling mediated by oxidative stress.

In summary, there are likely multiple factors related to aging that promote the development of age-related conditions such as OA. A central feature of OA is the imbalance in catabolic and anabolic signaling in cartilage that results in progressive matrix destruction. Our studies are providing evidence that age-related oxidative stress plays a key role in this catabolic-anabolic imbalance. Studies on the molecular mechanism are revealing excessive oxidation of key anti-oxidant systems in chondrocytes. Oxidative inactivation of anti-oxidant systems allows for rising levels of intracellular ROS that cause disruption of physiologic signaling. The failure of simple anti-oxidants to impact aging and age-related disease may be related to their inability to specifically target this disrupted signaling. Future interventions that can restore proper redox signaling in aging chondrocytes hold promise for the treatment of OA.

The accumulation of p16Ink4a-positive cells is observed in aged mice, and their eradication has been linked to certain improvements in the health state of older animals consistent with rejuvenation. Even though p16Ink4a-positive cells in vivo have been assumed to be senescent, little evidence exists to directly support this assumption. Our previous work identifying macrophage subtypes that co-express markers conventionally assigned to senescent cells (SCs), p16Ink4a/SAβG, has prompted additional interpretations of previously published experimental data regarding the role of p16Ink4a-positive cells in aging and age-related diseases.

As such, defining the exact nature of p16Ink4a-positive cells is crucial for proper development of therapeutics for the prevention and treatment of aging and age-related diseases. Today, the field of aging is focused on the development of senolytic compounds that are isolated for their ability to selectively kill SCs generated in vitro. If these cells are different from p16Ink4a-positive cells accumulating in vivo with age, this could misdirect both academic studies of senescence as a phenomenon, as well as practical efforts to develop anti-aging therapeutics. These considerations motivated our present work, which was aimed at defining the nature of p16Ink4a-positive cells found in mouse tissues in vivo and their relation to the phenomenon of cellular senescence.

What is "cellular senescence"? Currently, all definitions agree that SCs cease to proliferate. However, this parameter is not sufficient to define SCs since this is also the property of terminally differentiated cells. One apparent difference is that terminal differentiation occurs in response to various physiological stimuli, while induction of senescence almost always occurs in response to genotoxic stress. Accordingly, the onset of senescence commonly involves p53, a major universal genotoxic stress response mechanism that triggers cell cycle arrest, the first step in conversion to senescence. Another intrinsic property of the senescent phenotype is that it is not reversible through known physiological stimuli, only occurring through the acquisition of genetic mutation or epigenetic modulations. Thus, a more precise definition of SCs should include those cells that irreversibly cease to proliferate following genotoxic stress. Currently, none of the other properties of SCs that are being used for their recognition, such as p16Ink4a- or SAβG-positivity, are sufficiently specific for SCs as to be essential components of this definition.

We previously demonstrated that a significant proportion of p16Ink4a/SAβG-positive cells in the fat tissue of older mice are of hematopoietic origin, express surface markers of macrophages and are capable of phagocytosis. Here, we demonstrate that these cells appear and accumulate independently of their p53 status. Furthermore, induction of p16Ink4a/SAβG markers can be significantly modulated (in both directions) by physiological stimuli known to polarize macrophages. In recent literature, a role for p16Ink4a has been implicated in macrophage physiology with no relation to other properties of senescence. For example, p16Ink4a expression is induced during monocyte differentiation into macrophages in vitro without affecting the cell cycle, and macrophages from p16Ink4a-deficient mice are skewed towards an M2 phenotype, exhibiting defects in M1 polarization response.

In summary, we conclude that a significant proportion of p16Ink4a/SAβG-positive cells accumulating in aging mice are macrophages that acquired this phenotype as part of their physiological reprogramming towards an M2-like phenotype. This interpretation is consistent with reports that tumor-associated macrophages (TAMs), which possess also an M2 phenotype, were shown to express p16Ink4a. It is highly unlikely that senolytic compounds isolated for their ability to eradicate bona fide SCs would be equally potent and selective against cells that simply resemble SCs by two unreliable biomarkers (p16Ink4a/SAβG) yet lack the most definitive properties of senescence. However, several molecules identified with anti-SC activities, including ruxolitinib, dasatinib, and quercetin, have documented anti-inflammatory effects on macrophages that may contribute to improvements in healthspan. We believe that the assumptions made in a series of recent works - that p16Ink4a/SAβG-positive cells are SCs - needs to be carefully re-evaluated, and that the effects of anti-SC therapies on macrophages needs to be evaluated.

Importantly, our results do not overthrow the significance of the SC's role in aging or disprove the rationale for the development of senolytic compounds. Nevertheless, they do question the accuracy of interpretation of the reasons for the improvement of the health of mice following the eradication of p16Ink4a-positive cells, raising the possibility that SCs may not be the only ones implicated in age-related frailty and that other players may be involved that could require different approaches to target.

Forever Labs, a startup in Y Combinator's latest batch, is preserving adult stem cells with the aim to help you live longer and healthier. Stem cells have the potential to become any type of cell needed in the body. It's very helpful to have younger stem cells from your own body on hand should you ever need some type of medical intervention, like a bone marrow transplant as the risk of rejection is greatly reduced when the cells are yours. The founder spent the last 15 years studying stem cells. What he found is that not only do we have less of them the older we get, but they also lose their function as we age. So, he and his co-founders started looking at how to bank them while they were young.

The founder banked his cells two years ago at the age of 38. So, while he is biologically now age 40, his cells remain the age in which they were harvested - or as he calls it, "stem cell time travel." Stem cell banking isn't new. In fact, a lot of parents are now opting to store their baby's stem cells through cord blood banking. But that's for newborns. For adults, it's not so common, and there's a lot of snake oil out there.

The process involves using a patented device to collect the cells. Forever Labs can then grow and bank your cells for 2,500, plus another 250 for storage per year (or 7,000 for life). The startup is FDA-approved to bank these cells and is offering the service in seven states. What it does not have FDA approval for is the modification of those cells for rejuvenation therapy. The founders refer to what the company is doing as longevity as a service, with the goal being to eventually take your banked cells and modify them to reverse the biological clock. But that may take a few years. There are hundreds of clinical trials looking at stem cell uses right now. Forever Labs has also proposed its own clinical trial to take your stem cells and give them to your older cells.

Regular exercise is now considered an important form of treatment for heart failure, a condition in which the heart is unable to pump enough blood to meet the body's needs. The benefits of exercise range from prevention of cachexia - severe loss of weight and muscle mass - and control of arterial blood pressure to improved cardiac function, postponing a degenerative process that causes progressive heart cell death. About 70% of heart failure patients die from the condition within five years. A recent study helps to elucidate part of the mechanism whereby aerobic exercise protects the sick heart.

"Basically, we discovered that aerobic training facilitates the removal of dysfunctional mitochondria from heart cells. The removal of dysfunctional mitochondria increases the supply of ATP, the molecule that stores energy for the cell, and reduces the production of toxic molecules, such as oxygen free radicals and reactive aldehydes, an excess of which damages the cell structure." The long-term aim of the research is to identify intracellular targets that can be modulated by drugs to produce at least some of the cardiac benefits obtained by means of physical exercise. "Evidently, we don't aim to create an exercise pill, which would be impossible because exercise acts at many levels and throughout the organism, but it might be feasible for a drug to mimic or maximize the positive effect of physical activity on the heart."

In a previous study the group showed through experiments with rats that aerobic training reactivates the proteasome, an intracellular complex responsible for cleansing cells of damaged proteins. The results also showed that proteasome activity in the heart of a patient with heart failure decreases by more than 50% and that, as a result, highly reactive proteins build up in the cytoplasm, where they interact with other structures and cause heart cell death. In the recently published article the group showed that exercise also regulates the activity of another cellular cleansing mechanism, known as autophagy. "Instead of degrading isolated proteins, this system creates a vesicle, an autophagosome, around dysfunctional organelles and transports all this material at once to the lysosome, a sort of incinerator. The lysosome contains enzymes that destroy cell waste. However, we observed that autophagic flux is interrupted in the heart of a rat with heart failure and that there's a buildup of dysfunctional mitochondria."

The mitochondria may even divide to isolate the damaged part and facilitate its removal. The researchers were able to observe this by analyzing the activity of proteins related to the process of mitochondrial division. However, the system that should transport the rejects to the lysosome is unable to complete the task. When the researchers analyzed heart tissue from a rat model of heart failure, they found that the cells contained large clusters of small fragmented mitochondria. This was not observed in the group of healthy rats. These mitochondria were placed in an apparatus that measured oxygen consumption and hence assessed mitochondrial metabolism. The test confirmed that the mitochondrial respiration was not functioning properly.

"The images showed that membranes were trying to form around these small mitochondria, but the autophagosome failed to surround them completely. We concluded that they were accumulating because the removal system wasn't working. The rats were placed on the treadmill, and the dysfunctional mitochondria disappeared. The exercise restored the process of dysfunctional cardiac mitochondria removal. The benefits of exercise were abolished when we blocked autophagy pharmaceutically or genetically. Our hypothesis is that physical training modulates the expression and/or activity of one or more key proteins involved in mitophagy, or mitochondrial autophagy, thereby restoring its activity. We're now trying to confirm this hypothesis."

We previously reported that facilitating the clearance of damaged mitochondria through macroautophagy/autophagy protects against acute myocardial infarction. Here we characterized the impact of exercise, a safe strategy against cardiovascular disease, on cardiac autophagy and its contribution to mitochondrial quality control, bioenergetics and oxidative damage in a post-myocardial infarction-induced heart failure animal model.

We found that failing hearts displayed reduced autophagic flux depicted by accumulation of autophagy-related markers and loss of responsiveness to chloroquine treatment at 4 and 12 weeks after myocardial infarction. These changes were accompanied by accumulation of fragmented mitochondria with reduced O2 consumption, elevated H2O2 release and increased Ca2+-induced mitochondrial permeability transition pore opening. Of interest, disruption of autophagic flux was sufficient to decrease cardiac mitochondrial function in sham-treated animals and increase cardiomyocyte toxicity upon mitochondrial stress.

Importantly, 8 weeks of exercise training, starting 4 weeks after myocardial infarction at a time when autophagy and mitochondrial oxidative capacity were already impaired, improved cardiac autophagic flux. These changes were followed by reduced mitochondrial number:size ratio, increased mitochondrial bioenergetics and better cardiac function. Moreover, exercise training increased cardiac mitochondrial number, size and oxidative capacity without affecting autophagic flux in sham-treated animals.

Further supporting an autophagy mechanism for exercise-induced improvements of mitochondrial bioenergetics in heart failure, acute in vivo inhibition of autophagic flux was sufficient to mitigate the increased mitochondrial oxidative capacity triggered by exercise in failing hearts. Collectively, our findings uncover the potential contribution of exercise in restoring cardiac autophagy flux in heart failure, which is associated with better mitochondrial quality control, bioenergetics and cardiac function.

The immune system is made up of many different immune cell types, each with its own unique functions, to collectively protect the host against foreign pathogens. T cells comprise around 7-24% of the immune cells and around ~70% of the lymphocytes in human blood. The ability of T cells to proliferate upon antigen stimulation is crucial as it dramatically increases the number of antigen-specific T cells to aid in resolving the infection, otherwise known as clonal expansion. After the resolution of the infection, these T cells undergo apoptosis during the contraction phase to return to the steady state. However, as T cells replicate multiple times due to repeated stimulation with pathogens during a host's lifetime, they further differentiate, lose their proliferation capacity and may reach the stage of replicative senescence.

The inability of T cells to proliferate is partly due to the erosion of telomeres and the loss of telomerase activity, a phenomenon is analogous to the Hayflick Limit first characterized in fibroblasts. Besides having an impaired proliferative capacity and shorter telomere length, senescent fibroblasts also adopt a pro-inflammatory profile, whereby they could secrete pro-inflammatory cytokines into the environment and cause tissue damage by chronic inflammation. However, these features of senescence are only established in other cell types, and classical T cells may shares similar features but the signals and pathways leading to those functional hallmarks may be different. Whether cellular senescence shares common pathways across all immune cells and all mammalian cells still needs to be demonstrated.

It is not surprising that investigators are often confused with the terms senescence and exhaustion of T cells. Senescence and exhausted T cells do have some similarity in certain aspects of functionality but they are not entirely the same. Therefore, it is important to note the differences between senescence and exhaustion of T cells, as this will allow accurate interpretation of results and propose the right therapeutic approach to be used. First, the markers expressed by senescent T cells are markers such as CD57 and KLRG-1, which indicates replicative senescent. On the other hand, the markers associated with exhaustion of T cells are programmed cell death 1 (PD-1), lymphocyte activation gene 3 (LAG-3), T cell immunoglobulin mucin 3 (TIM-3) and cytotoxic T lymphocyte-associated protein 4 (CTLA-4).

Second, senescent T cells adopt a pro-inflammatory profile and are able to secrete high levels of pro-inflammatory cytokines with stimulation which is similar to the senescence associated secreting phenotype (SASP) observed in other senescent cell types. The SASP concept has been established in non-immune cells but it remains to be proven in T cells. However, as SASP cells are unable to proliferate but can produce a higher range of pro-inflammatory molecules, it is likely that senescent T cells exhibit some aspects of SASP. Exhausted T cells are unable to both proliferate and to secrete cytokine upon stimulation suggesting again that the two definitions refer to different cellular status.

Third, senescent T cells are more prevalent in the highly-differentiated phenotypes (effector memory/terminal effector) and resistant to apoptosis. Exhausted T cells on the other hand, are usually central memory/effector memory T cells that have undergone repetitive or chronic stimulation. They are programmed to undergo apoptosis as PD-1 pathway seems to strongly associate with survival. Lastly, replicative senescent seems to be irreversible whereas exhaustion is reversible. Studies have shown that blockade of PD-1 ligation is able to recover the function of cytokine secretion in T cells. "Reversing exhaustion" has been very successful in human clinical trials, raising the 5-year survival rate of different type of cancer patients in advanced cancer stages.

Senescent T cells were recently shown to regain function by inhibiting the p38 mitogen-activated protein kinase (MAPK) pathway. Restoring function of senescent T cells is very relevant in the context of human aging while restoring the function of exhausted T cells is more relevant in a pathological context (e.g., cancer immunotherapy, infectious diseases). Having clarified the differences between senescent and exhausted T cells, the markers associated with each phenotype could be co-expressed on the surface of the T cells, which means they could be both senescent and exhausted. It is not clear, however, whether senescent T cells are more susceptible to exhaustion and vice-versa.

Oxidative stress in animals is strongly correlated with aging and lifespan, as predicted by the free radical theory of aging (FRTA). Because most reactive oxygen species (ROS) are generated in the mitochondria (mROS), in close proximity to mitochondrial DNA (mtDNA) and the mitochondrial oxidative phosphorylation system, it was suggested that oxidative damage to mtDNA, mitochondrial proteins, and phospholipids is the direct cause of aging and determines lifespan. This more specific version of FRTA was named the mitochondrial free radical theory of aging. The evidence supporting mFRTA is extensive.

The mitochondrial permeability transition pore (mPTP) is an inner membrane protein complex that can be induced to form a nonselective channel. The channel exhibits several conducting states that can open for short (milliseconds) or long (seconds) periods, and with different permeabilities. Full opening of the mPTP results in increased production of mROS and release of most associated metabolites. As a result, the mitochondrial membrane potential collapses, oxidative phosphorylation and mitochondrial metabolism are inhibited, the matrix swells, and on prolonged opening the outer membrane ruptures, releasing intermembrane space proteins. Moreover, the release to the cytosol of ROS and metabolites disrupts cellular homeostasis and increases oxidative damage. Prolonged pore opening in a large number of mitochondria in the cell can lead to cell death by necrosis or similar pathways.

Frequent and extended opening of the mPTP, with its associated bursts of mROS, can overwhelm the cell's antioxidant systems resulting in extensive DNA damage. A more moderate ROS production by mitochondria may not lead to strong pro-apoptotic signals but is sufficient to trigger various mechanisms that adjust cellular processes and protect the mitochondria and the cell from damage. This level of ROS formation is mostly contained by antioxidant systems. When their capacity is exceeded, the increased oxidative stress activates the mPTP. While short, infrequent opening of the mPTP also triggers protective pathways, increasing the frequency and duration of the mPTP is associated with more persistent oxidative damage that may result in aging and even cell death.

Because it is difficult to untangle the protective effects of mROS from its deleterious effects, the concept of FRTA has not been widely accepted. Instead, a consensus is emerging in which the balance between mROS-induced protective pathways and cell damage-induced apoptotic pathways is somehow integrated in the mitochondria to determine the progression of aging and ultimately cell death. Here, we propose that these contrasting signals are integrated at the level of the mPTP, which largely determines the rate of aging and ultimately lifespan by the frequency and duration of pore openings.

The hypothesis that mPTP is the driver of aging can be considered a refinement of mFRTA as it is proposed that much of the oxidative damage to the mitochondria itself results from the activation of mPTP and that most of the effects of 'mitochondrial dysfunction' and mROS on aging and lifespan are mediated through activation of the mPTP. By controlling both the depletion of cellular NAD+ and the induction of a strong DNA damage response, mPTP can drive aging and death of postmitotic cells as well as senescence in mitotic cells. Moreover, it is likely that mPTP opening also mediates mROS-driven inflammation, because the formation of the NPLR3 inflammasome appears to depend on opening of the mPTP, and chronic activation of the mPTP (by deletion of MICU1) was found to extend the pro-inflammatory response in response to injury.

The fact lifespan can be extended experimentally in several animal models of aging, and the findings that in many cases lifespan extension appears to depend on mROS signaling are often cited as the strongest evidence against mFRTA. Evidently, in these cases, mROS initiate the mitochondria protection pathways at an early age and this leads to lifespan extension. The mitochondrial protection pathways invariably lead to inhibition of the mPTP, whether indirectly by inhibition of mROS production, increased antioxidant protection, increased mitophagy, and increased mitochondrial biogenesis, or by direct inhibition of mPTP activation. In a study of a very large number of C. elegans lifespan modulations by mutations and environmental manipulations, it was shown that lifespan correlates negatively with the frequency of 'mitoflashes' at an early adult age. If one accepts the interpretation that 'mitoflashes' signal the opening of the mPTP, it could be argued that in all these cases lifespan extension is the result of inhibition of mPTP opening in early adulthood. Metformin, the first drug approved for clinical trials for retarding the progress of human aging, was shown to inhibit the mPTP. Thus, it is likely that in most, if not all, manipulations that extend animal lifespan, the mPTP is inhibited, directly or indirectly.

In summary, we suggest that the mPTP itself is the elusive site of integration of the contrasting pro- and antiapoptotic signals that determine the rate of progression to aging. While many processes upstream of the mPTP (e.g., oxidative phosphorylation, electron transport, mROS production, mitochondrial antioxidant defense, mitophagy, mitochondrial biogenesis) are also affected by the various protection mechanisms, it is likely that these upstream processes affect aging largely through their effects on mPTP activation. There is still much to be learned about the composition and structure of the mPTP, the mechanisms that control mPTP opening, the various activation states of the mPTP, the extent and types of ions and metabolites that are released, and how the progression of aging affects these processes. The progression of aging to death does not follow a uniformly shaped curve in all animals. An animal's lifespan can be determined by the failure of one particular critical organ, by either postmitotic or mitotic cells, and differences between the control of the mPTP in different organs, and different types of cells, may account for some of the differences between species. Further studies of the control of mPTP in aging can open the door to a much better understanding of the determinants of longevity.

Researchers report encouraging preclinical results as they pursue elusive therapeutic strategies to repair scarred and poorly functioning heart tissues after cardiac injury. They inhibited a protein that helps regulate the heart's response to adrenaline. This alleviated the disease processes in mouse models of human heart failure, and in cardiac cells isolated from heart failure patients. The experimental approach focuses on the role of the proteins Gβγ and GRK2, which are involved in a signaling pathway activated by adrenaline stimulation. The adrenergic system plays a fundamental role in maintaining normal heart function. Data shows that chronic over stimulation of the system (which happens after a heart attack) prompts hypertrophy - a thickening and enlargement of the heart muscle. It also causes fibrosis, the formation of scar tissue.

In a mouse model that closely simulates the disease progression in humans after a heart attack, the researchers blocked Gβγ-GRK2 molecular signaling with an experimental small molecular inhibitor called gallein. When treatment was started one week after the initial cardiac injury, it preserved heart function and reduced tissue scarring and enlargement - essentially rescuing the animals from heart failure. The authors also reported a similar level of protection in a new genetically altered mouse model in which GRK2 is removed from a specific cell type in the heart - the cardiac fibroblast. "Regrettably, there are essentially no clinical interventions that effectively target these tissue-damaging cardiac fibroblasts. This work may provide evidence that shifts the way we think about treating heart failure."

Researchers first tested the compound gallein by administering it one week following cardiac injury in control mice with unaltered expression of GRK2. Four weeks after the initial cardiac injury, control mice showed signs of significant fibrosis and heart dysfunction, although targeted Gβγ-GRK2 inhibition with gallein offered the animals substantial cardiac functional protection. This included preservation of the heart muscle's contractile abilities and a reduction of fibrosis within the cardiac tissue. In a second group of mice, the team genetically removed the GRK2 protein shortly after cardiac injury from cardiomyocytes, the contractile/functional cells of the heart. In mice that had GRK2 specifically removed from their cardiomyocytes post-injury, gallein treatment demonstrated significant protection of heart function in the animals. This suggests a potential protective role for the drug beyond cardiomyocyte cells.

In a third group of mice, GRK2 expression was eliminated post injury from just heart fibroblast cells. These animals maintained nearly normal heart function and showed significant improvements in ejection fraction (how forcefully the heart muscle pumps blood) with no further cardiac protection provided by gallein treatment. Researchers attribute the benefits of Gβγ-GRK2 inhibition to a decrease in the pathologic activation of cardiac fibroblasts, as well as a subsequent reduction in fibrosis in the injured cardiac tissue. Taken together, these findings suggest that the improvements observed in the heart's contractile performance after injury may be the result of an overall reduced fibrotic burden.

During a heart attack, blood stops flowing into the heart; starved for oxygen, part of the heart muscle dies. The heart muscle does not regenerate; instead it replaces dead tissue with scars made of cells called fibroblasts that do not help the heart pump. The heart weakens; most people who had a severe heart attack will develop heart failure, which remains the leading cause of mortality from heart disease. A team of researchers has shown that administration of a cocktail made of transcription factors Gata4, Mef2c and Tbx5 (GMT) results in less scar tissue, or fibrosis, and up to a 50 percent increase in cardiac function in small animal models of the disease. This result was presumed to be mostly a consequence of the reprograming of heart fibroblasts into cardiomyocyte-like cells. Interestingly, the team noticed that reduced fibrosis and improved cardiac function far exceeded the extent of induced new cardiomyocyte-like cells.

"We and others had described that, in addition to inducing reprograming of fibroblasts into cardiomyocyte-like cells, the GMT cocktail also induced reduction of post-heart attack fibrosis. However, not much attention had been paid to the latter." The research team investigated in more detail how the GMT cocktail activated mechanisms that reduced fibrosis. They found the first evidence that, of the three components in the GMT cocktail, only Gata4 was able to reduce post-heart attack fibrosis and improve cardiac function in a rat model of heart attack. Further exploration of the molecular mechanism mediating this novel effect showed that administering Gata4 to rat fibroblasts in the lab resulted in reduced expression of Snail, the master gene of fibrosis. "Gata4 plays a complex role in heart regeneration: as part of the GMT cocktail, it contributes to the reprograming of fibroblasts into cardiomyocyte-like cells; we know it contributes to heart hypertrophy - the development of an enlarged heart - and now we discovered that it alone can decrease cardiac fibrosis. Others have reported that Gata4 also can suppress liver fibrosis. There is still a lot to be done before we can transfer these discoveries to the bedside, but they are important first steps."

How does the skin develop follicles and eventually sprout hair? A new study addresses this question using insights gleaned from organoids, 3D assemblies of cells possessing rudimentary skin structure and function - including the ability to grow hair. Scientists started with dissociated skin cells from a newborn mouse and then took hundreds of timelapse movies to analyze the collective cell behavior. They observed that these cells formed organoids by transitioning through six distinct phases: 1) dissociated cells; 2) aggregated cells; 3) cysts; 4) coalesced cysts; 5) layered skin; and 6) skin with follicles, which robustly produce hair after being transplanted onto the back of a host mouse. In contrast, dissociated skin cells from an adult mouse only reached phase 2 - aggregation - before stalling in their development and failing to produce hair.

To understand the forces at play, the scientists analyzed the molecular events and physical processes that drove successful organoid formation with newborn mouse cells. At various time points, they observed increased activity in genes related to: the protein collagen; the blood sugar-regulating hormone insulin; the formation of cellular sheets; the adhesion, death or differentiation of cells; and many other processes. In addition to determining which genes were active and when, the scientists also determined where in the organoid this activity took place. Next, they blocked the activity of specific genes to confirm their roles in organoid development.

By carefully studying these developmental processes, the scientists obtained a molecular "how to" guide for driving individual skin cells to self-organize into organoids that can produce hair. They then applied this "how to" guide to the stalled organoids derived from adult mouse skin cells. By providing the right molecular and genetic cues in the proper sequence, they were able to stimulate these adult organoids to continue their development and eventually produce hair. In fact, the adult organoids produced 40 percent as much hair as the newborn organoids - a significant improvement. "Normally, many aging individuals do not grow hair well, because adult cells gradually lose their regenerative ability. With our new findings, we are able to make adult mouse cells produce hair again. In the future, this work can inspire a strategy for stimulating hair growth in patients."

Hair follicle stem cells are long-lived cells in the hair follicle; they are present in the skin and produce hair throughout a person's lifetime. They are quiescent, meaning they are normally inactive, but they quickly activate during a new hair cycle, which is when new hair growth occurs. The quiescence of hair follicle stem cells is regulated by many factors. In certain cases they fail to activate, which is what causes hair loss.

Researchers found that hair follicle stem cell metabolism is different from other cells of the skin. Cellular metabolism involves the breakdown of the nutrients needed for cells to divide, make energy and respond to their environment. The process of metabolism uses enzymes that alter these nutrients to produce metabolites. As hair follicle stem cells consume the nutrient glucose - a form of sugar - from the bloodstream, they process the glucose to eventually produce a metabolite called pyruvate. The cells then can either send pyruvate to their mitochondria - the part of the cell that creates energy - or can convert pyruvate into another metabolite called lactate. "Our observations about hair follicle stem cell metabolism prompted us to examine whether genetically diminishing the entry of pyruvate into the mitochondria would force hair follicle stem cells to make more lactate, and if that would activate the cells and grow hair more quickly."

The research team first blocked the production of lactate genetically in mice and showed that this prevented hair follicle stem cell activation. Conversely, they increased lactate production genetically in the mice and this accelerated hair follicle stem cell activation, increasing the hair cycle. "Before this, no one knew that increasing or decreasing the lactate would have an effect on hair follicle stem cells. Once we saw how altering lactate production in the mice influenced hair growth, it led us to look for potential drugs that could be applied to the skin and have the same effect."

The team identified two drugs that, when applied to the skin of mice, influenced hair follicle stem cells in distinct ways to promote lactate production. The first drug, called RCGD423, activates a cellular signaling pathway called JAK-Stat, which transmits information from outside the cell to the nucleus of the cell. The research showed that JAK-Stat activation leads to the increased production of lactate and this in turn drives hair follicle stem cell activation and quicker hair growth. The other drug, called UK5099, blocks pyruvate from entering the mitochondria, which forces the production of lactate in the hair follicle stem cells and accelerates hair growth in mice.

Repairing heart tissue destroyed by a heart attack or medical condition with regenerative cells or tissues usually requires invasive open-heart surgery. But now researchers have developed a technique that lets them use a small needle to inject a repair patch a little smaller than a postage stamp, without the need to open up the chest cavity. The team are experts in using polymer scaffolds to grow realistic 3D slices of human tissue in the lab. One of their creations, AngioChip, is a tiny patch of heart tissue with its own blood vessels - the heart cells even beat with a regular rhythm.

Such lab-grown tissues are already being used to test potential drug candidates for side effects, but the long-term goal is to implant them back into the body to repair damage. "If an implant requires open-heart surgery, it's not going to be widely available to patients. It's just too dangerous." After a heart attack the heart's function is reduced so much that invasive procedures like open-heart surgery usually pose more risks than potential benefits.

The researchers spent nearly three years developing a patch that could be injected, rather than implanted. After dozens of attempts, they found a design that matched the mechanical properties of the target tissue, and had the required shape-memory behaviour: as it emerges from the needle, the patch unfolds itself into a bandage-like shape. The shape-memory effect is based on physical properties, not chemical ones. This means that the unfolding process doesn't require additional injections, and won't be affected by the local conditions within the body. Over time, the scaffold will naturally break down, leaving behind the new tissue.

The next step was to seed the patch with real heart cells. After letting them grow for a few days, the team injected the patch into rats and pigs. Not only does the injected patch unfold to nearly the same size as a patch implanted by more invasive methods, the heart cells survive the procedure well. "When we saw that the lab-grown cardiac tissue was functional and not affected by the injection process, that was very exciting. Heart cells are extremely sensitive, so if we can do it with them, we can likely do it with other tissues as well." The team also showed that injecting the patch into rat hearts can improve cardiac function after a heart attack: damaged ventricles pumped more blood than they did without the patch.

Old age is the greatest risk factor for many diseases, including various types of cancer, inflammatory and neurodegenerative diseases. Traditional medical science combats one disease at a time, instead of combating the underlying biological ageing process that leads to many age-related diseases. From a whole body system's point of view, this traditional one-disease-at-a-time approach focuses on the downstream diseases, rather than considering the underlying mechanisms of age-related functional decline. This approach has limited effectiveness at present and is likely to be less effective in the future, because of an increasingly larger elderly population suffering from multiple age-related diseases. In contrast, interventions that slow down ageing and promote "healthy ageing" could in principle delay the onset of all age-related diseases, with a significant benefit to human health and a large reduction of healthcare costs.

Pharmacological interventions are arguably the most practical ageing intervention for humans, avoiding the main problems with genetic interventions (generally unethical in humans) and dietary interventions such as caloric restriction, which are difficult to maintain for the vast majority of people. For instance, there is currently great interest in discovering drugs that mimic the process of caloric restriction. In addition, promising research on pharmacological interventions on the ageing process is underway at the National Institute of Aging's Intervention Testing Program (ITP), which consists of administering drugs or chemical compounds to mice under carefully controlled conditions. However, as mouse experiments are costly and time consuming, so far only a limited number of drugs or compounds have been evaluated. Thus, using simpler model organisms for evaluating a chemical compound's effect on an organism's lifespan is appealing, and a substantially larger number of studies have administered compounds to C. elegans than other organisms. As the ITP for mice, the Caenorhabditis Intervention Testing Program has been introduced for assessing longevity variation for chemical compounds.

In this work we analyse data from the DrugAge database, which contains information about chemical compounds and their effect on the lifespan of organisms. DrugAge contains a variety of compounds with anti-ageing properties such as gerosuppressant, geroprotective and senolytic activity as well lifespan increasing properties for a specific species. In order to analyse such data, we use random forests, which is a supervised machine learning method. In this work, the random forest builds a classification model to predict whether or not a chemical compound will increase the lifespan of C. elegans, based on predictive features describing that compound. The best model produced by the random forest method was applied to a screening "external" dataset with compounds from the DGIdb database, where the effect of the compounds on an organism's lifespan is unknown. The predictions of that model were used to identify the "top hit" compounds in the DGIdb dataset, i.e. compounds with higher probabilities of increasing lifespan in C. elegans.

In conclusion we have built, using machine learning, a model to predict the longevity effects of chemical compounds in C. elegans, using the recently published DrugAge dataset. The list of top-hit compounds and their analysis contributes to our knowledge of likely longevity-extending compounds, and experimental confirmation of these predictions would be an interesting direction for future research.

While it has long been recognized that certain viruses can cause cancer by inserting oncogenes into the host cell DNA, the fact that some bacteria can also cause cancer has been slower to emerge and much harder to prove. While it is now clear that most cases of stomach cancer are linked to chronic infections with H. pylori, the mechanism remains unknown. Researchers have spent many years investigating this bacterium and the changes it induces in the cells of the stomach epithelium. In particular, they were puzzled how malignancy could be induced in an environment in which cells are rapidly replaced.

It was suspected that the answer might lie in the stem cells found at the bottom of the glands that line the inside of the stomach, which continually replace the remaining cells 'from the bottom up' - and which are the only long-lived cells in the stomach. Researchers have now overturned the established dogma to show that H. pylori not only infects the surface cells, which are about to be sloughed off, but that some of the bacteria manage to invade deep into the glands and reach the stem cell compartment. They have now found that these stem cells do indeed respond to the infection by increasing their division - producing more cells and leading to the characteristic thickening of the mucosa observed in affected patients.

The researchers used different transgenic mice to trace cells expressing particular genes, as well as all their daughter cells. The results indicate that the stomach glands contain two different stem cell populations. Both respond to a signalling molecule called Wnt, which maintains stem cell turnover in many adult tissues. Crucially, they discovered that myofibroblast cells in the connective tissue layer directly underneath the glands produce a second stem cell driver signal, R-spondin, to which the two stem cell populations responded differently. It is this signal, which turned out to control the response to H. pylori: Following infection, the signal is ramped up, silencing the more slowly cycling stem cell population and putting the faster cycling stem cell population into overdrive.

These findings substantiate the rising awareness that chronic bacterial infections are strong promoters of cancer. 'Our findings show that an infectious bacterium can increase stem cell turnover. Since H. pylori causes life-long infections, the constant increase in stem cell divisions may be enough to explain the increased risk of carcinogenesis observed. Our new findings shed light on the intriguing ways through which chronic bacterial infections disturb tissue function and provide invaluable clues on how bacteria, in general, may increase the risk of cancer'.

Angina pectoris is the most common symptom of coronary artery disease (CAD). In spite of improved medical and revascularization therapies, 5-10% of patients undergoing coronary angiography have refractory angina (RA), i.e. they are severely symptomatic while on optimal medical therapy and prior revascularization and not amenable to further revascularization procedures. Some patients with CAD develop collateral arteries, which can rescue ischaemic myocardium in spite of significant occlusions in coronary arteries and alleviate ischaemic symptoms. Therapeutic vascular growth stimulates this natural process and offers a potential new treatment for RA. However, most previous cardiovascular proangiogenic trials have been unsuccessful. This is likely due to (i) poor gene transfer efficiency in the myocardium, (ii) tested growth factors may not have been the most optimal ones, and (iii) inability to target therapy into ischaemic, but viable myocardium.

To address these challenges, we used PET perfusion imaging and an electromechanical catheter system for gene transfer to identify ischaemic, hibernating myocardium with the lowest perfusion reserve for the targeted therapy. For the first time, we also used VEGF-DΔNΔC, a new member of the VEGF family that stimulates both angiogenesis and lymphangiogenesis. In addition, because Lp(a) is associated with pro-atherogenic, pro-inflammatory, and pro-thrombotic effects, elevated plasma levels were tested as a potential new biomarker to identify patients who might benefit from the induced therapeutic vascular growth.

Thirty patients with severe RA were randomized 4:1 to VEGF-DΔNΔC therapy (AdVEGF-D group) and placebo (controls) in blocks of five patients. To select optimal sites for gene injections, the left ventricle was mapped to detect areas of viable myocardium with reduced contraction. Coronary angiography and PET imaging were used to confirm viable myocardial segments with impaired myocardial perfusion reserve (MPR). In the AdVEGF-D group, MPR of the treated area increased from 1.00 ± 0.36 at baseline to 1.31 ± 0.46 at 3 months and to 1.44 ± 0.48 at 12 months. Myocardial perfusion reserve of the reference area (myocardium with the highest MPR at baseline) showed no significant change. On the contrary, it tended to decrease by 10.7% at 3 months and 8.8% at 12 months. Myocardial perfusion reserve in the control group showed no significant change from baseline to 3 and 12 months.

A potential impact of elevated Lp(a) was also noted in the response of the RA patients to this therapy, with the most benefit in patients with the highest Lp(a) levels. This is consistent with a recent report that 50% of patients with RA have elevated Lp(a), and in whom Lp(a) lowering achieved by lipid apheresis was associated with objective evidence of myocardial blood flow improvement by MRI and significant relief of RA symptoms.