The role in longevity and healthspan of nicotinamide (NAM), the physiological precursor of NAD+, is elusive. In the present study, we aimed to characterize the effects of chronic NAM supplementation on the longevity and healthspan characteristics of male C57BL/6J mice fed a synthetic low-fat diet (SD) and the corresponding high-fat diet (HFD). Because of the liver's importance in maintaining metabolic homeostasis, we carried out histological, biochemical, and untargeted metabolomics surveys to provide an unbiased view of the metabolic impact exerted by 62-week NAM supplementation on liver from SD- and HFD-fed mice.

Protein target validation combined with metabolic flux analysis enabled the identification of the underlying mechanisms of enhanced glucose disposal and reduced oxidative stress in response to NAM supplementation. Surprisingly, our data showed that NAM depresses NAD salvage and has complex effects on sirtuin expression and activity. NAM appears to have greater beneficial effects in mice subjected to HFD than SD, which might provide important clues about its therapeutic potential in the fight against obesity and associated comorbidities.

We report that chronic NAM supplementation improves healthspan measures in mice without extending lifespan. Analysis revealed NAM-mediated improvement in glucose homeostasis in mice on a high-fat diet (HFD) that was associated with reduced hepatic steatosis and inflammation concomitant with increased glycogen deposition and flux through the pentose phosphate and glycolytic pathways. Although neither hepatic NAD+ nor NADP+ was boosted by NAM, acetylation of some SIRT1 targets was enhanced by NAM supplementation in a diet- and NAM dose-dependent manner. Collectively, our results show health improvement in NAM-supplemented HFD-fed mice in the absence of survival effects.

Nicotinamide adenine dinucleotide (NAD) is one of the most important and interesting molecules in the body. It is required for over 500 enzymatic reactions and plays key roles in the regulation of almost all major biological processes. Above all, it may allow us to lead healthier and longer lives. Much of the renewed interest in NAD over the last decade can be attributed to the sirtuins, a family of NAD+-dependent protein deacetylases (SIRT1-7). Sirtuins have been shown to play a major regulatory role in almost all cellular functions. At the physiological level, sirtuins impact inflammation, cell growth, circadian rhythm, energy metabolism, neuronal function, and stress resistance.

By modulating NAD+-sensing enzymes, NAD+ controls hundreds of key processes from energy metabolism to cell survival, rising and falling depending on food intake, exercise, and the time of day. NAD+ levels steadily decline with age, resulting in altered metabolism and increased disease susceptibility. Restoration of NAD+ levels in old or diseased animals can promote health and extend lifespan, prompting a search for safe and efficacious NAD-boosting molecules that hold the promise of increasing the body's resilience, not just to one disease, but to many, thereby extending healthy human lifespan.

Researchers have fused living and non-living cells for the first time in a way that allows them to work together, paving the way for new applications. The system encapsulates biological cells within an artificial cell. Using this, researchers can harness the natural ability of biological cells to process chemicals while protecting them from the environment. This system could lead to applications such as cellular 'batteries' powered by photosynthesis, synthesis of drugs inside the body, and biological sensors that can withstand harsh conditions.

Previous artificial cell design has involved taking parts of biological cell 'machinery' - such as enzymes that support chemical reactions - and putting them into artificial casings. The new study goes one step further and encapsulates entire cells in artificial casings. The artificial cells also contain enzymes that work in concert with the biological cell to produce new chemicals. In the proof-of-concept experiment, the artificial cell systems produced a fluorescent chemical that allowed the researchers to confirm all was working as expected.

"Biological cells can perform extremely complex functions, but can be difficult to control when trying to harness one aspect. Artificial cells can be programmed more easily but we cannot yet build in much complexity. Our new system bridges the gap between these two approaches by fusing whole biological cells with artificial ones, so that the machinery of both works in concert to produce what we need. This is a paradigm shift in thinking about the way we design artificial cells, which will help accelerate research on applications in healthcare and beyond."

In the cells of higher organisms, organelles such as the nucleus or mitochondria perform a range of complex functions necessary for life. Researchers are working to produce organelles of this kind in the laboratory, to introduce them into cells, and to control their activity in response to the presence of external factors (e.g. change in pH values or reductive conditions). These cellular implants could, for example, carry enzymes able to convert a pharmaceutical ingredient into the active substance and release it "on demand" under specific conditions. Administering drugs in this way could considerably reduce both the amounts used and the side effects. It would allow treatment to be delivered only when required by changes associated with pathological conditions (e.g., a tumor).

Now, researchers have succeeded in integrating artificial organelles into the cells of living zebrafish embryos. The artificial organelles are based on tiny capsules that form spontaneously in solution from polymers and can enclose various macromolecules such as enzymes. The artificial organelles presented here contained a peroxidase enzyme that only begins to act when specific molecules penetrate the wall of the capsules and support the enzymatic reaction. To control the passage of substances, the researchers incorporated chemically modified natural membrane proteins into the wall of the capsules. These act as gates that open according to the glutathione concentration in the cell. At a low glutathione value, the pore of the membrane proteins are "closed" - that is, no substances can pass. If the glutathione concentration rises above a certain threshold, the protein gate opens and substances from outside can pass through the pore into the cavity of the capsule. There, they are converted by the enzyme inside and the product of the reaction can leave the capsule through the open gate.

The researchers chose zebrafish embryos because their transparent bodies allow excellent tracking of the cellular implants under a microscope when they are marked with a fluorescent dye. After the artificial organelles were injected, they were "eaten" by macrophages and therefore made their way into the organism. The researchers were then able to show that the peroxidase enzyme trapped inside the artificial organelle was activated when hydrogen peroxide produced by the macrophages entered through the protein gates.

Researchers have found that preventing the early infiltration of CCR2+ macrophages into the heart, after experimental pressure overload in a mouse model, significantly lessened the heart's enlargement and reduced pumping ability that leads to later heart failure. Thus, this infiltration is a required step in the path toward heart failure. Macrophages are immune cells that engulf and remove damaged or dead cells in response to tissue injury or infection. They also may present antigens to other immune cell types. The most common forms of pressure overload are aortic stenosis - a narrowing of the aortic valve of the heart that forces the heart muscle to overwork - and high blood pressure.

The researchers used two different methods to prevent early macrophage infiltration - an inhibitor of the macrophage cell-surface CCR2 chemokine receptor, and an antibody that selectively removes CCR2+ macrophages. Migrating macrophages use the CCR2 receptor to home in on damaged tissues in the body that are releasing chemokines. Preventing early macrophage infiltration may offer a therapeutic target in human disease. Researchers had previously known that pressure-overload heart failure is associated with inflammation caused by activated T-cells. The present study showed the link between infiltrating macrophages and the T-cell response during pressure overload of the heart.

One week after inducing pressure load, that the heart showed increased expression of three attractant chemokines that are able to bind to the CCR2 receptor on macrophages. The researchers also found an increased number of monocytes with the cell-surface markers Ly6C and CCR2 circulating in the blood, and they saw an eightfold increase in CCR2+ macrophages infiltrating into the heart. Those macrophages are derived from the circulating monocytes. Thus increased circulating monocytes might serve as an easily measurable biomarker that reflects cardiac tissue CCR2+ macrophage expansion. The circulating monocytes - along with other clinical, imaging and biochemical biomarkers - could guide patient selection for a prospective clinical trial to find out whether modulating CCR2 macrophages in humans with pressure-overload hypertrophy will delay or prevent later transition to heart failure.

Inflammation is a hallmark of chronic heart failure (HF) initially triggered by nonimmune modes of cardiac injury, such as myocardial infarction, genetic mutations, and mechanical stress (e.g., pressure overload). Moreover, the systemic and myocardial immune cell profiles underlying the inflammatory response in the various etiologies of HF are of considerable importance for disease progression. For example, in chronic ischemic HF, expanded populations of both innate immune cells (e.g., macrophages) and T cells in the heart promote tissue injury and pathological remodeling. Chronic nonischemic HF due to pressure overload is characterized by CD4+ T-cell activation, which has been shown to play a critical role in promoting adverse cardiac remodeling. We recently demonstrated that during cardiac pressure overload, proinflammatory macrophage expansion in the heart occurs early, before sustained systolic dysfunction, but resolves during the chronic stage.

Importantly, although pressure-overload HF is characterized by T-cell activation, prior work also indicates that such activation is dependent on antigen presentation, because the progression of HF is ameliorated upon blockade of T-cell costimulatory molecules on antigen presenting cells (APCs). The requirement for specific antigen recognition implies an essential pathogenetic role for macrophages and other APCs, although their specific function in the development of pressure-overload HF remains poorly defined. Recent studies have characterized cardiac macrophage populations in the heart with disparate functions, including tissue-resident, embryonically derived macrophages and infiltrating monocyte-derived macrophages. The normal heart is seeded with resident macrophages that are not replenished by circulating monocytes under steady-state conditions. Resident cardiac macrophages are minimally inflammatory and promote angiogenesis and tissue repair. However, cardiac injury and aging stimulate the infiltration of monocyte-derived macrophages that are proinflammatory, promote tissue injury, and the death and substitution of resident cells.

Monocyte-derived macrophages can be distinguished by the expression of C-C chemokine receptor 2 (CCR2). Although we and others have documented expansion of cardiac macrophages during the early phase of pressure overload, it is unknown whether the macrophages are monocyte-derived, and whether these cells play an important role in subsequent T-cell recruitment and activation, and associated long-term adverse cardiac remodeling. Accordingly, here we tested the hypothesis that CCR2+ monocyte-derived macrophages infiltrate the heart early following pressure-overload-induced hemodynamic stress, and that this macrophage population plays a critical role in the activation of T cells and the ensuing transition to failure.

"The benefits of methionine restriction in rodents are fascinating because they resemble those of calorie restriction, but without enforced restriction of food intake." Previous work has shown that a methionine-restricted diet increases production of the gas, hydrogen sulfide, made in our cells where it functions in myriad beneficial ways. One of these is to promote the growth of new blood vessels from endothelial cells - a process known as angiogenesis. So the researchers decided to test whether there was a direct connection between a methionine-restricted diet and angiogenesis.

They fed mice a synthetic diet containing limited methionine and lacking the only other sulfur-containing amino acid, cysteine. These two amino acids are found in high amounts in protein-rich foods. After two months, the diet-restricted mice had increased the number of small blood vessels, or capillaries, in skeletal muscles compared to mice fed a control diet. The authors identified a requirement for the amino acid-sensing kinase GCN2 and the transcription factor ATF4 in angiogenesis triggered by methionine restriction.

Researchers found that a decline in the blood flow to tissues and organs with age can be reversed by restoring molecules that improved exercise capacity and physical endurance in mice. The researchers found that the two molecules could replicate the benefits of exercise, a finding that could lead to better athletic performance, improved mobility in the elderly and the prevention of aging-associated diseases like cardiac arrest, stroke, liver failure, and dementia.

For the first time, the study showed that as levels of the metabolite NAD+ decline with age, the body's capacity to exercise decreases because of fewer blood vessels and reduced blood flow. By treating mice with the NAD+ booster NMN and increasing levels of hydrogen sulphide, physical endurance was extended in mice by over 60%. This was the case in both young and old mice. "With exercise, the effect is even more dramatic. We saw 32-month-old mice, roughly equivalent to a 90-year-old human - receiving the combination of molecules for four weeks ran, on average, twice as far as untreated mice. Mice treated only with NMN alone ran 1.6 times further than untreated mice." The scientists identified that this mechanism is due to a restoration of capillary formation in muscle by stimulating the activity of the protein SIRT1, a key regulator of blood vessel formation.

As we age, our tiniest blood vessels wither and die, causing reduced blood flow and compromised oxygenation of organs and tissues. Vascular aging is responsible for a constellation of disorders, such as cardiac and neurologic conditions, muscle loss, impaired wound healing and overall frailty, among others. Scientists have known that loss of blood flow to organs and tissues leads to the build-up of toxins and low oxygen levels. The endothelial cells, which line blood vessels, are essential for the health and growth of blood vessels that supply oxygen-rich and nutrient-loaded blood to organs and tissues. But as these endothelial cells age, blood vessels atrophy, new blood vessels fail to form and blood flow to most parts of the body gradually diminishes. This dynamic is particularly striking in muscles, which are heavily vascularized and rely on robust blood supply to function.

Muscles begin to shrivel and grow weaker with age, a condition known as sarcopenia. The process can be slowed down with regular exercise, but gradually even exercise becomes less effective at holding off this weakening. Researchers wondered: What precisely curtails the blood flow and precipitates this unavoidable decline? Why does even exercise lose its protective power to sustain muscle vitality? Is this process reversible? In a series of experiments, the team found that reduced blood flow develops as endothelial cells start to lose a critical protein known as sirtuin1, or SIRT1. Previous studies have shown that SIRT1 delays aging and extends life in yeast and mice. SIRT1 loss is, in turn, precipitated by the loss of NAD+, a key regulator of protein interactions and DNA repair that was identified more than a century ago. Previous research has shown that NAD+, which also declines with age, boosts the activity of SIRT1.

Researchers decided to explore the role of sirtuins in endothelial cells, which line the inside of blood vessels. To do that, they deleted the gene for SIRT1, which encodes the major mammalian sirtuin, in endothelial cells of mice. They found that at 6 months of age, these mice had reduced capillary density and could run only half as far as normal 6-month-old mice.

The researchers then decided to see what would happen if they boosted sirtuin levels in normal mice as they aged. They treated the mice with a compound called NMN, which is a precursor to NAD, a coenzyme that activates SIRT1. NAD levels normally drop as animals age, which is believed to be caused by a combination of reduced NAD production and faster NAD degradation. After 18-month-old mice were treated with NMN for two months, their capillary density was restored to levels typically seen in young mice, and they experienced a 56 to 80 percent improvement in endurance. Beneficial effects were also seen in mice up to 32 months of age (comparable to humans in their 80s).

The researchers also found that SIRT1 activity in endothelial cells is critical for the beneficial effects of exercise in young mice. In mice, exercise generally stimulates growth of new blood vessels and boosts muscle mass. However, when the researchers knocked out SIRT1 in endothelial cells of 10-month-old mice, then put them on a four-week treadmill running program, they found that the exercise did not produce the same gains seen in normal 10-month-old mice on the same training plan. If validated in humans, the findings would suggest that boosting sirtuin levels may help older people retain their muscle mass with exercise. Studies in humans have shown that age-related muscle loss can be partially staved off with exercise, especially weight training.

In aging societies, the discrepancy between the total lifespan and the healthy lifespan is becoming a major problem. Chronological aging is associated with a higher prevalence of age-related diseases, including heart failure, diabetes, and atherosclerotic disorders with or without various comorbidities, resulting in impairment of the quality of life by limitation of normal activities. Thus, aging is associated with several undesirable processes. The mechanisms of aging and age-associated disorders are complex, and thus cannot be comprehended by a simple approach. However, recent studies have indicated a pivotal role of cellular senescence in the progression of age-related disorders.

p53 signaling is thought to have a central role in cellular senescence. Somatic cells have a finite lifespan and eventually enter a state of irreversible growth arrest termed "replicative senescence." Telomeres are repetitive nucleotide sequences located at the terminals of mammalian chromosomes that undergo incomplete replication during cell division, resulting in telomere shortening. Because telomeres are essential for chromosomal stability and DNA replication, DNA damage is recognized when telomere shortening exceeds the physiological range and this triggers cellular senescence, mainly via the p53 or p16 signaling pathways. "Stress-induced premature senescence" is another type of cellular senescence that is triggered by various stress signals. It is also mediated via the p53 or p16 signaling pathways.

It was reported that p53 is increased in the failing heart, in aged vessels, and in the visceral fat of patients with obesity or heart failure. Studies have indicated a pathological role of p53-induced cellular senescence in aging and age-related disorders, including heart failure, atherosclerotic disease, obesity, and diabetes. However, there is controversy about the role of p53 in aging and age-related diseases. In some settings, p53 signaling has been shown to have a beneficial effect by suppression of aging; various reports suggest that the p53/p21 signaling pathways regulate cellular senescence in a context-dependent manner.

Interestingly, it was recently reported that elimination of senescent cells by genetic manipulation inhibited age-related degenerative changes in several organs of mice, such as the heart and kidneys. Other studies have identified several pharmacological agents that selectively damage and remove senescent cells, and these compounds have been described as "senolytic agents". For example, an inhibitor of anti-apoptotic proteins (ABT263) depletes senescent bone marrow hematopoietic stem cells and senescent muscle cells in a chronological aging model, leading to rejuvenation of these tissues. Studies have shown that senescent cells damage their local environment and promote tissue remodeling in age-related disorders, suggesting that inhibition of cellular senescence and/or elimination of senescent cells could be potential next generation therapies for diseases associated with aging.

Reactive oxygen species and chronic low-grade sterile inflammation are two major contributors to the progression of age-related vascular dysfunction. Senescent cells accumulate in the arteries with aging irrespective of whether or not a person has age-related vascular disorders. Along with aging, vascular tissues of rodents and humans show elevation of the levels of p16, p21, phosphorylated p38, and double-stranded DNA breaks, in association with high SA-β Gal activity. It was reported that expression of p53 and p21 is increased in the arteries of elderly persons, together with structural breakdown of telomeres known as telomere uncapping.

Endothelial cells and vascular smooth muscle cells (VSMCs) from patients with abdominal aortic aneurysm (AAA) have the phenotypic features commonly observed in senescent cells. Hypertension is an established risk factor for atherosclerotic diseases, and it was reported that binding of p53 to the p21 promoter is increased in the arteries of hypertensive patients. While telomere length is comparable between patients with hypertension and controls, telomere uncapping is 2-fold higher in hypertensive patients. A murine model of genomic instability demonstrated senescence of endothelial cells and VSMCs in the aorta, along with impaired vasodilation, increased vascular stiffness, and hypertension.

Endothelial cells are critically important for maintaining vascular homeostasis and are involved in various biological functions, including angiogenesis, blood pressure regulation, coagulation, and systemic metabolism. Aged endothelial cells develop a dysfunctional phenotype that is characterized by reduced proliferation and migration, decreased expression of angiogenic molecules, and low production of nitric oxide (NO), which is synthetized by NO synthase (NOS) and mediates vasodilatation. Senescent endothelial cells have been found in atherosclerotic plaque. An autopsy study of patients with ischemic heart disease revealed that SA-β-gal activity is increased in the coronary arteries. In the coronary arteries, SA-β-gal activity is high in cells located on the luminal surface (probably endothelial cells). Both endothelial nitric oxide synthase (eNOS) and NO activity are reduced in these cells compared to young cells.

One of the problems related to an increase of senescent cells is development of the senescence-associated secretory phenotype, which is characterized by production of pro-inflammatory cytokines with a causal role in tissue remodeling. In human arterial endothelial cells with replicative senescence, levels of H2O2 and O2- are high and NO production is reduced. High ROS levels in senescent endothelial cells are thought to accelerate senescence. Aging is reported to be linked with increased circulating levels of pro-inflammatory cytokines, such as interleukin-6, tumor necrosis factor alpha, and monocyte chemoattractant protein-1. It is highly possible that accumulation of senescent endothelial cells in the arteries of elderly persons induces chronic sterile inflammation and vascular remodeling, increasing susceptibility to atherosclerotic diseases.

In conclusion, senescence of vascular cells promotes the development of age-related disorders, including heart failure, diabetes, and atherosclerotic diseases, while suppression of vascular cell senescence ameliorates phenotypic features of aging in various models. Recent findings have indicated that specific depletion of senescent cells reverses age-related changes. Although the biological networks contributing to maintenance of homeostasis are extremely complex, it seems reasonable to explore senolytic agents that can act on specific cellular components or tissues. Several clinical trials of senolytic agents are currently ongoing.

Survivors of hematopoietic stem cell transplantation are prone to premature aging, and one pilot clinical study is designed to test whether dasatinib and quercetin (D + Q) can suppress aging in these patients (NCT02652052). Another clinical trial is testing whether D + Q reduces pro-inflammatory cells obtained by skin biopsy in patients with idiopathic pulmonary fibrosis (NCT02874989). Furthermore, a clinical trial is ongoing to determine whether D + Q can reduce the senescent cell burden and frailty in patients with chronic kidney disease, as well as improving the function of adipose tissue-derived mesenchymal stem cells (NCT02848131). So far, only D + Q has been assessed in the clinical setting, and none of the current clinical trials are testing whether senolytic agents can inhibit cardiovascular disorders. However, depletion of senescent cells was demonstrated to suppress pathological progression of atherosclerotic plaque in rodents, suggesting that senolytic agents could become a next generation therapy for cardiovascular disorders.

A new study suggests that at least part of the gains in life expectancy over recent decades may be due to a change in the rate of biological aging, rather than simply keeping ailing people alive. "This is the first evidence we have of delayed aging among a national sample of Americans. A deceleration of the human aging process, whether accomplished through environment or biomedical intervention, would push the timing of aging-related disease and disability incidence closer to the end of life. Life extension without changing the aging rate will have detrimental implications. Medical care costs will rise, as people spend a higher proportion of their lives with disease and disability. However, lifespan extension accomplished through a deceleration of the aging process will lead to lower healthcare expenditures, higher productivity, and greater well-being."

Using data from the National Health and Nutrition Examination Survey (NHANES) III (1988-19994) and NHANES IV (2007-2010), the researchers examined how biological age, relative to chronological age, changed in the U.S. while considering the contributions of health behaviors. Biological age was calculated using several indicators for metabolism, inflammation, and organ function, including levels of hemoglobin, total cholesterol, creatinine, alkaline phosphatase, albumin, and C-reactive protein in blood as well as blood pressure and breath capacity data.

While all age groups experienced some decrease in biological age, the results suggest that not all people may be faring the same. Older adults experienced the greatest decreases in biological age, and men experienced greater declines in biological age than females; these differences were partially explained by changes in smoking, obesity, and medication use. Slowing the pace of aging, along with increasing life expectancy, has important social and economic implications. The study suggests that modifying health behaviors and using prescription medications does indeed have significant impact on the health of the population.

Two new studies describe how TREM2, a receptor found on immune cells in the brain, interacts with toxic amyloid beta proteins to restore neurological function. The research, performed on mouse models of Alzheimer's disease, suggests boosting TREM2 levels in the brain may prevent or reduce the severity of neurodegenerative disorders including Alzheimer's disease. "Our first paper identifies how amyloid beta binds to TREM2, which activates neural immune cells called microglia to degrade amyloid beta, possibly slowing Alzheimer's disease pathogenesis. The second study shows that increasing TREM2 levels renders microglia more responsive and reduces Alzheimer's disease symptoms."

One of the hallmarks of Alzheimer's disease is the accumulation of amyloid plaques that form between neurons and interfere with brain function. Many drug companies have been working for years to reduce amyloid beta production to thwart Alzheimer's - but with minimal success. "TREM2 offers a potential new strategy. Researchers have known that mutations in TREM2 significantly increase Alzheimer's risk, indicating a fundamental role for this particular receptor in protecting the brain. This new research reveals specific details about how TREM2 works, and supports future therapeutic strategies to strengthen the link between amyloid beta and TREM2, as well as increasing TREM2 levels in the brain to protect against pathological features of the disease."

The first study showed that TREM2 binds quite specifically to amyloid beta. In particular, it connects with amyloid beta oligomers (proteins that bind together to form a polymer), which are the protein's most toxic configuration. Without TREM2, microglia were much less successful at binding to, and clearing out, amyloid beta. Further investigation showed that removing TREM2 downregulated microglial potassium ion channels, impairing the electrical currents associated with the activation of these immune cells. In addition, TREM2 turned on a number of mechanisms associated with the amyloid beta response in microglia.

In the second study researchers added TREM2 to a mouse model with aggressive Alzheimer's disease. They found that the added TREM2 signaling stopped disease progression and even restored cognitive function. As they learn more about how TREM2 modulates the amyloid signals that put microglia to work, the researchers have their work cut out for them. "It could be beneficial in early stages to activate microglia to eat up amyloid beta, but if you over-activate them, they may release an overabundance of cytokines (causing extensive inflammation) damaging healthy synaptic junctions as a side-effect from overactivation." Still, the ability to use the brain's existing immune mechanisms to clear amyloid offers intriguing possibilities.

Doctors say a stem cell transplant could be a "game changer" for many patients with multiple sclerosis (MS). Results from an international trial show that it was able to stop the disease and improve symptoms. It involves wiping out a patient's immune system using cancer drugs and then rebooting it with a stem cell transplant. Just over 100 patients took part in the trial, in hospitals in Chicago, Sheffield, Uppsala in Sweden and Sao Paolo in Brazil. They all had relapsing remitting MS - where attacks or relapses are followed by periods of remission. The interim results were released at the annual meeting of the European Society for Bone and Marrow Transplantation in Lisbon.

The patients received either haematopoietic stem cell transplantation (HSCT) or drug treatment. After one year, only one relapse occurred among the stem cell group compared with 39 in the drug group. After an average follow-up of three years, the transplants had failed in three out of 52 patients (6%), compared with 30 of 50 (60%) in the control group. Those in the transplant group experienced a reduction in disability, whereas symptoms worsened in the drug group. "The data is stunningly in favour of transplant against the best available drugs - the neurological community has been sceptical about this treatment, but these results will change that."

The treatment uses chemotherapy to destroy the faulty immune system. Stem cells taken from the patient's blood and bone marrow are then re-infused. These are unaffected by MS and they rebuild the immune system. "We are thrilled with the results - they are a game changer for patients with drug resistant and disabling multiple sclerosis. This is an interim analysis, but with that caveat, this is the best result I have seen in any trial for multiple sclerosis." The transplant costs around 40,000, about the same as the annual price of some MS drugs. Doctors stress it is not suitable for all MS patients and the process can be gruelling, involving chemotherapy and a few weeks in isolation in hospital.

Human embryonic stem cells (ESCs) represent a promising source for cellular replacement therapies owing to their availability, pluripotency, and unlimited self-renewal capacity. However, they also carry risks of neoplastic change, uncontrolled proliferation, and differentiation to inappropriate cell types. The eye is advantageous in investigating hESC-based cell therapy as it is accessible and confined, and the transplanted cells can be monitored directly in vivo, with the possibility of being removed or destroyed if there is evidence of neoplastic change. Furthermore, long-term immunosuppression can be delivered locally.

Late age-related macular degeneration (AMD) is characterized by irreversible cell loss, initially of retinal pigment epithelium (RPE) cells and subsequently of neuroretinal and choroidal cells, and thus may be amenable to hESC-based cell therapy. Suspensions of hESC-derived RPE (hESC-RPE) cells have been transplanted in human subjects with dry AMD and Stargardt's disease, but the extent of cell survival and restoration of vision remains ambiguous.

We developed a therapeutic, biocompatible hESC-RPE monolayer on a coated synthetic membrane, herein termed a 'patch', for transplantation in wet and early-stage dry AMD. The choice of membrane material and its preparation, including the human vitronectin coating, has not been described previously to our knowledge. In contrast to RPE suspensions, cells on the patch are delivered fully differentiated, polarized, and with the tight junction barrier formed, that is, in a form close to their native configuration. The synthetic membrane allows the patch to be handled easily and robustly. The main disadvantage of the patch is that it requires a purpose-built delivery tool and a more complicated surgery compared to cell suspensions, and the use of hESCs may require immunosuppression, unlike an autologous cell source.

The clinical trial was designed as a phase 1, open-label, safety and feasibility study of implantation of an hESC-RPE patch in two subjects with acute wet AMD and recent rapid vision decline. For safety reasons and to obtain an early efficacy signal, the trial involved patients with severe wet AMD only, although we aim to study the RPE patch in early dry AMD in the future. We reported three serious adverse events to the regulator. These were exposure of the suture of the fluocinolone implant used for immunosuppression, a retinal detachment, and worsening of diabetes following oral prednisolone. All three incidents required readmission to the hospital, with the first two incidents requiring further surgery and the third being treated medically. The three incidents were treated successfully. Both patients achieved an improvement in best-corrected visual acuity of more than 15 letters at 12 months after transplantation.

Although 12 months is sufficient to begin to describe cell survival and clinical outcomes, it is early in terms of safety monitoring, especially for late teratoma formation. The patients will be followed for five years after surgery. These two early cases are also instructive as they show an encouraging outcome despite very advanced disease, which increases the complexity of surgery and involves more damaged neuroretina.

Arteries in young, healthy humans and other mammals stretch easily because they contain a protein called elastin. Elastin is produced only during development, however, and is slowly lost with aging. Stiff arteries contribute to development of high blood pressure and significantly increase the risk of sudden death, stroke, myocardial infarction, and cognitive decline. "We know that genetic conditions, such as Williams-Beuren Syndrome (WS) and supravalvar aortic stenosis (SVAS), lead to abnormally low levels of elastin in developing arteries. As a result, children with WS or SVAS have stiff, narrow arteries and high blood pressure. Like older adults, they are also at increased risk of sudden death and stroke. We therefore tested whether a medicine called minoxidil would not only reduce blood pressure but also would help relax arteries and increase their diameter, thus improving organ perfusion."

Minoxidil is perhaps best known for its potential to improve hair growth when applied to the skin. In a different formulation, minoxidil is sometimes prescribed orally for high blood pressure that has not responded to other medications. Earlier studies have suggested that minoxidil may increase elastin deposition even in mature tissues. The research team conducted the work in experimental models of hypertension and chronic vascular stiffness associated with WS and SVAS. They used ultrasound imaging and magnetic resonance imaging-based arterial spin labeling to gauge minoxidil's impact on vessel mechanics, carotid and cerebral blood flow, and gene expression.

"Minoxidil not only lowered blood pressure, but also increased arterial diameter and restored carotid and cerebral blood flow. Minoxidil also reduced functional arterial stiffness and increased arterial elastin content. Equally important, these beneficial changes persisted weeks after the drug was no longer in the bloodstream. The sustained improvements and the increased elastin gene expression suggest that minoxidil treatment may help remodel stiff arteries. Such remodeling may benefit humans whose elastin insufficiency is due to either advanced age or genetic conditions."

Wealthy people usually donate money towards research into and treatment of cancer, Alzheimer's disease, and other diseases. Why did you decide to donate Ethereum to the fight against aging?

The first reason is just because there are many other people who donate to fight against cancer and other specific diseases, which, of course, is very important and necessary. The second reason is that there is strong scientific evidence that aging is the root of the most serious diseases.

It turns out that if you slow down aging or even reverse it, you can save people from serious illnesses such as malignant tumors, stroke, and Alzheimer's disease.

Exactly. After all, if you do not prevent these diseases by eliminating aging, you will have to provide treatment to people who are already sick and suffering and whose quality of life is worsening, and the economy will be under enormous pressure because the treatment is often expensive, caregiving is needed, etc. These problems could be avoided. Studies of aging are very important right now, yet there are still very few people who invest money in this field, unfortunately.

Why do you think that is so?

Most people simply do not know or do not believe that aging can be successfully manipulated. However, I have read Ending Aging by Dr. Aubrey de Grey, I'm interested in scientific discoveries, and I see that this is plausible. Researchers can already extend the life of laboratory animals significantly, and it is necessary to refine these technologies in order to transfer them to humans. And research and full-scale clinical trials of anti-aging therapies in humans requires money.

Do you have plans to continue supporting research projects on aging and life extension, or is your current contribution of 2.4 million likely to be all?

Of course I'm ready to invest more into it. However, right now, I am mostly investigating what the scientists are working on, what the most promising directions are, and what else should be supported.

What, in your opinion, is the main problem currently hampering the fight against aging on Earth?

There is not enough public support. Huge resources, as I said, are invested in research and treatment of single diseases, but the problem is that if we focus only on specific diseases, this will only slightly improve the lives of people who are already chronically sick. Only a few years will be added to their lives.

Parkinson's disease (PD) and Lewy body dementia (LBD), behind Alzheimer's disease (AD), are the most common neurodegenerative disorders with no effective therapies targeting the cause of disease. The pathological hallmarks of PD are cytoplasmic inclusions called Lewy bodies (LB), comprised primarily of α-synuclein, along with hyperphosphorylated tau and other sequestered proteins, in dopaminergic neurons. However, the importance of LB to the neurotoxicity in disease has been questioned. A number of studies have shown that oligomeric α-synuclein is the toxic species, rather than fibrils comprising LBs, and that α-synuclein oligomers may be the most effective therapeutic target.

In spite of the clear prevalence of α-synuclein pathology in disease, one of the greatest genetic risk factors for PD is tau, the role of which is understudied and poorly understood. Phosphorylated tau aggregates have been reported in numerous synucleinopathy mouse models, suggesting a possible synergistic interaction between α-synuclein and tau in mediating neurodegeneration in PD, as α-synuclein may increase tau aggregation and tau may have a similar effect on α-synuclein. While neurofibrillary tangles (NFTs) characterize tauopathies and are not correlative of synucleinopathies, recent studies suggest that intermediate forms of tau - tau oligomers - that form prior to or independently of NFTs, are the true toxic species in disease and the optimum targets for anti-tau therapies.

We have evaluated the efficacy of targeting the toxic, oligomeric form of tau protein by passive immunotherapy in a mouse model of synucleinopathy. We treated seven-month-old mice overexpressing mutated α-synuclein (A53T mice) with tau oligomer-specific monoclonal antibody (TOMA) and a control antibody and assessed both behavioral and pathological phenotypes. We found that A53T mice treated with TOMA were protected from cognitive and motor deficits two weeks after a single injection. Levels of toxic tau oligomers were specifically decreased in the brains of TOMA-treated mice. Tau oligomer depletion also protected against dopamine and synaptic protein loss. These results indicate that targeting tau oligomers is beneficial for a mouse model of synucleinopathy and may be a viable therapeutic strategy for treating diseases in which tau and α-synuclein have a synergistic toxicity.

An international team of longevity and deep learning experts working on the crowdfunded non-profit MouseAge project announce the launch of the MouseAge mobile application on the iOS platform to enable a community of researchers to contribute to the data collection and research. The MouseAge team is working on an exciting crowd-funded and crowd-sourced research project intended to develop the proof of concept for the deep learned photographic aging clock in mice.

Development of a reliable biomarker of aging based on photographic images of mice has the potential to accelerate aging research and help identify new interventions that extend lifespan. We would like to address this need while engaging the broader research community, with the goal of offering a simple, freely available tool to anybody working with mice. The group recently ran a successful crowdfunding campaign and developed a specialized mobile app called MouseAge. The app allows the scientists to take pictures of mice of different age and short videos that will be used for training of the deep neural networks.

Even though there is a great degree of risk with the project and it might not be possible to develop the most accurate predictor of age using the many body parts of a large number of mice, in the case the effort is successful, the team plans to make the results public and publish a research paper describing the effort. Scientists working with C57BL/6 mice are invited to contribute images to the project. A collaboration would entail downloading the app and taking pictures of 200 normal aging mice. Qualified researchers actively contributing to the project are expected to be co-authors on the research paper in the case of a successful project completion.

Years ago, researchers noted that people with Alzheimer's disease have high levels of tau in the cerebrospinal fluid, which surrounds their brain and spinal cord. Tau - in the tangled form or not - is normally kept inside cells, so the presence of the protein in extracellular fluid was surprising. As Alzheimer's disease causes widespread death of brain cells, researchers presumed the excess tau on the outside of cells was a byproduct of dying neurons releasing their proteins as they broke apart and perished. But it was also possible that neurons make and release more tau during the disease.

In order to find the source of the surplus tau, researchers decided to measure how tau was produced and cleared from human brain cells. The researchers applied a technique known as Stable Isotope Labeling Kinetics (SILK). The technique tracks how fast proteins are synthesized, released and cleared, and can measure production and clearance in models of neurons in the lab and also directly in people in the human central nervous system. Using SILK, the researchers found that tau proteins consistently appeared after a three-day delay in human neurons in a laboratory dish. The timing suggests that tau release is an active process, unrelated to dying neurons.

Further, by studying 24 people, some of whom exhibited amyloid plaques and mild Alzheimer's symptoms, they found a direct correlation between the amount of amyloid in a person's brain and the amount of tau produced in the brain. Whether a person has symptoms of Alzheimer's disease or not, if there are amyloid plaques, there is increased production of this soluble tau. The findings are a step toward understanding how the two key proteins in Alzheimer's disease - amyloid and tau - interact with each other. "We knew that people who had plaques typically had elevated levels of soluble tau. What we didn't know was why. This explains the why: The presence of amyloid increases the production of tau."

For the past 40 years, aging research has focused on the mechanisms underlying the beneficial health impact of a sustained reduction in caloric intake below usual levels, while maintaining adequate intake of essential nutrients. Observations in a variety of laboratory animals indicate that calorie restriction (CR), beginning early or in mid-life and sustained for a substantial portion of the lifespan, increases longevity in a wide variety of, but not all, species. While the field of CR research eagerly awaits final lifespan data from the two remaining colonies of CR primates, despite differences in study designs, current data support the observation that sustained CR extends life without chronic disease and promotes a more youthful physical and mental functionality. In terms of CR in humans, few controlled clinical trials exist.

A variety of mechanisms have been proposed as mediators of the effects of CR on lifespan. An old but arguably a prevailing theory supporting lifespan extension with CR is a hybrid between two long-standing hypotheses of aging: the "rate of living" and the "oxidative damage" theories of aging. There are data from studies in rodents, non-human primates, and humans indicating that CR results in a decrease in metabolic rate that is greater than that expected on the basis of loss of tissue mass. This phenomenon, referred to as metabolic adaptation, was associated with less oxidative damage to DNA in our 6-month pilot study of CR in humans. The CR field has also focused on the ability for CR to attenuate age-related changes in physiological and endocrine factors that are known to change with age, such as core body temperature, plasma insulin, DHEAS, and thyroid hormones, as well as endocrine mediators of metabolic slowing such as plasma leptin.

Phase 1 CALERIE or the Comprehensive Assessment of the Long-Term Effects of Reducing Intake of Energy studies were the first randomized controlled trials to test the metabolic effects of CR in non-obese humans. Then, the phase 2 CALERIE study, a 2-year 25% CR prescription in non-obese volunteers, was shown to be safe and without any untoward effects on quality of life. Importantly, the study confirmed the presence of a CR-induced decrease in total daily energy expenditure (EE). However, in the CR group compared with the control group, resting metabolic rate adjusted for loss of fat-free and fat masses was only lower during the weight loss phase. Furthermore, reductions in core body temperature were noted in the CR group, but were not different from the controls, and changes in oxidative damage were not assessed.

We hypothesized a reduction in oxidative damage after 1 and 2 years of CR. Taken together with lower EE, such results would speak in favor of the long-standing hypotheses of biological aging stating that prolonged CR enhances energy efficiency at rest and therefore results in less reactive oxygen species production and reduced oxidative damage to tissues and organs, thus a combination of the rate of living and the oxidative damage theories of aging. To test this hypothesis, we delivered a highly controlled and intensive behavioral intervention targeting a 25% CR diet over 2 years and obtained reliable measurements of the most robust component of daily sedentary EE, i.e., energy metabolism during sleep, measured in a room calorimeter. Hormonal mediators of metabolism were measured along with urinary F2-isoprostane excretion as an index of oxidative damage.

According to the rate of living theory, those individuals who are the most efficient at utilizing energy should experience the greatest longevity. Observational studies of human aging have shown higher mass-adjusted metabolic rate (24hEE or resting EE) is associated with disease burden and is a predictor of early mortality. Interventions with the capacity to induce a sustained slowing of energy metabolism such as CR should remain a focus of longevity research because randomized clinical trials and cohort studies are lacking. With careful phenotyping of energy metabolism, biomarkers of aging, and oxidative stress, this modest, 2-year study of human CR identified a reduction in the rate of living along with a reduction in systemic oxidative stress. The duration of imposed CR being for only 2 years clearly limits any extrapolation or speculation of the impact of CR on longevity in humans.

Notably, many biomarkers of aging (that could be a consequence of the overall improved metabolic profile commensurate with adipose tissue loss) were also improved in these young, healthy individuals. There is a clear need for continued investigations of CR in humans, since the non-human primate data are not entirely conclusive on the extension in the average and maximal lifespan but provide strong evidence for extensive health benefits including improved quality of life.