Fight Aging! Newsletter, November 13th 2017

Cardiovascular disease is a major health problem and the leading cause of death globally. Cardiac function deterioration hampers the ability of the heart to support blood circulation, resulting in heart failure (HF). The pathogenic mechanism leading to this end stage is complicated. Myocardial infarction, hypertension, cardiomyopathy, valvular heart disease, and inflammation-induced oxidative stress are known risk factors for disease progression.

Changes in metabolites have been identified in plasma and are associated with clinical outcomes in patients with HF. These findings suggest that metabolic remodeling in patients may occur during HF progression, and the metabolite profile can thus be used as a biomarker panel for a variety of assessment purposes. Lipid metabolism alterations have been increasingly demonstrated to underlie the pathogenesis of cardiovascular disease. Currently, research on lipids has focused on the analysis of plasma lipids such as cholesterol, triacylglyceride, and phospholipids. Reports seldom indicate specific fatty acids and total cholesterol in erythrocytes (red blood cells) as a predictor of cardiovascular events. Given the relatively long life (approximately 120 days) of erythrocytes, any change in the lipid profile of erythrocyte membrane may reflect pathophysiologic changes associated with disease progression.

Few studies have reported on the comprehensive assessment of the metabolome and lipidome of erythrocytes, especially in the scenario of HF. The aim of this study was to identify lipid profiles of HF erythrocytes using high-throughput liquid chromatography time-of-flight mass spectrometry. Our findings suggested that the erythrocyte lipid profiles of patients with HF were significantly different from those of normal subjects. The levels of phosphatidylcholines (PCs), phosphatidylethanolamines (PEs), and sphingomyelins (SMs) decreased in HF erythrocytes. However, the levels of lysoPCs, lysoPEs, and ceramides increased in these cells. Of these lipids, 7-ketocholesterol (7KCh) accumulated in the erythrocytes of patients with HF. This accumulation may be of significance as a potential discriminator and as a player in the pathogenesis of HF. At molecular level, we demonstrated that intracellular 7KCh accumulation caused reactive oxygen species (ROS) formation and cardiomyocyte death.

Chronic inflammation is associated with HF progression. A number of proinflammatory cytokines, such as tumor necrosis factor α, interleukin (IL)-1, and IL-6, were implicated in this process. In general, chronic inflammation leads to increased oxidative stress and damage and probably accounts for some of the observed changes in HF erythrocytes. Oxidative stress induces phospholipase activity, which leads to a decline in phospholipid levels and an increase in lysophospholipids levels. Moreover, 7KCh, an oxidation product of cholesterol, accumulates as a consequence of oxidative stress. Previous studies have revealed that oxidative damage products, such as oxidized LDL and oxysterols, are found in patients with cardiovascular disease. 7KCh is considered an important metabolite for monitoring cardiovascular disease outcomes and mortality as well as for predicting the incidence of cardiovascular disease events in general population. Accumulation of 7KCh in HF erythrocytes suggests that 7KCh is a risk factor for HF, with a potential for clinical applications.

A new way to rejuvenate old cells in the laboratory, making them not only look younger, but start to behave more like young cells, has been discovered. A team has discovered a new way to rejuvenate inactive senescent cells. Within hours of treatment the older cells started to divide, and had longer telomeres - the 'caps' on the chromosomes which shorten as we age. This discovery builds on earlier findings showed that a class of genes called splicing factors are progressively switched off as we age. The team found that splicing factors can be switched back on with chemicals called resveratrol analogues. The chemicals caused splicing factors, which are progressively switched off as we age to be switched back on, making senescent cells not only look physically younger, but start to behave more like young cells and start dividing.

The discovery has the potential to lead to therapies which could help people age better, without experiencing some of the degenerative effects of getting old. Most people by the age of 85 have experienced some kind of chronic illness, and as people get older they are more prone to stroke, heart disease, and cancer. "This is a first step in trying to make people live normal lifespans, but with health for their entire life. Our data suggests that using chemicals to switch back on the major class of genes that are switched off as we age might provide a means to restore function to old cells. When I saw some of the cells in the culture dish rejuvenating I couldn't believe it. These old cells were looking like young cells. It was like magic. I repeated the experiments several times and in each case the cells rejuvenated. I am very excited by the implications and potential for this research."

As we age, our tissues accumulate senescent cells which are alive but do not grow or function as they should. These old cells lose the ability to correctly regulate the output of their genes. This is one reason why tissues and organs become susceptible to disease as we age. When activated, genes make a message that gives the instructions for the cell to behave in a certain way. Most genes can make more than one message, which determines how the cell acts. Splicing factors are crucial in ensuring that genes can perform their full range of functions. One gene can send out several messages to the body to perform a function - such as the decision whether or not to grow new blood vessels - and the splicing factors make the decision about which message to make. As people age, the splicing factors tend to work less efficiently or not at all, restricting the ability of cells to respond to challenges in their environment. Senescent cells, which can be found in most organs from older people, also have fewer splicing factors.

"This demonstrates that when you treat old cells with molecules that restore the levels of the splicing factors, the cells regain some features of youth. They are able to grow, and their telomeres are now longer, as they are in young cells. Far more research is needed now to establish the true potential for these sort of approaches to address the degenerative effects of ageing."

Messenger RNA (mRNA) processing has been implicated as a key determinant of lifespan. Splicing factor expression is dysregulated in the peripheral blood of aging humans, where they are the major functional gene ontology class whose transcript patterns alter with advancing age and in senescent primary human cells of multiple lineages. Splicing factor expression is also an early determinant of longevity in mouse and man, and in both species these changes are likely to be functional, since they are associated with alterations in splice site usage for many genes. Recent data suggests that modification of the levels of SFA-1, a core component of the spliceosome, influences lifespan in C. elegans through interaction with TORC1 machinery.

The splicing process is regulated on two levels. Firstly, constitutive splicing is carried out by the core spliceosome, which recognises splice donor and acceptor sites that define introns and exons. However, fine control of splice site usage is orchestrated by a complex interplay between splicing regulator proteins such as the Serine Arginine (SR) class of splicing activators and the heterogeneous ribonucleoprotein (hnRNP) class of splicing repressors. Other aspects of information transfer from DNA to protein, such as RNA export and mRNA stability are also influenced by splicing factors. Intriguingly, in addition to their splicing roles, many splicing factors have non-canonical additional functions regulating processes relevant to ageing. For example, hnRNPK, hnRNPD and hnRNPA1 have been shown to have roles in telomere maintenance and hnRNPA2/B1 is involved in maintenance of stem cell populations.

Splicing factor expression is known to be dysregulated in senescent cells of multiple lineages and it is now well established that the accumulation of senescent cells is a direct cause of multiple aspects of both ageing and age-related disease in mammals. These observations suggest that an interrelationship may exist between well characterised mechanisms of ageing, such as cellular senescence, and the RNA splicing machinery where the mechanistic relationship to ageing remains largely correlational.

In contrast to the situation with core spliceosomal proteins such as SFA-1, perturbation of a single splicing regulator by standard molecular techniques such as knockdown or overexpression is unlikely to be informative for assessment of effects on ageing and cell senescence, since ageing is characterised by co-ordinate dysregulation of large modules of splicing factors. Thus experimental tools capable of co-ordinately modulating the expression of multiple components simultaneously are required to address the potential effects of the dysregulation of large numbers of splicing factors that we note during the ageing process. Small molecules such as resveratrol have been reported to influence splicing regulatory factor expression. Unfortunately, resveratrol has multiple biological effects, and thus a 'clean' assessment of the effects of moderation of splicing factor levels on cell physiology cannot be achieved using this compound alone.

We have overcome this limitation through development of a novel library of resveratrol-related compounds (resveralogues) which are all capable of either directly or indirectly influencing the expression of multiple splicing factors of both SRSF and HNRNP subtypes. Treatment of senescent human fibroblasts from different developmental lineages with any of these novel molecules shifts expression patterns of multiple splicing factors to those characteristic of much younger cells. This change occurs regardless of cell cycle traverse and is associated with a marked decrease in key biochemical and molecular biomarkers of senescence without any significant alteration in levels of apoptosis. Elevated splicing factor expression is also associated with elongation of telomeres, and in growth permissive conditions, these previously senescent populations show significant increases in growth fraction and in absolute cell number, indicating cell cycle re-entry.

When a lot of people look it aging, they view it in a very simplistic way: "Well, things fall apart, what do you expect?" You're accumulating amyloid, tau tangles, your collagen and elastin break down. But they're thinking about it mechanically, not biologically. I'll give you an analogy: I have a beautiful picture of a 1930 Duesenberg, and the car looks absolutely gorgeous - spot free, runs smoothly. If compare that to my five-year-old car, mine is in much worse shape. But the reason the 1930 Duesenberg looks fantastic is that five generations of absolute fanatics took care of it.

What happens with humans is that our rate of turnover comes down with age. If you look at beta-amyloid in regard to Alzheimer's disease, for example, you find that the pool of beta-amyloid is dynamic. It's continually being picked up, brought through the cell membrane, broken down, reconstituted, rebuilt, and put out again. But if you measure the rate of turnover in, for example, microglial cells with age, you find that the more senescent a cell is, the slower all of these turnover processes are - the rate of capture, the transmembrane translation, the rate of degradation. It's not that beta-amyloid denatures and therefore you get plaques. Instead, as the rate of turnover goes down, the percentage of denatured molecules goes up.

This is true throughout the entire human body. Everything that you think of as aging or age-related disease is a dynamic process, and all of those processes slow with age. The Duesenberg doesn't do well because it was well-made or because it had "great genes". It's the epigenetics, the turnover rate, that counts. And that's why telomeres matter - telomeres per se aren't important, but they modulate a slew of genes controlling turnover rate.

The mechanism of aging is a cascade of changes. Let's take Alzheimer's, for example. Why does Alzheimer's occur? Well, it occurs because the neurons die. Why does that happen? Well, because of the beta amyloid, and the tau tangles, and the changes in mitochondria and the oxidative damage. Well, what's upstream of that? I would argue it's because the microglial cells have changed their behavior. And why did that happen? Because the telomeres were shortened and now the pattern of epigenetic expression is playing a different tune. Why did that happen? Well, because the cell divided.

Then it gets messier and brings you back to clinical medicine. For example, we know that the rate of microglial cell senescence - that is, microglial cell divisions - goes up in patients with closed head injury and infection. So is that why you find that some patients are people with viral infection, bacterial infection, fungal infection, closed head injury? Well, again you have to go back and ask yourself what you're exposing for underlying genetic risks. You could also ask why the cells are dividing in the first place, if that's how far up you want to trace it.

I would never say that telomeres cause aging - they don't! The question I'm asking is, out of this whole cascade of changes, where's the single most effective point of intervention? I don't think it's preventing infection or preventing closed head injuries. I think the more effective point of intervention has to do with changing the pattern of gene expression. But rather than going after gene by gene by gene, rather than approaching an orchestra instrument by instrument, I would rather go to the conductor and say, "Play this tune." And that's where the telomere comes in.

If you asked me when we would first able to reverse human aging, technically I'd have to say it already happened back in 1999. That was when we showed in the lab that when you reset the telomere length in individual human cells like fibroblasts, you reset the pattern of gene expression, and then they act like young cells. Alright, but that's cells. Let's get a little more realistic: what about human tissue? There, the answer is the year 2000, when someone showed that you could grow young human skin cells. And likewise you can do the same thing with endothelial cells, vascular structures, bone, and a number of other tissues. But if you look at the data on the supplement TA-65 and a number of other things, it's just not impressive. It is suggestive and intriguing, though.

There are at least four ways, probably five, that we can reset telomeres in patients. The problem is that we need techniques that allow us to actually do that. Ronald DePinho did some really nice work seven years ago, but what he'd done was to alter the germ cell line so that he could turn telomerase on and off. I can't do that to you! Then Maria Blasco did the same thing with gene therapy. And the viral vector she used has been used in humans already, so we can actually do this now.

There are a couple of odd variables. Let's say I put a telomerase gene into one of your cells and it resets your telomeres. The first question is, how long does it stay there before the cell tears up the little plasmid that I put in there, because it's not on your chromosome? The answer is that it gets torn down at a certain rate that's a little hard to predict, since it depends on which cells and which species you're looking at. But it also depends on how fast your cells divide. If I put one little plasmid into a microglial cell and it divides, now I've got one cell with the plasmid and one without, or two with half a plasmid. So if this happens every time your cells divide, the more rapidly they divide, the less they have the telomerase. It's not like I've made you immortal - all I've done is reset your telomeres and gene expression, and they will un-reset again over time.

I actually see this as an advantage in several ways. One of the academic fads in the last twenty years (that's not well-substantiated) is that telomerase causes cancer. It really doesn't, but it is permissive of cancer. Even then, telomerase's effect on DNA repair means it's a genomic stabilizer which decreases the rate of new mutations. That doesn't mean telomerase is totally safe though. I think of it as three different zones a cell can be in. If you have long telomeres, you repair DNA really quickly. If your telomeres are short enough, the cell can no longer divide, so it's damaged, but it's not a complex problem. But if they're a bit less short, your cells are still dividing but you're not repairing damage - a cancer disaster. Most cancers maintain their telomeres just long enough that they remain unstable from a genetic standpoint, but not long enough that they can repair. So if I give you telomerase, I want to make sure that I either give you a lot, enough to get through that risk zone, or none at all.

Physical inactivity is estimated to cause as many deaths globally each year as smoking. Current guidelines recommend ≥150 minutes per week of moderate-intensity aerobic physical activity (PA) and muscle-strengthening exercises on ≥2 days per week. These guidelines are based primarily on studies using self reported moderate-to vigorous-intensity PA (MVPA). Technological developments now enable device assessments of light-intensity PA (LPA) and sedentary behavior, and well-designed studies with such assessments that investigate clinical outcomes are needed for updating current guidelines. Here, we present data from the WHS (Women's Health Study).

Women were mailed a triaxial accelerometer and asked to wear it on the hip for 7 days (except during sleep and water-based activities) and then to mail back the device. A total of 17,708 women wore their devices. Of 17,466 devices recording data (242 devices failed), 16,741 (96%) had data from ≥10 hours/day on ≥4 days. Women were followed up through December 31, 2015, for mortality, with deaths confirmed with medical records, death certificates, or the National Death Index. We examined the associations of total volume of PA (total accelerometer counts per day), MVPA (minutes per day), LPA (minutes per day), and sedentary behavior (minutes per day) with mortality using proportional hazards regression.

At baseline, the mean age was 72.0 years, and mean wear time was 14.9 hours/day. The median times of MVPA, LPA, and sedentary behavior were 28, 351, and 503 minutes/day, respectively. During an average follow-up of 2.3 years, 207 women died. Total volume of PA was inversely related to mortality after adjustment for potential confounders. For MVPA, there also was a strong inverse association. This association persisted in sensitivity analyses that excluded women with cardiovascular disease and cancer and those rating their health as fair/poor or deaths in the first year.

Three main findings emerged. First, we observed a strong inverse association between overall volume of PA and all-cause mortality. Although this inverse relation is not novel, the magnitude of risk reduction (≈60%-70%, comparing extreme quartiles) was far larger than that estimated from meta-analyses of studies using self-reported PA (≈20%-30%). Second, the strong inverse association for overall volume of activity was attributable primarily to the strong inverse association between MVPA and mortality. Third, we did not find any associations of LPA or sedentary behavior with mortality after accounting for MVPA.

This study is one of the first investigations of PA and a clinical outcome using newer-generation accelerometers capable of measuring activity along 3 planes. Using triaxial instead of uniaxial data increases the sensitivity for recognizing PA, detecting more time in LPA and less time in sedentary behavior. This study provides support for the 2008 federal guideline recommendation of MVPA, but it does not support either increasing LPA or decreasing sedentary behavior for mortality risk reduction.

The largest study to compare the mortality outcomes of different types of exercise found people who did strength-based exercise had a 23 percent reduction in risk of premature death by any means, and a 31 percent reduction in cancer-related death. "The study shows exercise that promotes muscular strength may be just as important for health as aerobic activities like jogging or cycling."

Public health guidance includes strength-promoting exercise (SPE) but there is little evidence on its links with mortality. Using data from the Health Survey for England (HSE) and Scottish Health Survey (SHS) from 1994-2008 we examined the associations between SPE and all-cause, cancer, and cardiovascular disease mortality. The core sample comprised 80,306 adults aged ≥30 years corresponding to 5,763 any cause deaths (681,790 person years).

Following exclusions for prevalent disease/events in the first 24 months, participation in any SPE was favorably associated with all cause (0.77) and cancer mortality (0.69). Adhering only to the SPE guideline of (≥2 sessions/week) was associated with all-cause (0.79) and cancer (0.66) mortality; adhering only to the aerobic guideline (equivalent to 150 minutes/week of moderate intensity activity) was associated with all-cause (0.84) and cardiovascular disease (0.78) mortality. Adherence to both guidelines was associated with all-cause (0.71), and cancer (0.70) mortality. Our results support promoting adherence to the strength exercise guidelines over and above the generic physical activity targets.

As far back as the eighteenth and early nineteenth centuries, microbial infections were responsible for vast numbers of deaths. The trend reversed with the introduction of antibiotics coinciding with longer life. Increased life expectancy, however, accompanied the emergence of age related chronic inflammatory states including the sporadic form of Alzheimer's disease (AD). Taken together, the true challenge of retaining health into later years of life now appears to lie in delaying and/or preventing the progression of chronic inflammatory diseases, through identifying and influencing modifiable risk factors.

Diverse pathogens, including periodontal bacteria have been associated with AD brains. Amyloid-beta (Aβ) hallmark protein of AD may be a consequence of infection, called upon due to its antimicrobial properties. Up to this moment in time, a lack of understanding and knowledge of a microbiome associated with AD brain has ensured that the role pathogens may play in this neurodegenerative disease remains unresolved. The oral microbiome embraces a range of diverse bacterial phylotypes, which especially in vulnerable individuals, will excite and perpetuate a range of inflammatory conditions, to a wide range of extra-oral body tissues and organs specific to their developing pathophysiology, including the brain.

This offers the tantalizing opportunity that by controlling the oral-specific microbiome; clinicians may treat or prevent a range of chronic inflammatory diseases orally. Evolution has equipped the human host to combat infection/disease by providing an immune system, but Porphyromonas gingivalis and selective spirochetes, have developed immune avoidance strategies threatening the host-microbe homeostasis. It is clear from longitudinal monitoring of patients that chronic periodontitis contributes to declining cognition.

Undoubtedly, a complex etiology underlies the clinical manifestations seen in AD. Candidate microbes conforming to the AD microbiome would be those that induce immunosuppression, are pathogenic, are able to evade the innate and adaptive immune recognition, incite local inflammation and are incapable of allowing entry of activated peripheral blood myeloid cells in the brain. The periodontal microbiome does concur with the type of expected bacteria in AD brains. As an analogy to the dysbiotic periodontal microbial communities driving periodontal disease, the AD microbiome may reflect similar traits.

One such example is the keystone periodontal pathogen P. gingivalis, which is a master immune evader and an immunosuppressor of the host through IL-2 suppression. Although P. gingivalis lacks the curli gene, it has alternative inflammatory mechanisms to indirectly activate β secretases and contribute to host derived Aβ as well as correlate with loss of mental function. A recent systematic review and a 16-year follow-up retrospective cohort study significantly link 10-year exposure to chronic periodontitis as a risk factor for AD. These reports, together with effort from other researchers firmly places periodontitis as a risk factor for AD.

Currently, aging and anti-aging research has become a focus worldwide. Living standards and quality of life will continue to improve in the 21st century as scientific countermeasures to aging progress. With increasing age and cell degeneration, vascular endothelial cells (VEC) renew very slowly and show manifestations of aging. Long-term stimulation by pro-inflammatory cytokines, such as tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and interleukin-6 (IL-6), leads to chronic and low-grade microinflammation of VECs, which leads to age-related degenerative diseases. Many studies have shown close correlations between inflammation and DNA damage and between cell senescence and aging. Animal experiments have found that inhibition of VEC inflammation could delay aging and prolong life, thus it is imperative that we further investigate inhibition of VEC senescence.

Studies have shown that the AU-rich region connecting factor 1 (AUF1) gene controls the inflammatory response and maintains chromosome integrity by activating telomerase to repair the ends of chromosomes, thus AUF1 reduces inflammation and prevents rapid aging. By delivering AUF1 to VECs, we may be able to weaken the inflammatory cytokine response. Platelet endothelial cell adhesion molecule-1, which is also called cluster of differentiation 31 (CD31), is a member of the immunoglobulin superfamily and is expressed on endothelial cells, platelets, macrophages, and neutrophils and is involved in inflammatory angiogenesis. Inflammation, cell adhesion, and migration of endothelial cells play important roles in inflammatory angiogenesis, thus it is feasible to target CD31 to modulate VECs.

By inhibiting VEC inflammation, aging may be delayed and life may be prolonged. However, there is no targeted therapy for the aging of vascular endothelial cells. To enhance the effects of anti-aging treatments, we constructed a drug delivery system using liposomes conjugated with anti-CD31 monoclonal antibody (CD31-PILs) because anti-CD31 monoclonal antibody targets VECS. This CD31-PILs delivery system was able to encapsulate the AUF1 plasmid and to deliver it to VECs. A decline in cell proliferation ability is one of the biological signs of aging, and cell cycle changes can reflect the ability of a cell to proliferate. Analysis of cell cycle distributions showed that after treatment with CD31-PILs-AUF1, the percentages of cells in division phases significantly increased, while the percentages reduced non-division phases. These data are consistent with previous reports that AUF1 plays roles in anti-aging and in maintaining cell proliferation, thus, delivery of the AUF1 plasmid may play a role in anti-aging.

Our findings are consistent with earlier work showing increased IL-6 expression in old rats compared with young rats and after anti-inflammatory treatment, inflammation related factors are reduced and symptoms of aging can be improved. Whether the effects of these cytokines are mediated through the generation of intracellular reactive oxygen species, or through another defined cell-signaling mechanism, is under further study.

To verify the effect of CD31-PILs-AUF1 in vivo, we developed an aging mouse model using D-galactose. The result show D-galactose accelerates aging in rodents by inducing oxidative stress by increasing the malondialdehyde (MDA) level and reducing superoxide dismutase (SOD) activity. This is consistent with previous reports, indicating the success of the aging mouse model. MDA content decreased and the SOD content increased in mice treated with CD31-PILs-AUF1 indicating that CD31-PILs-AUF1 may delay the senescence induced by D-galactose. In conclusion, we have developed an effective PILs strategy to deliver the AUF1 plasmid to a specific target, and this system may be useful for the development of new anti-aging drugs.

Amyloid is found in the aortic walls of almost 100% of the population above 50 years of age, and also aged people are susceptible to hypertension and atherosclerosis, which indicates that vascular amyloidosis (VA), hypertension, and atherosclerosis are highly associated with aging. However, few studies have focused on the relationship between amyloidosis and arterial diseases. Amyloidosis is a disorder of protein metabolism characterized by extracellular accumulation of abnormal insoluble amyloid fibrils. About 30 proteins are known to form pathogenic amyloid or amyloid-like fibrillary networks in a wide range of human tissues which are associated with diseases having high morbidity and mortality rates.

However, there are only four kinds of amyloid proteins which are mainly associated with VA. In general, these four amyloid proteins TTR (Transthyretin), Apo1 (Apolipoprotein A-1), immunoglobin γ, and medin are susceptible to deposit, respectively at cerebral artery, coronary artery and aorta. If amyloid proteins deposit within the walls of the cerebral vasculature with subsequent aggressive vascular inflammation, it will lead to recurrent hemorrhagic strokes; If they deposit within the walls of the coronary artery, they will lead to angina pectoris, even ischemic cardiomyopathy; If they deposit within the wall of aorta, they will lead to hypertension, atherosclerosis, and even dissecting aneurysm eventually.

Growing evidence has indicated that MFG-E8 is a secreted inflammatory mediator that orchestrates diverse cellular interactions involved in the pathogenesis of various diseases, including vascular aging and amyloidosis. During aging, both MFG-E8 transcription and translation increase within the arterial walls of various species. Many inflammatory molecules within the Ang II signal pathway are induced by MFG-E8. During amyloidosis, as the origin of amyloid protein, MFG-E8 cleaves into medin which increases the stiffness of vascular wall through the binding to tropoelastin. These medin amyloids have been observed within arterial walls, including that of both aorta and temporal artery.

Endothelial integrity is important to vascular health, with endothelial cells (ECs) building the frontline cells of the arterial wall. It is suggested that the amyloidosis associated protein medin is toxic to aortic ECs in vitro and may underlie the pathogenesis of aortic aneurysm in vivo through a weakening of the aortic wall. In addition, the increased inflammatory load, such as elevated MFG-E8 in the old endothelia may damage endothelial mitochondrial DNA and interfere with the mitochondria life cycle via enhanced reactive oxygen species generation, which consequently initiates and promotes EC senescence and apoptosis. These cellular events and micro-environments lead to endothelia dysfunction which renders the arterial wall a fertile soil in which amyloidosis and atherosclerosis may flourish. Interestingly, endothelial dysfunction also occurs with aging even in healthy adults, and collectively, endothelial dysfunction can be viewed as a prelude for arterial disease.

Alzheimer's disease, the leading cause of dementia, has long been assumed to originate in the brain. But new research indicates that it could be triggered by breakdowns elsewhere in the body. The findings offer hope that future drug therapies might be able to stop or slow the disease without acting directly on the brain, which is a complex, sensitive and often hard-to-reach target. Instead, such drugs could target the kidney or liver, ridding the blood of a toxic protein before it ever reaches the brain.

The scientists demonstrated this mobility through a technique called parabiosis: surgically attaching two specimens together so they share the same blood supply for several months. The team attached normal mice, which don't naturally develop Alzheimer's disease, to mice modified to carry a mutant human gene that produces high levels of a protein called amyloid-β. In people with Alzheimer's disease, that protein ultimately forms clumps, or "plaques," that smother brain cells. Normal mice that had been joined to genetically modified partners for a year "contracted" Alzheimer's disease. The amyloid-β traveled from the genetically-modified mice to the brains of their normal partners, where it accumulated and began to inflict damage.

Not only did the normal mice develop plaques, but also a pathology similar to "tangles" - twisted protein strands that form inside brain cells, disrupting their function and eventually killing them from the inside-out. Other signs of Alzheimer's-like damage included brain cell degeneration, inflammation, and microbleeds. In addition, the ability to transmit electrical signals involved in learning and memory - a sign of a healthy brain - was impaired, even in mice that had been joined for just four months. Besides the brain, amyloid-β is produced in blood platelets, blood vessels and muscles, and its precursor protein is found in several other organs. But until these experiments, it was unclear if amyloid-β from outside the brain could contribute to Alzheimer's disease. "The blood-brain barrier weakens as we age. That might allow more amyloid-β to infiltrate the brain, supplementing what is produced by the brain itself and accelerating the deterioration."

Many lizards can detach a portion of their tail to avoid a predator and then regenerate a new one. Unlike in mammals, the lizard tail includes part of the spinal cord. Researchers have found that the spinal cord in the tail contained a large number of stem cells and proteins known to support stem cell growth. "We knew the gecko's spinal cord could regenerate, but we didn't know which cells were playing a key role. Humans are notoriously bad at dealing with spinal cord injuries, so I'm hoping we can use what we learn from geckos to coax human spinal cord injuries into repairing themselves."

Geckos are able to regrow a new tail within 30 days - faster than any other type of lizard. In the wild, they detach their tails when grabbed by a predator. The severed tail continues to wiggle, distracting the predator long enough for the reptile to escape. In the lab, researchers simulate this by pinching the gecko's tail, causing the tail to drop. Once detached, the site of the tail loss begins to repair itself, eventually leading to new tissue formation and a new spinal cord. For this study, the team investigated what happens at the cellular level before and after detachment.

They discovered that the spinal cord houses a special type of stem cell known as the radial glia. These stem cells are normally fairly quiet. "But when the tail comes off, everything temporarily changes. The cells make different proteins and begin proliferating more in response to the injury. Ultimately, they make a brand new spinal cord. Once the injury is healed and the spinal cord is restored, the cells return to a resting state." Humans, on the other hand, respond to a spinal cord injury by making scar tissue rather than new tissue, he added. The scar tissue seals the wound quickly, but sealing the injury prevents regeneration. "It's a quick fix, but in the long term it's a problem. This may play a role in why we have a limited ability to repair our spinal cords. We are missing the key cell types required."

When people talk about the future of technology, especially artificial intelligence, they very often have the common dystopian Hollywood-movie model of us versus the machines. My view is that we will use these tools as we've used all other tools - to broaden our reach. And in this case, we'll be extending the most important attribute we have, which is our intelligence.

How will all this help us live longer? Let's start with genetics. It's beginning to revolutionize clinical practice and will completely transform medicine within one to two decades. We're starting to reprogram the outdated software of life - the 23,000 little programs we have in our bodies, called genes. We're programming them away from disease and away from aging. We can subtract genes. We can modify stem cells to have desirable effects such as rejuvenating the heart if it's been damaged in a heart attack, which is true of half of all heart attack survivors. The point is health care is now an information technology subject to the same laws of acceleration and progress we see with other technologies. We'll soon have the ability to rejuvenate all the body's tissues and organs and develop drugs targeted specifically at the underlying metabolic process of a disease rather than taking a hit-or-miss approach. But nanotechnology is where we really move beyond biology.

By the 2020s we'll start using nanobots to complete the job of the immune system. Our immune system is great, but it evolved thousands of years ago when conditions were different. It was not in the interest of the human species for individuals to live very long, so people typically died in their 20s. The life expectancy was 19. Your immune system, for example, does a poor job on cancer. It thinks cancer is you. It doesn't treat cancer as an enemy. It also doesn't work well on retroviruses. It doesn't work well on things that tend to affect us later in life, because it didn't select for longevity. We can finish the job nature started with a nonbiological T cell. T cells are, in fact, nanobots - natural ones. We could have one programmed to deal with all pathogens and could download new software from the internet if a new type of enemy such as a new biological virus emerged.

I believe we will reach a point around 2029 when medical technologies will add one additional year every year to your life expectancy. By that I don't mean life expectancy based on your birthdate but rather your remaining life expectancy. People say they don't want to live forever. Often their objection is that they don't want to live hundreds of years the way the quintessential 99-year-old is perceived to be living - frail or ill and on life support. First of all, that's not what we're talking about. We're talking about remaining healthy and young, actually reversing aging and being an ideal form of yourself for a long time. They also don't see how many incredible things they would witness over time - the changes, the innovations. Me, I'd like to stick around.

I regard death as the greatest tragedy. People talk about getting used to death and accepting it, but the end of each life is a terrible loss, like the Library of Alexandria burning down. All that information, all their skills, their personality, their memories are gone. The people who loved that person also suffer. A significant portion of their neocortex had evolved to understand the person and interact with them, and then suddenly that person is no longer there for them to use that part of their brain, which leads to the shock of mourning. But I think it's humanity's mission to transcend our limitations, and the most profound limitation we have is that of our life span. That's the hardest thing for people to accept, because birth and life and death have been with us since the beginning of recorded history. But I can see a path that's not far off where we can indefinitely extend our lives.

Rejuvenation biotechnology would allow older adults to continue working and producing wealth for much longer than they can today, thus benefiting society in many ways. However, some people are concerned that this might do more harm than good; imagine all those rejuvenated elders holding onto their jobs forever, preventing the young from getting jobs themselves! Not to mention the risk of a gerontocratic world, where powerful older people get a touch too attached to their chairs, never allowing younger people a chance!

Quite frankly, what's wrong with that? Just because someone has been in charge of the same position for long, it doesn't mean that it's necessarily a bad thing. If you think otherwise, you might be making the incorrect assumption that, rejuvenated or not, older people will always tend to do things in old ways, eventually making them a worse choice than younger people. On the contrary, their long experience might make them more fit than others, especially if we're talking about chronologically older but open-minded people who keep up to date. Personally, I think what matters is that people in certain positions, whether within government or a company, are the right people for the job. If they aren't, old or young, they should be replaced by other people who are more fit, and, generally, there are more efficient and humane ways to do so than letting them get age-related diseases - for example, voting for someone else or hiring a different person.

It's easy to hypothesize that a generation of rejuvenated 200-year-olds could end up becoming a gerontocratic elite that maintains power over younger people, but how would this be accomplished, exactly? Maybe the older generation is rich and powerful, but unless we're talking about a totalitarian world in which the masses are intentionally kept ignorant and poor, younger generations do have fair chances to make positions for themselves. Power and wealth come from knowledge, and, these days, knowledge is more freely and widely available than ever before.

Yet power and wealth don't come only from knowledge; they also come from powerful and wealthy ancestors. If we didn't develop rejuvenation, certainly all the Scrooge McDucks of the world would die sooner than they would otherwise, but their power and wealth would go to their heirs, and so on over the generations, which wouldn't do much to prevent the creation of an elite. So, no, old age is not an easy way out of the problem of powerful elites ruling the world, and its absence wouldn't make the problem any worse, really. The only possible way out is giving everyone equal access to knowledge and equal opportunities. Inevitably, some will end up being more successful and thus more powerful than others anyway; however, if this allows them to become an oppressive force on the rest of us, I think this is a problem with our socio-economic system, not with the existence of lifesaving medical technology. I don't know about you, but I'm not very keen on waiting until the "perfect" society or "perfect" economic system are built before we decide to cure the diseases of old age.

I think fears of a society where rejuvenated elderly make younger people's lives more difficult are misplaced in that they assume present-day scenarios will exist in the far future. Take the concern about jobs, for example, rejuvenated old people would stick to their jobs forever and make it harder for young people to enter the workforce. It sounds bad, but there are a few assumptions behind it that we should question. First, would rejuvenated old people actually stick to their jobs forever? Why? You hardly hear of a professional who was in the exact same job for forty years these days. More broadly, career change is a thing already. After all, after forty years in the same line of work, it's conceivable you might want to try something else, thus making room for others to take your place. Will rejuvenated old people be allowed to stick to their jobs forever? Not everyone is a manager in charge of decisions, and your boss may well decide to lay you off, rejuvenated or not, and hire someone else.

I'd say it's rather silly to oppose rejuvenation today for the reason that, in a century or two, it might cause an unemployment problem due to too many people being alive. It's simply too long a time to make any even remotely accurate predictions on what the job market will be like or if there even will be any. In all honesty, I think it makes more sense to worry about a concrete problem that we already have today - the ill health of old age - than worry about a hypothetical one that might or might not happen in a hundred years' time. As time goes by, we'll have a better picture of potential future problems lying ahead, and we'll be in a better position than we are in today to do something about them.

A soon-to-be-published study indicates that protecting nerve cells with a specific compound helps prevent memory and learning problems in lab animals. Although the treatment protects the animals from Alzheimer's-type symptoms, it does not alter the buildup of amyloid plaques and neurofibrillary tangles in the rat brains. "We have known for a long time that the brains of people with Alzheimer's disease have amyloid plaques and neurofibrillary tangles of abnormal tau protein, but it isn't completely understood what is cause or effect in the disease process. Our study shows that keeping neurons alive in the brain helps animals maintain normal neurologic function, regardless of earlier pathological events in the disease."

Researchers used an experimental compound called P7C3-S243 to prevent brain cells from dying in a rat model of Alzheimer's disease. P7C3-based compounds have been shown to protect newborn neurons and mature neurons from cell death in animal models of many neurodegenerative diseases. P7C3 compounds also have been shown to protect animals from developing depression-like behavior in response to stress-induced killing of nerve cells in the hippocampus, a brain region critical to mood regulation and cognition.

The researchers tested the P7C3 compound in a well-established rat model of Alzheimer's disease. As these rats age, they develop learning and memory problems that resemble the cognitive impairment seen in people with Alzheimer's disease. The new study, however, revealed another similarity with Alzheimer's patients. By 15 months of age, before the onset of memory problems, the rats developed depression-like symptoms. Developing depression for the first time late in life is associated with a significantly increased risk for developing Alzheimer's disease, but this symptom has not been previously seen in animal models of the disease.

Over a three-year period, researchers tested a large number of male and female Alzheimer's and wild type rats that were divided into two groups. One group received the P7C3 compound on a daily basis starting at six months of age, and the other group received a placebo. The rats were tested at 15 months and 24 months of age for depressive-type behavior and learning and memory abilities. At 15 months of age, all the rats - both Alzheimer's model and wild type, treated and untreated - had normal learning and memory abilities. However, the untreated Alzheimer's rats exhibited pronounced depression-type behavior, while the Alzheimer's rats that had been treated with the neuroprotective P7C3 compound behaved like the control rats and did not show depressive-type behavior.

At 24 months of age (very old for rats), untreated Alzheimer's rats had learning and memory deficits compared to control rats. In contrast, the P7C3-treated Alzheimer's rats were protected and had similar cognitive abilities to the control rats. The team also examined the brains of the rats at the 15-month and 24-month time points. They found the traditional hallmarks of Alzheimer's disease - amyloid plaques, tau tangles, and neuroinflammation - were dramatically increased in the Alzheimer's rats regardless of whether they were treated with P7C3 or not. However, significantly more neurons survived in the brains of Alzheimer's rats that had received the P7C3 treatment.

There is now substantial evidence from human and rodent studies that early-life nutrition can have a long-term effect (often termed nutritional programming) upon the risks of coronary heart disease, stroke, hypertension, obesity, type 2 diabetes and osteoporosis during adulthood. Similarly, developmental nutrition has been shown to regulate lifespan, increasing or decreasing it depending upon the particular dietary alteration and when it was experienced. For example, a maternal low protein diet during suckling increases the longevity of male mice.

Drosophila has proved a useful genetic and physiological model for studying nutrition, growth, and metabolism. Developmental nutrition is known to influence several aspects of adult metabolism in Drosophila. Lifespan in Drosophila and in other species can be extended by dietary restriction (DR) during adulthood. In contrast to studies of adult diet, much less is known about how developmental diet regulates Drosophila lifespan. Depriving larvae of dietary yeast, the major protein source, during only the last (third) instar is known to produce adults with a small body size without significantly altering lifespan. It has also been reported that diet or yeast dilution throughout larval development can lead respectively to minor (~7%) or moderate (~25%) increases in lifespan. Hence, there is some evidence that developmental dietary history influences Drosophila lifespan but the regimes tested thus far have only generated modest effects and the underlying mechanisms have not yet been identified.

This study shows that dietary yeast restriction during Drosophila development can induce long-term changes in adult triglyceride storage, xenobiotic resistance, and lifespan. It can also extend lifespan even when adults are switched to a high yeast diet. In contrast, longevity obtained via adult-onset dietary restriction (DR) is largely reversible upon switching to a non-restricted diet. Developmental-diet induced extensions of median lifespan can be as large or larger than those observed with adult DR but this depends strongly upon the adult environment. We found that yeast restricted males reproducibly lived longer than controls, with median lifespan increases ranging from 20% up to a striking 145%, varying with adult diet. Hence, it is the combination of developmental and adult environments that determines survival outcomes, not one or the other.

We explored the possibility that flies themselves might condition the environment with endogenously produced substances detrimental to survival (hereafter called autotoxins). A differential production and/or response to these autotoxins could then contribute to lifespan regulation by developmental diet. A major finding of this study is that male and female flies condition their environment with alkene autotoxins that decrease the survival of both adult sexes. Developmental yeast restriction influences adult oenocytes to synthesise a hydrocarbon blend that contains a lower proportion of alkene autotoxins. In turn, this promotes increased longevity in many adult environments but not those where lifespan is limited by other toxic factors, such as paraquat or a high glucose-to-yeast ratio diet.

Alkenes appear to have a selective mechanism-of-action as physiological amounts of tricosene kill adult flies but not larvae. Their influence upon Drosophila adults is far-reaching and affects not only how survival is regulated by developmental dietary history but also by population density, sex, and insulin signalling. This has important implications for laboratory lifespan studies, with our results suggesting that the autotoxin contribution can be teased apart from other mechanisms by measuring survival curves on a case-by-case basis. During evolution, the selective advantages conferred by alkenes as sex pheromones, barrier lipids, and/or mediators of other beneficial activities are likely to have outweighed any disadvantages due to decreased longevity.

It is surprising that a major class of Drosophila autotoxins corresponds to lipids on the body surface, some of which are known to act as sex pheromones. This link is also emerging in Caenorhabditis elegans, where recent work shows that male pheromone contains ascaroside lipids that mediate the density-dependent mortality of grouped males and that shorten the survival of both sexes. Future studies will be needed to determine whether physiological amounts of skin-derived lipids can influence longevity in mammals, as they do in Drosophila.

Our brain swims. It is fully immersed in an aqueous liquid known as cerebrospinal fluid. Every day, the human body produces about half a litre of new cerebrospinal fluid in the cerebral ventricles; this liquid originates from the blood. This same quantity then has to exit the cranial cavity again every day. Researchers have now shown that in mice, the cerebrospinal fluid exits the cranial cavity through the lymph vessels. Past research has inadequately explained how cerebrospinal fluid exits the cranial cavity. Scientists knew that two paths were available - blood vessels and lymphatic vessels, but for a long time, and due due to insufficient research tools, they had assumed that drainage through the veins was by far the predominant pathway.

The researchers have now been able to refute this assumption. They injected tiny fluorescent dye molecules into the ventricles (cavities) of the brain in mice and observed how these molecules exited the cranial cavity. They used a sensitive non-invasive imaging technique to examine the blood vessels in the periphery of the animals' bodies, as well as the lymphatic and blood vessels directly draining the skull. It turned out that the dye molecules appeared after just a few minutes in the lymphatic vessels and lymph nodes outside the brain. The researchers were unable to find any molecules in blood vessels so quickly after the injection.

They were also able to determine the exact path of the dye molecules and thus the cerebrospinal fluid: it leaves the skull along cranial nerve sheaths - in particular around the olfactory and optic nerves. Once in tissue outside the brain, it is removed by the lymphatic vessels. The scientists are not entirely able to rule out whether a small portion of the cerebrospinal fluid also leaves the brain as previously assumed - through the veins. However, based on their research findings, they are convinced that the lion's share travels through the lymphatic system, and that the anatomy textbooks will have to be rewritten.

"The immune system eliminates toxins elsewhere in the body, but the brain is considered to be largely disconnected from this system. Only a few immune cells have access under normal conditions. The cerebrospinal fluid steps into the breach here. By constantly circulating, it flushes the brain and removes unwanted substances." This flushing function could offer a starting point for treatment of neurodegenerative diseases such as Alzheimer's. Alzheimer's is caused by misfolded proteins that accumulate in the brain. Researchers speculate that these misfolded proteins could be eliminated by, for example, drugs that induce lymphatic flow.

Chronic inflammation in the elderly is partially attributed to atrophy of the thymus - an organ that regulates the immune system - and in particular the ability of organisms to recognize their own cells-a phenomenon known as central tolerance. Immune central tolerance is established by two processes: first, immune cells that react strongly to self are eliminated in a process called negative selection, and second, thymic regulatory T (tTreg) cells are generated to suppress self-reactive immune reactions. The former has already been reported to be defective in the aged thymus, but whether the generation of new tTreg cells is also impaired has remained unclear.

Here, we analyzed the effect of aging on tTreg cell generation and found that the atrophied thymus is still able to make new tTreg cells; indeed, we show that tTreg cell generation capacity is enhanced when compared with other naïve T cells from the same thymus. We conclude that the balance of defective negative selection with enhanced tTreg cell generation may be necessary to avoid autoimmune diseases during aging.

Both negative selection and tTreg cell generation are critically dependent on medullary thymic epithelial cell (mTEC)-presentation (promiscuous expression) of self-antigens/peptides. Changes with age are potentially attributed to decreased T cell receptor (TCR) signaling strength due to inefficiency in promiscuous expression of self-antigens or presenting a neo-self-antigen by medullary thymic epithelial cells, displaying decreased negative selection-related marker genes (Nur77 and CD5high) in CD4 single positive (SP) thymocytes. Our results provide evidence that the atrophied thymus attempts to balance the defective negative selection by enhancing tTreg cell generation to maintain central T-cell tolerance in the elderly. Once the balance is broken, age-related diseases could take place.