Fight Aging! Newsletter, November 27th 2017

Folding your laundry or doing the dishes might not be the most enjoyable parts of your day. But simple activities like these may help prolong your life, according to the findings of a new study in older women. In the U.S. study of more than 6,000 white, African-American and Hispanic women ages 63 to 99, researchers reported significantly lower risk of death in those who were active at levels only slightly higher than what defines being sedentary. Women who engaged in 30 minutes per day of light physical activity - as measured by an accelerometer instead of a questionnaire - had a 12 percent lower risk of death. Women who were able to do a half-hour each day of moderate to vigorous activity had a 39 percent lower mortality risk.

For the age group in this study, light physical activities include regular chores such as folding clothes, sweeping the floor or washing the windows. Activities like these account for more than 55 percent of how older people spend their daily activity. Moderate to vigorous activities would be brisk walking or bicycling at a leisurely pace. The bottom line? "Doing something is better than nothing, even when at lower-than-guideline recommended levels of physical activity."

Even when researchers simultaneously accounted for the amount of each type of activity (light and moderate-to-vigorous) a woman did, they still observed significantly lower mortality associated with each time, independently of the other. "Current public health guidelines require that physical activity be of at least moderate or higher intensity to confer health benefits. Our study shows, for the first time in older women, that health is benefitted even at physical activity levels below the guideline recommendations. The mortality benefit of light intensity activity extended to all subgroups that we examined, and was similar for women younger than 80 compared to women over the age of 80. It was similar across racial/ethnic backgrounds, and among obese and non-obese women. Perhaps most importantly for this population, the mortality benefit was similar among women with high and low functional ability."

Age-related deterioration in health is associated with a reduction in physical activity (PA). U.S. and international guidelines on PA and public health recommend that healthy older adults perform at least 2.5 hours/week of moderate-intensity or 1.25 hours/week of vigorous-intensity aerobic PA for health benefits, a target that few older U.S. adults meet, often because they are not capable of engaging in moderate- to vigorous-intensity PA (MVPA). Substantially lower all-cause mortality risk is associated with relatively high MVPA levels (3-5 times guideline recommended) assessed using questionnaires. The extent to which this extends to older adults is unclear.

Typically, self-reported activity explains only 10% to 20% of the variance in device-measured PA. PA misclassification is large in older adults, especially for light-intensity PA, which these individuals commonly perform but is currently not recommended for public health. Use of accelerometers to measure PA is novel in prospective studies on older adults and provides the ability to calibrate the effect of PA much better than with self-report, especially for light-intensity PA. We examined associations between mortality and accelerometer-measured PA using age-relevant intensity cutpoints in older women of various ethnicities.

The results support the hypothesis that higher levels of accelerometer-measured PA, even when below the moderate-intensity threshold recommended in current guidelines, are associated with lower all-cause and CVD mortality in women aged 63 to 99. Our findings expand on previous studies showing that higher self-reported PA reduces mortality in adults aged 60 and older, specifically in older women, and at less than recommended amounts. Moreover, our findings challenge the conclusion of recent meta-analyses that MVPA, measured by to self-report, is required to offset mortality risk in adults.

First, absolute rates of all-cause and cardiovascular disease mortality were at least 50% lower in cohort members in the middle tertile of each PA exposure than in those in the lowest tertile. This is particularly impressive when considering the small mean differences between these tertiles of 50 minutes/day for low light-intensity PA, 33 minutes/day for high light-intensity PA, and 20 minutes/day for MVPA. Use of accelerometers enhanced accurate quantification of such small differences in usual daily PA, which is not possible using questionnaire assessments. Small increases in daily PA, which older adults can achieve, could have a substantial effect on mortality in later life. Even in the oldest cohort members, ages 80-89 and ≥90 years, absolute rates of all-cause mortality were 44% and 15% lower, respectively, when comparing the middle and lowest total PA tertile.

Scientists have known for a long time that two proteins, β-amyloid and tau, clump and accumulate in the brains of Alzheimer patients, and this accumulation is thought to cause nerve cell injury that results in dementia. Recent work by these researchers has shown that the clumping and accumulation of tau occurs as a normal response to stress, producing RNA/protein complexes termed "stress granules," which reflect the need for the brain to produce protective proteins. The persistence of this stress response leads to excessive stress, the accumulation of pathological stress granules, and the accumulation of clumped tau, which drives nerve cell injury and produces dementia.

In the current study, the researchers use this new model and show that reducing the level of stress granule proteins yields strong protection, possibly by reducing persistent pathological stress granules as well as changing the type of tau clumping that occurs. The team hypothesized that they could delay the disease process by reducing stress granules and decreasing this persistent stress response by genetically decreasing TIA1, which is a protein that is required for stress granule formation. Reducing TIA1 improved nerve cell health and produced striking improvements in memory and life expectancy in an experimental model of AD.

Although the experimental models had better memory and longer lives, the team observed more clumped tau in the form of neurofibrillary tangles. To explain how this might be associated with a better outcome, the researchers looked at the type of tau pathology and showed that reducing TIA1 dramatically lowered the amount of tiny clumps, which are termed tau oligomers and are particularly toxic. "Reducing TIA1 shifted tau accumulation from small to large clumps, decreasing the amount of small tau clumps and producing a proportional increase in the large tau clumps that generate neurofibrillary tangles and are less toxic."

Emerging studies suggest a role for tau in regulating the biology of RNA binding proteins (RBPs). We now show that reducing the RBP T-cell intracellular antigen 1 (TIA1) in vivo protects against neurodegeneration and prolongs survival in transgenic P301S Tau mice. Biochemical fractionation shows co-enrichment and co-localization of tau oligomers and RBPs in transgenic P301S Tau mice. Reducing TIA1 decreased the number and size of granules co-localizing with stress granule markers. Decreasing TIA1 also inhibited the accumulation of tau oligomers at the expense of increasing neurofibrillary tangles.

Despite the increase in neurofibrillary tangles, TIA1 reduction increased neuronal survival and rescued behavioral deficits and lifespan. These data provide in vivo evidence that TIA1 plays a key role in mediating toxicity and further suggest that RBPs direct the pathway of tau aggregation and the resulting neurodegeneration. We propose a model in which dysfunction of the translational stress response leads to tau-mediated pathology.

None of us was made from scratch. Every human being develops from the fusion of two cells, an egg and a sperm, that are the descendants of other cells. The lineage of cells that joins one generation to the next - called the germline - is, in a sense, immortal. Over time, a cell's proteins become deformed and clump together. When cells divide, they pass that damage to their descendants. Over millions of years, the germline ought to become too devastated to produce healthy new life. "You take humans - they age two, three or four decades, and then they have a baby that's brand new. There's some interesting biology there we just don't understand."

Researchers have now reported the discovery of one way in which the germline stays young. Right before an egg is fertilized, it is swept clean of deformed proteins in a dramatic burst of housecleaning. The researchers discovered this process by studying a tiny worm called Caenorhabditis elegans. Most C. elegans are hermaphrodites, producing both eggs and sperm. As the eggs mature, they travel down a tube, at the end of which they encounter sperm. Researchers discovered that a worm's eggs carry a surprisingly heavy burden of damaged proteins, even more than in the surrounding cells. But in eggs that were nearing the worm's sperm, the researchers found far less damage. These experiments raised the possibility that the sperm were sending out a signal that somehow prompted the eggs to rid themselves of damaged proteins.

The researchers then created mutant "female" worms and observed that their eggs all became littered with protein clumps. When the researchers let them mate with males, however, the clumps disappeared from the eggs. They then carried out additional studies, such as looking for other mutant worms that could not clear out protein clumps even though they could make sperm. Combining these findings, the researchers worked out the chain of events by which the eggs rejuvenate themselves.

It begins with a chemical signal released by the sperm, which triggers drastic changes in the egg. The protein clumps within the egg "start to dance around." The clumps come into contact with little bubbles called lysosomes, which extend fingerlike projections that pull the clumps inside. The sperm signal causes the lysosomes to become acidic. That change switches on the enzymes inside the lysosomes, allowing them to swiftly shred the clumps. Researchers hypothesize that the worms normally keep their eggs in a dormant state. The eggs accumulate a lot of damage, but make little effort to repair it. Only in the last minutes before fertilization do they destroy protein clumps and damaged proteins, so that their offspring won't inherit that burden.

"The hypothesis is that it's not just a worm thing." In their new paper, the researchers reported that they had tested this hypothesis on frogs, which are much more closely related to humans than is C. elegans. The scientists exposed frog eggs to a hormone that signals them to mature. The lysosomes in the frog eggs became acidic, just as happens in worms. The germline may not be the only place where cells restore themselves in this way. Throughout our lives, we maintain a supply of stem cells that can rejuvenate our skin, guts and brains. It may be that stem cells also use lysosomes to eradicate damaged proteins. It might be possible, for example, to treat diseases by giving aging tissues a signal to clean house.

Although individuals age and die with time, an animal species can continue indefinitely, because of its immortal germ-cell lineage. How the germline avoids transmitting damage from one generation to the next remains a fundamental question in biology. Here we identify a lysosomal switch that enhances germline proteostasis before fertilization. We find that Caenorhabditis elegans oocytes whose maturation is arrested by the absence of sperm exhibit hallmarks of proteostasis collapse, including protein aggregation. Remarkably, sperm-secreted hormones re-establish oocyte proteostasis once fertilization becomes imminent.

Key to this restoration is activation of the vacuolar H+-ATPase (V-ATPase), a proton pump that acidifies lysosomes. Sperm stimulate V-ATPase activity in oocytes by signalling the degradation of GLD-1, a translational repressor that blocks V-ATPase synthesis. Activated lysosomes, in turn, promote a metabolic shift that mobilizes protein aggregates for degradation, and reset proteostasis by enveloping and clearing the aggregates. Lysosome acidification also occurs during Xenopus oocyte maturation; thus, a lysosomal switch that enhances oocyte proteostasis in anticipation of fertilization may be conserved in other species.

So, my grandfather was kind of my hero, growing up. He was kind, smart, super-passionate about every little thing he was doing. And really argumentative about it too. He was happy, successful, loved his family, and if you asked me what living a good life meant when I was a kid, I would have told you it was to be like my granddad. So when he was diagnosed with cancer when I was 14 it shattered my world. We were going to go on vacation that summer, but his doctors found two tumors at the same time, one in his throat and another in his brain. So instead, I spent that summer watching week by week, month by month, as he got sicker and frailer, and also, heartbreakingly, forgetful and paranoid. He was given medicine that kept him alive a little bit longer, but he never really was himself again. And in my last conversations with him, he talked with me about how terrifying it was, knowing that, day by day, he was slipping away. Knowing that he wasn't getting better.

When he died I fell into a depression. I couldn't stop thinking about the fact that no matter how good of a life we live, every one of us has the same thing waiting for us that my granddad did. Months or years of suffering of some terrible disease, like cancer, or dementia, or a stroke. What was the point of getting 'A's in school or scoring the winning goal in the big game if that's all we have to look forward to? I spent months feeling this way, and it wasn't until I stumbled across an idea that I was finally able to crawl out of that depression. I latched on to something that gave me a purpose. What if I spent my life fighting against those diseases, so that other people didn't have to suffer from them the way that my granddad did? That purpose has been keeping me going until this very day.

So there I was, I had my epiphany, the big idea, but I had no idea how to go about doing it. How could I fight against the diseases that had killed every single person I knew who had died? I started casting around and learning as much as I could, and it didn't take me long to find something interesting. While cancer and heart attacks are today's biggest killers, they haven't always been. As recently as 1900, most people died of infectious diseases. The leading causes of death were pneumonia, tuberculosis, and influenza, and the average life expectancy was 45 years old.

Doctors and scientists spent the last century struggling heroically against these diseases - and we invented antibiotics and vaccines in order to fight them. Those were the biggest challenges of the 20th century. We've been so successful fighting them that now we live in a world where the average life expectancy is 80. In developed countries all ten of the leading causes of death are caused by simply living long enough to not die of anything else. The 21st century will be defined by our struggle against these diseases of aging, and it is not going to be an easy one. For 75 years, these have been the leading causes of death for humanity, and everything we've done to fight them has barely made a dent in the number of people dying of any one of them. In fact, they are rising as a fraction of total deaths in the world, as we continue to make strides against infectious disease, malnutrition, and violence around the world.

You see, as a society we look to medicines to make us well when we're sick, and so far almost everything that we've designed to treat the diseases of aging has fit in that paradigm. We wait for someone to get cancer, to have a stroke, or start losing their memories, and then we try to do something about it. But this approach hasn't really been working. Since 2000, we've done 200 clinical trials in humans just for Alzheimer's disease, and 99% of those have failed. The two that succeeded haven't even given us a drug that does much to treat Alzheimer's disease. We spend over 20 billion a year on cancer research and trials, but most of the gains we've made against cancer since 1970 have come from better diagnosis of cancer, not from curing the disease.

This should tell us that we're doing something wrong in our approach to the diseases of aging, because, unlike infections, the diseases of aging are caused by the slow, gradual build up of damage to our bodies over a lifetime, before they ever cause enough of a problem for us to go see a doctor. And by the time that we go to see that doctor, so much has happened inside of our bodies, that there is not much that they can do to help us. So this is how I started my academic career. I was one of a small group of scientists, and we were all thinking the same thing: if we ever wanted to eliminate Alzheimer's and cancer, the way that we eliminated smallpox, we would have to take a different approach to healthcare. We would have to treat the diseases of aging by anticipating them, building medicines that could remove damage caused by getting old before it ever accumulated enough to make us sick.

And this kind of makes sense, right? Because we all feel the effects of getting old right now, even when we're not sick. I mean, who here can run as fast as they could when they were 18 years old? Or maybe bounce back up after falling out of a tree like they could when they were 12. I am by no means old, and even though my risk of osteoporosis or cancer is diminishingly small, I am getting older, just like all of you are. My blood vessels are hardening. My neurons are starting to get tired. My DNA is mutating. I'm losing the battle to keep my cells and tissues in good condition. Right now we only think of this progressive accumulation of damage as a problem when everything goes to hell, and it erupts as some kind of disease. If we want to stop this gradual build up of damage in our bodies, we're told that the old things we can do are eat better, exercise, avoid smoking, hope that we've gotten lucky with our genes. It's not exactly a hopeful message. We're not leveraging the power of modern medicine to prevent us from getting sick from the things that are killing us the most.

But that is all changing. Because for the first time in history, we understand what makes us get older. We've traced to the biochemical level the diseases of aging and what causes them, and we've been able to categorize the damage of aging into nine buckets. Things like the random mutations of DNA, or the exhaustion of our stem cells. Our understanding is now at the cellular and molecular level, which means that we can actually design medicines to target and treat these things. And those medicines actually exist. We have a repository of over 50 interventions, whether a small molecule drug or a genetic change, that can extend healthy life by as much as 50%. Think about that: 50% longer without getting Alzheimer's disease, or cancer, or having a stroke, or having our bones and muscles wear down. 50%! In mice. And so the mice are super-excited about this. But what does it mean for us humans?

Well, luckily this is how new medicines are usually born. We take a piece of research and test it in mice to see if it works, and if it does then we advance that to human trials. And the good news is that we have 50 things that are ready to test. But making the jump from mice to humans for these sorts of diseases won't exactly be straightforward. You see, a trial to prevent a disease instead of to treat it has some additional challenges. It is more time-consuming and more expensive, which means the companies that would have to pay the tens of millions for these trials are often hesitant to do so, when they are used to doing the more traditional reactive trials. However, we have a glimmer of hope here too, that may be able to fast-track some of these preventative medicines into the clinic. You see, if you build a medicine that does a good job preventing damage that could eventually cause disease, it turns out that the same medicine can stop a disease from getting any worse by halting that same damage. And sometimes we can even repair the damage, reversing the effects of a disease.

Now, if you caught yourself thinking "but wait, that sounds completely obvious!" I might forgive you for that. It does seem reasonable that if something is going wrong with my cells, and I fix that thing, then it would help whether or not I've labelled my cells as diseased. But until very recently we just didn't know that, because it hadn't really been tested. The people who are working on studying what goes wrong in an old mouse and the people who are giving treatments to Alzheimer's patients weren't really talking to each other. But now they are, and armed with this new knowledge of what makes us age, and what we can do about it, we're able to pursue two ambitious goals at the same time. First, we have the ability to create new medicines to treat patients suffering from diseases of aging. This is what motivates me and the people that I work with, every single day, using this new research to come up with a medicine that can impact millions of people who are sick right now.

But there's also a second thing we can be doing. As we create new medicines for these diseases, and test them in the traditional way, we have to remember that what we really want is a medicine that can prevent disease instead of just treating it. And to get there, we're going to need to have proven, safe, effective medicines targeted at treating the damage of aging, and there has been progress on this front as well. One of the 50 interventions I told you guys about before happens to be an approved drug that's already been used in humans for decades. So after results in mice came out showing that we could extend their healthspan, a group of researchers started combing through hundreds of thousands of patient records who had been taking this drug, and they found something incredible. This drug - that people didn't take to prevent the diseases of aging, they took to prevent their blood glucose from going up, because they had diabetes - but when then were on this drug, they had a lower incidence of both cancer and Alzheimer's disease. Even compared to healthy people that didn't have diabetes.

So this thing may actually be working. This drug, which is called metformin, can extend mouse life span on average by 5-10%, which, if it works the same in humans, would mean 4 to 8 extra healthy years. And that's a lot, because if we invented a pill that miraculously cured all cancer in all of humanity right now, we would expect an average life span gain of about three and a half years, because we would succumb to another disease as we got older. So based on this research, a new clinical trial has started to test whether people who are healthy can take metformin and avoid cancer and Alzheimer's disease. So you might want to wait for the results of that trial before you go and beg your doctor for diabetes meds.

So now you may be asking yourself, whether it's this trial or another medicine that gets approved, who is going to pay for these preventative medicines? And it's worth pausing here for a moment to reflect that insurance companies are actually already paying for something very similar. Many of us in this room may be taking medicines that lower our cholesterol, which reduce the chances of getting stroke. When we invent new medicines that can not just reduce your chances of getting a stroke, but also Alzheimer's disease and cancer, which are way more expensive for those insurance companies to treat, you can bet that they'll be lining up to pay for those drugs too. With insurance companies in the game, this means that pharma companies are going to pay well for the rights to test and sell these medicines. And that means that scientists working at universities or at biotech companies are going to be competing with each other to create the next greatest preventative medicine. It's a positive feedback loop, and the cycle can be kicked off with just one victory. Even a drug that extends healthy life span by a year or two can start a cycle of investment and research and testing that can change the way we do healthcare forever.

And I have good news, because there are 50 interventions that we already have ready to go. We just need to get to work. As I close up here, I think it's worth addressing one little thing, which is that I get asked all the time if we even should be trying to treat aging or extend life. I think that this is absolutely the wrong question. I think that the question we should be asking ourselves is "when do you want to get Alzheimer's disease?" When do you want to have a stroke? When do you want your muscles to break down? For most of these, I think everyone that I know would say "never". It's like asking someone in 1900 at what age they'd like to get tuberculosis. Or polio. "No thank you!" The evidence we have suggests that we can make new medicines based on our understanding of aging that can help people who are suffering from today's biggest killers. Yes, this will change healthcare. It will redefine medicine in the 21st century in the same way that vaccines and antibiotics redefined medicine in the 20th. But that's good! That's progress. Because I want to be able to enter the 22nd century and face our newest medical challenges, whatever those may be.

We have the opportunity in our lifetimes to flip healthcare on its head, by wedding the power of modern medicine with our understanding of what makes us age. We're going to invent new medicines that can treat the damage caused by getting old before we ever get sick. And that? That's a future that I can look forward to.

Israeli scientists are convinced the maximum life span can be increased to 140 years or more, if science treats not only diseases but also specifically tackles the aging processes. That's quite a boast, given that the longest confirmed life span so far is 122 years. As the means of intervening with and holding back the ravages of age increase, scientists are now asking whether our natural genetic makeup is actually limited to a maximum life span of 115 to 120 years, or whether this limit can be breached. As you might expect, the scientific community is home to a lively debate on the subject. Other scientists are convinced that developing ways of delaying the aging process is only a matter of time, and that mankind must not accept 120 years as a limit.

Haim Cohen, head of the Molecular Mechanism of Aging Laboratory at Bar-Ilan University, is one of those who believes the maximum life span can be increased by 30 percent and eventually cross the 140-year threshold (compared to 115 to 120 years today). "In the past century we've experienced a dramatic increase in human life expectancy. In the past 60 years, life expectancy at birth has risen by an average of 72 percent. However, the maximum life expectancy has risen by only 8 percent. In the study, we examined whether the minor increase in maximal life expectancy means humanity has reached its maximum potential. The average rise in life expectancy stemmed mainly from medical solutions dealing directly with disease symptoms, and that increased the number of people who lived to a more advanced age."

Until 100 years ago, dying of old age was a privilege. The new study shows that in 1900, only 30 percent of all deaths were related to age or age-related diseases, while more than half were caused by infections. From the 1950s onward, the picture changed dramatically, as infections became curable and some of the terminal diseases turned into chronic ones. Today, more than 80 percent of deaths are related to diseases that occur mostly among the elderly. These factors certainly contributed to extending the overall life expectancy, but why is that barely reflected in the maximum life expectancy? Cohen and his colleagues say it stems from the approach that has characterized medicine. "The changes in life expectancy have so far stemmed from medical treatments developed in response to various illnesses - but there was no intervention in the basic aging mechanisms. What will happen when we deal directly with those biological mechanisms and metabolic processes responsible for aging?"

To examine whether intervention in the aging processes will affect life expectancy, Cohen and his team gathered and analyzed all the studies made in the last 20 years ("There are hundreds of them," he noted). In them, scientists succeeded in delaying the aging of organisms such as fungi, worms, flies, mice, rats and even monkeys. "We found something interesting in all of them: The increase in the maximum age was almost identical to the rise in the average or median age, reaching up to 30 percent." Cohen believes the findings indicate that focusing on the biological and genetic causes of aging will allow for a further leap in maximal life expectancy in the future. "Aging is a natural biological process whose basic characteristic is decreased functioning. Though the aging process looks different in various organisms, it is based on very similar mechanisms."

While average human life expectancy has increased dramatically in the last century, the maximum lifespan has only modestly increased. These observations prompted the notion that human lifespan might have reached its maximal natural limit of ~115 years. To evaluate this hypothesis, we conducted a systematic analysis of all-cause human mortality throughout the 20th century. Our analyses revealed that, once cause of death is accounted for, there is a proportional increase in both median age of death and maximum lifespan.

To examine whether pathway targeted aging interventions affected both median and maximum lifespan, we analyzed hundreds of interventions performed in multiple organisms (yeast, worms, flies, and rodents). Three criteria: median, maximum, and last survivor lifespans were all significantly extended, and to a similar extent. Altogether, these findings suggest that targeting the biological/genetic causes of aging can allow breaking the currently observed ceiling of human maximal lifespan.

Obesity and related metabolic disorders are growing health challenges; they mainly result from an imbalance between energy intake and energy expenditure. Emerging evidence suggests that non-shivering thermogenesis can re-establish energy balance and therefore counter the effects of elevated energy intake. This process is mediated primarily by the thermogenic activity of uncoupling protein 1 (UCP1), mainly in brown and beige fat cells. In this context, activating brown adipose tissue (BAT) or browning of white adipose tissue (WAT) could be a promising therapy for obesity and related metabolic diseases.

Recently, intermittent fasting was demonstrated to optimize energy metabolism and promote health. However, the mechanism for these benefits is unclear. Notably, one study found that time-restricted feeding can counteract obesity without reducing energy intake. Although perturbation of circadian rhythm was considered as a significant contributor to the increased energy expenditure, the possibility exists that white adipose browning would be a more direct mechanism. Therefore, in the current study, mice were placed on an every-other-day fasting (EODF) regimen to explore its effect on white adipose beiging and metabolic disorders. Evidence suggests that EODF selectively activates beige fat thermogenesis and ameliorates obesity-related metabolic diseases, probably via a microbiota-beige fat axis.

Gut microbiota play a critical role in energy metabolism and lipid homeostasis, and germfree or microbiota-depleted rodents have decreased susceptibility to diet-induced obesity and metabolic syndrome. Based on the above findings, EODF treatment could alter the microbiota compositions and prevent high-fat-diet-induced obesity and metabolic disorders. To further clarify the role of gut microbiota in mediating the beneficial effects of EODF regimen on metabolic diseases, the effect of EODF in control and microbiota-depleted high-fat-diet-induced obesity mice was compared. EODF treatment significantly reduced obesity and hepatic steatosis and improved insulin sensitivity in control mice, but not in microbiota-depleted mice, indicating that the effects of EODF depend on gut microbiota.

To examine whether gut microbiota are sufficient to replicate the effects of EODF, microbiota-depleted mice with high-fat-diet-induced obesity were transplanted with microbiota from ad libitum (AL) feeding and EODF mice, respectively. Compared with the AL microbiota-transplanted group, EODF microbiota transplantation did mimic all the beneficial effects of EODF treatment on metabolic dysfunctions.

In summary, the present work uncovered novel perspectives on beige-fat development in white adipose tissue. EODF was shown to selectively activate beige fat, probably by re-shaping the gut microbiota, which led to increases in the beiging stimuli acetate and lactate. EODF also dramatically ameliorated metabolic syndrome in a mouse model of obesity. This alternative beige fat activation by EODF offers new insights into the microbiotabeige fat axis and provides a novel therapeutic approach for the treatment of obesity-related metabolic disorders.

In the past, osteoporosis and atherosclerosis were considered as separate entities with a similar increasing prevalence with aging. Recently, studies have outlined that patients with low bone mineral density (BMD) are at significantly greater risk of developing cardiovascular disease (CVD) as well as unexpected cardiovascular events, more severe coronary atherosclerosis and vascular calcification. In addition, it is known that postmenopausal women with osteoporosis have an increased risk of developing cardiovascular events and that the increased risk is proportional to the severity of osteoporosis. These data have also suggested a possible influence of drugs affecting bone metabolism on lipid and atherosclerosis mechanisms, or that drugs effective on the atherosclerosis process could also be efficacious in fracture prevention.

An initial interesting theory was that CVD and osteoporosis were linked by a common denominator, such as serum lipid profile, which could act in parallel on both vascular and bone cells. However, an interesting observational study showed that in a multiple regression analysis, lipid profile did not predict osteoporosis or fracture risk, whereas aortic calcification severity significantly explained BMD at the hip. On the other hand, low BMD at the distal radius was found to be associated with increased risk of stroke and CVD mortality.

The common finding of simultaneous vascular calcification and osteoporosis in individual patients suggests that local tissue factors could have a crucial role in the regulation of mineralization and cell differentiation. Cardiovascular calcification was conventionally viewed as an inevitable consequence of aging, but some landmark studies have demonstrated that it is a highly regulated process of mineralization which involves cellular and molecular signaling processes similar to those found in normal osteogenesis. The similarity of the molecular mechanisms in osteogenesis and vascular calcification has led to the knowledge that atherosclerotic calcification is an actively regulated process, not a passive mineralization.

The growing evidence that atherosclerosis and osteoporosis share several pathophysiologic mechanisms reinforces the interest in pharmacologic agents which could inhibit bone loss and also provide benefits in terms of slowing the progression of atherosclerosis. At present, only bisphosphonates (BPs), currently considered the drug of choice for the prevention and treatment of osteoporosis, could have this potential.

The interest in the relationships between BPs and atherosclerosis has recently shown a further increase after the publication of the results of the HORIZON study which reported a 28% reduction in mortality in hip fracture patients treated with an annual i.v. dose of zoledronic acid. In another study, it was revealed that patients who received BP therapy for osteoporotic fracture had a lower hazard of myocardial infarction during the 2-year follow-up period with respect to controls. Moreover, two recent studies have reported that oral BPs reduce mortality in osteoporotic patients and that the reduction in mortality could be mainly due to cardiovascular and cerebrovascular deaths.

To sum up, the BPs seem to have the potential of influencing atherosclerosis and calcium homeostasis at the level of vascular walls with several possible mechanisms which may differ according to the type, potency, dosage and administration route of BPs. However, until the present time, it is not yet clear which of these above-mentioned mechanisms may be the most important in humans and additional studies are needed to specifically address the mechanism by which BPs use could influence cardiovascular morbidity and mortality.

Cellular senescence is generally defined as irreversible cell-cycle arrest. Importantly, senescence is characterised by the development of a pro-inflammatory secretory phenotype, termed the senescence-associated secretory phenotype (SASP). The SASP is thought to be important for the immune-mediated clearance of senescent cells, however, may also be a contributor to tissue dysfunction. Evidence suggests that accumulation of senescent cells with time, leads to age-related loss of tissue function. Accordingly, senescent cells are found at sites of chronic age-related disease and have been causally implicated in the development of osteoarthritis, atherosclerosis, liver steatosis and pulmonary fibrosis.

The lung is particularly affected by the ageing process, showing clear decline in structure and function with age. Moreover, the ageing lung is characterised by the presence of senescent cells and several respiratory diseases have been identified as diseases of accelerated lung ageing. Chronic obstructive pulmonary disease (COPD) and idiopathic pulmonary fibrosis (IPF) are classic examples of respiratory diseases that increase in prevalence with age and have been associated with senescence.

The mitochondria can impact on aspects of the senescence phenotype in a number of possible ways and it has been suggested that dysfunctional mitochondria are an additional feature of senescent cells that enable them to mediate paracrine effects. Mitophagy, the selective degradation of defective mitochondria by autophagy, is reduced in senescent cells. This could, in part, be responsible for the increase in mitochondrial mass that has been described in senescence. The accumulation of the mitochondrial compartment and of dysfunctional mitochondria in particular, may be an important contributor to the pro-inflammatory aspects of cellular senescence.

It has been shown that mitochondrial dysfunction induced by mitochondrial DNA depletion, knockdown of mitochondrial sirtuin 3 (SIRT3), or through inhibition of the electron transport chain (ETC) induces senescence with a distinct phenotype, termed MiDAS (mitochondrial dysfunction-associated senescence). Our group recently designed a proof-of-principle experiment, which interrogated whether mitochondria are truly necessary for senescence. Utilising the parkin-mediated mitophagy system to completely remove mitochondria upon their depolarisation, we found that following a variety of senescence triggers (e.g. oxidative stress and oncogene activation) features of cellular senescence, including Sen-β-Gal activity and the SASP, were suppressed. The mitochondria may therefore be key to the regulation of some aspects of cellular senescence, such as the pro-inflammatory phenotype, and may be promising targets for SASP modulation.

Alzheimer's disease (AD) is the most common dementia type, with no treatment to slow down the progression of the disease currently available. The mechanisms of AD are poorly understood, and drug therapy has focused on restoring the normal function of neurons and microglia, i.e. cells mediating brain inflammation. The new study shows that astrocytes, also known as the housekeeping cells of the brain, promote the decline of neuron function in AD. The findings suggest that at least some familial forms of AD are strongly associated with irregular astrocyte function, which promotes brain inflammation and weakens neurons' energy production and signalling.

Astrocytes are important brain cells, as they support neurons in many different ways. Astrocytes are responsible, for example, for the energy production of the brain, ion and pH balance, and they regulate synapse formation, the connections between neurons. Recent evidence suggests that human astrocytes are very different from their rodent counterparts and thus, it would be essential to use human cells to study human diseases. However, the availability of human astrocytes for research has been very limited. The study used the induced pluripotent stem cell technology, which enables the generation of pluripotent stem cells from human skin fibroblasts. These induced stem cells can then be further differentiated to brain cells, e.g. neurons and astrocytes, with the same genetic background as the donor had. The study compared astrocytes from familial AD patients carrying a mutation in the presenilin 1 gene to astrocytes from healthy donors, and the effects of these cells on healthy neurons were also analysed.

The researchers found out that astrocytes in patients with Alzheimer's disease produced significantly more beta-amyloid than astrocytes in persons without AD. Beta-amyloid is a toxic protein that is known to accumulate in the brains of AD patients. In addition, AD astrocytes secreted more cytokines, which are thought to mediate inflammation. AD astrocytes also showed alterations in their energy metabolism which likely led to increased production of reactive oxygen species and reduced production of lactate, an important energy substrate for neurons. Finally, when astrocytes were co-cultured with healthy neurons, AD astrocytes caused significant changes on the signaling activity of neurons when compared to healthy astrocytes.

This study compared the association between different levels of physical activity and the risk of cardiovascular disease in elderly to middle-aged individuals. "We know that regular physical activity has major health benefits. Healthy adults are advised to do at least 150 minutes a week of moderate intensity or 75 minutes a week of vigorous intensity aerobic exercise to reduce their risk of cardiovascular disease. These recommendations are based primarily on research in middle-aged adults and we wanted to know whether regular physical activity yields comparable cardiovascular health benefits in elderly people."

The study included 24,502 adults aged 39 to 79 years who participated in the European Prospective Investigation into Cancer (EPIC) Norfolk cohort, a prospective population study that is part of the ten-country collaboration EPIC study. The cohort was primarily designed to assess dietary and other determinants of cancer, but data were also collected on determinants of cardiovascular disease. Participants were recruited between 1993 and 1997 from registries of general practices in the county of Norfolk, UK. On enrollment into the study, participants completed a health and lifestyle questionnaire, underwent a standardised physical examination and gave blood samples. Physical activity during work and leisure time was assessed with a questionnaire and participants were categorised as active, moderately active, moderately inactive and inactive.

Patients were followed up until 31 March 2015 for hospitalisation or death from cardiovascular events (coronary heart disease or stroke). Physical activity levels and time to cardiovascular events were investigated in three age categories: less than 55, 55 to 65 (middle-aged), and over 65 years of age (elderly). During a median follow-up of 18 years there were 5,240 cardiovascular disease events. In elderly participants, hazard ratios for cardiovascular events were 0.86, 0.87, and 0.88 in moderately inactive, moderately active and active people, respectively, compared to inactive people. In those aged 55-65 and less than 55 years, the associations were directionally similar, but not statistically significant.

"We observed an inverse association between physical activity and the risk of cardiovascular disease in both elderly and middle-aged people. As expected, there were more cardiovascular events in elderly participants, which could explain why the association only reached significance in this age category. Elderly people who were moderately inactive had a 14% reduced risk of cardiovascular events compared to those who were completely inactive. This suggests that even modest levels of physical activity are beneficial to heart health. Elderly people should be encouraged to at least do low intensity physical activities such as walking, gardening, and housework."

It is undeniable that the incidence of cardiovascular diseases, mainly heart failure, increases in the elderly population. Global aging is a hallmark of our century: the eldery population comprise roughly 15% of the population, and this scenario will increase of an additional 25% on average by 2050. This unprecedented population profile will inevitably imply, among others, an increasing burden of cardiovascular events, some of which are directly linked to cellular senescence and dysfunction. Thus, increasing knowledge on the various mechanisms causing the progressive decline of cellular and tissue function may aid in developing therapies to delay or treat age-related conditions and diseases. Consequently, the discovery of pathways responsible for increasing life span and health span, as both potential biomarkers and targets, is currently of primary interest.

Endothelial progenitor cells (EPCs) are considered a main circulating stem cell population finely controlling vascular homeostasis and repair, therefore representing an interesting crossroad between circulating markers, regenerative cells, and aging mechanisms. Importantly, the demonstration that EPCs can be systemically recruited from the bone marrow-associated niche, and that after engraftment are able to replace old vasculature with new mature endothelial cells, has completely overturned the theory about aging and can be considered a significant reference for the relationship between progenitor cells and aging. To date, EPCs represent one of the most studied example tools to rejuvenate the vascular system or to potentially delay the damages induced by aging.

Notably, multiple studies suggest that, in the settings of cell transplantation for cardiovascular regenerative purposes, it is important not only to enhance intrinsic "young" properties of therapeutic cells, such as EPCs, but also to grant an ideal host microenvironment where engraftment can occur. Therefore, approaches able to rejuvenate regenerative cells and/or preserve tissue homeostasis and physiology (i.e., delaying overall aging) should be synergistically combined.

One of the main mechanisms affecting senescence and aging at multiple levels is oxidative stress, which originates from several biochemical pathways triggered, among others, by environmental factors, and overall imbalancing the final amount of reactive oxygen species. In this review, we will discuss few circulating molecules, proteins and microRNAs, selected among those whose levels and related signaling pathways have been correlated to life span and healthy aging. In particular, we will discuss pathways with specific biological and rejuvenating roles in cellular senescence, cardiovascular functions, and with a potential or known role in the control of regenerative cell populations.

Accurate estimates of mortality at advanced ages are essential for forecasts of population aging and for testing the predictions of competing theories of aging. They also contribute to more reliable forecasts of future longevity. Earlier studies suggest that exponential growth of mortality (Gompertz law) is followed by a period of deceleration, with slower rates of mortality increase at extreme old ages. This mortality deceleration eventually produces the "late-life mortality leveling-off" and "late-life mortality plateaus" at extreme old ages. Researchers have provided a detailed description of this phenomenon in humans and even made the first estimates for the asymptotic value of the upper limit to human mortality. The same phenomenon of "almost non-aging" survival dynamics at extreme old ages is detected in other biological species, and in some species the mortality plateau can occupy a sizable part of their life.

Studies of mortality after age 110 years are scarce because of difficulties in obtaining reliable age estimates. It was demonstrated that the age misreporting at older ages results in mortality underestimation. Also, it was found that mortality deceleration is more expressed in the case of poor-quality data than with data of better quality. Recent analysis of detailed records from the U.S. Social Security Administration Death Master File for several single-year extinct birth cohorts demonstrated that the Gompertz law fits mortality data better than other models up to ages 105-106 years. However, existing studies of mortality after age 110 years reported flat mortality, which does not grow with age.

In this paper, we analyze mortality trajectories for supercentenarians, using data on a sufficiently large sample of supercentenarians (aged 110 and older) available in the International Database on Longevity (IDL). All ages of supercentenarians in the database were subjected to careful validation. These results demonstrate that hazard rates after age 110 years do not stay constant and suggest that mortality deceleration at older ages is not a universal phenomenon. These findings may represent a challenge to the existing theories of aging and longevity, which predict constant mortality in the late stages of life. One possibility for reconciliation of the observed phenomenon and the existing theoretical consideration is a possibility of mortality deceleration and mortality plateau at very high yet unobservable ages.

A new study identifies a signaling pathway that is essential for angiogenesis, the growth of new blood vessels from pre-existing vessels. The findings may improve current strategies to improve blood flow in ischemic tissues. "Our research shows that the formation of fully functional blood vessels requires activation of protein kinase Akt by a protein called R-Ras, and this mechanism is necessary for the formation of the hallow structure, or lumen, of a blood vessel. The findings are important because they shed new light on the biological process needed to increase blood flow in ischemic tissues."

Previous efforts to treat ischemia by creating new blood vessels have focused on delivering angiogenic growth factors like vascular endothelial growth factor (VEGF) to ischemic sites. But all of these studies, including more than 25 phase II and III clinical trials, have failed to offer significant benefit to patients. The research team used a combination of 3D cell culture and living tissue to show that VEGF promotes vascularization, but the vessel structures formed are chaotic, unstable and non-functional. "Functional vessels need to have a lumen; a pipe-like opening that allows oxygenated blood and nutrients to travel through the body, and VEGF alone cannot fully support the formation of such a vessel structure."

"Generating new blood vessels is similar to the way trees grow; sprouts develop from existing vessels and then branch out further and further to restore vascularity. This study shows that there are distinct steps and signals that control the process. First, VEGF activates Akt to induce endothelial cells to sprout. Then, R-Ras activates Akt to induce lumen formation. The second step involving Akt activation by R-Ras stabilizes the microtubule cytoskeleton in endothelial cells, creating a steady architecture that promotes lumen formation. We propose that VEGF and R-Ras activation of Akt signaling are complementary to each other, both are necessary to generate fully functional blood vessels to repair ischemic tissue. Our next step is to work toward promoting the combined signaling of Akt in clinical studies; prompting R-Ras activation through either gene therapy or pharmacologically in parallel with VEGF therapy."

The health advantages of high-intensity exercise are widely known but new research points to another major benefit: better memory. The findings could have implications for an aging population which is grappling with the growing problem of catastrophic diseases such as dementia and Alzheimer's. Scientists have found that six weeks of intense exercise - short bouts of interval training over the course of 20 minutes - showed significant improvements in what is known as high-interference memory, which, for example, allows us to distinguish our car from another of the same make and model.

The findings are important because memory performance of the study participants, who were all healthy young adults, increased over a relatively short period of time. The researchers also found that participants who experienced greater fitness gains also experienced greater increases in brain-derived neurotrophic factor (BDNF), a protein that supports the growth, function and survival of brain cells. "Improvements in this type of memory from exercise might help to explain the previously established link between aerobic exercise and better academic performance. At the other end of our lifespan, as we reach our senior years, we might expect to see even greater benefits in individuals with memory impairment brought on by conditions such as dementia."

For the study, 95 participants completed six weeks of exercise training, combined exercise and cognitive training or no training (the control group which did neither and remained sedentary). Both the exercise and combined training groups improved performance on a high-interference memory task, while the control group did not. Researchers measured changes in aerobic fitness, memory, and neurotrophic factor, before and after the study protocol. Now, researchers have begun to examine older adults to determine if they will experience the same positive results with the combination of exercise and cognitive training. "One hypothesis is that we will see greater benefits for older adults given that this type of memory declines with age. However, the availability of neurotrophic factors also declines with age and this may mean that we do not get the synergistic effects."

Thymic senescence contributes to increased incidence of infection, cancer, and autoimmunity at senior ages. This process manifests as adipose involution. As with other adipose tissues, thymic adipose involution is also controlled by PPARgamma. This is supported by observations reporting that systemic PPARgamma activation accelerates thymic adipose involution. Therefore, we hypothesized that decreased PPARgamma activity could prevent thymic adipose involution, although it may trigger metabolic adverse effects.

We have confirmed that both human and murine thymic sections show marked staining for PPARgamma at senior ages. We have also tested the thymic lobes of PPARgamma haplo-insufficient and null mice. Supporting our working hypothesis both adult PPARgamma haplo-insufficient and null mice show delayed thymic senescence. Delayed senescence showed dose-response with respect to PPARgamma deficiency. Functional immune parameters were also evaluated at senior ages in PPARgamma haplo-insufficient mice (null mice do not reach senior ages due to metabolic adverse affects). As expected, sustained and elevated T-cell production conferred oral tolerance and enhanced vaccination efficiency in senior PPARgamma haplo-insufficient, but not in senior wild-type littermates.

Of note, humans also show increased oral intolerance issues and decreased protection by vaccines at senior ages. Moreover, PPARgamma haplo-insufficiency also exists in human known as a rare disease (FPLD3) causing metabolic adverse effects, similar to the mouse. When compared to age- and metabolic disorder-matched other patient samples (FPLD2 not affecting PPARgamma activity), FPLD3 patients showed increased measures of T cell activity suggesting delayed thymic senescence, in accordance with mouse results and supporting our working hypothesis. In summary, our experiments prove that systemic decrease of PPARgamma activity prevents thymic senescence, albeit with metabolic drawbacks. However, thymic tissue-specific PPARgamma antagonism would likely solve the issue.