Aging is associated with an increased risk of metabolic disorders such as obesity, insulin resistance (IR), and other manifestations of metabolic syndrome in both humans and rodents. In parallel with these alterations, a low grade of inflammation has also been described in several tissues associated with aging. Aging is typically associated with increased adiposity and redistribution of adipose tissue (AT), characterized by a loss of subcutaneous adipose depot mass and a gain of fat in the abdominal visceral compartment.

Caloric restriction (CR) is the most efficient intervention to delay the deleterious effects of age-related metabolic diseases. Previous studies in several animal models have shown that CR has physiological effects on lifespan, and reduces body weight and glucose and insulin serum levels. Whether CR interventions in humans slow aging is not yet known. Accumulating data indicate that moderate CR with adequate nutrition has numerous beneficial effects against obesity, diabetes, inflammation, and cardiovascular diseases. However, the mechanisms involved in the amelioration of aging effects by CR are not well understood. Accretion of AT has been related to the development of age-associated metabolic alterations such as IR. Moreover, reduction of adiposity by CR or fat removal have demonstrated to ameliorate age-associated IR. The improvement of the metabolic status achieved by CR may well be due, at least in part, to the decreased adiposity.

Furthermore, increased adiposity by hypertrophy and/or hyperplasia has been demonstrated to increase macrophage infiltration. This circumstance, together with changes in adipocyte physiology that includes hypoxia, reticulum, and oxidative stress, leads to an inflammatory state which is a key factor in the AT expandability capacity. Nevertheless, AT is a complex organ with different localizations and functions beyond its traditional role as a fat storage unit.

A complete understanding of CR effects on AT biology requires the elucidation of whether these effects are preferentially mediated by white AT (WAT) and/or brown AT (BAT), the contribution of specific WAT depots, and the relevance of differentiation/trans-differentiation to beige AT. WAT also has an important endocrine role by secreting different peptide hormones (adipokines) including adiponectin, which regulates insulin sensitivity, as well as glucose and energy homeostasis. In contrast to WAT, BAT plays a central role in energy expenditure via expression of uncoupling protein 1 (UCP-1). BAT is the major site for both cold- and diet-induced thermogenesis, and its atrophy has been observed in obese and older individuals in association with increased visceral fat and hyperglycemia. Consequently, defective WAT and BAT function may exacerbate the development of metabolic complications of obesity/aging.

Here, we aimed to investigate whether the plasticity of the WAT and BAT depots (hypertrophy and/or hyperplasia, extracellular matrix remodeling, inflammation, and browning or whitening capacity) is differentially affected at middle age, and whether moderate CR results in beneficial metabolic effects regulating the functionality of these AT depots. We show that several metabolic alterations of old animals are already being developed in middle-aged animals. These alterations include development of IR, altered WAT and BAT plasticity, as well as alteration of thyroid axis status, which can be mitigated, at least to some extent, by moderate and long-term CR.

Dramatic breakthroughs in medicine, public health, and social and economic development have resulted in unprecedented extensions of the human lifespan across the world over the past century. This triumph for humanity provides new opportunities as well as new challenges. Globally, we are facing a major demographic shift. Today, 8.5% of people worldwide (617 million) are aged 65 and over. By 2050, this percentage is projected to more than double, reaching 1.6 billion. The global population of the "oldest old" - people aged 80 and older - is expected to more than triple between 2015 and 2050, growing from 126 million to 447 million.

At the current pace, population aging is poised to impose a significant strain on economies, health systems, and social structures worldwide. But it doesn't have to. We can envision, just on the horizon, an explosion of potential new medicines, treatments, technologies, and preventive and social strategies that could help transform the way we age and ensure better health, function, and productivity during a period of extended longevity. Multidisciplinary solutions are urgently needed to maximize the number of years lived in good health and a state of well-being. Now is the time to support the next breakthroughs in healthy longevity, so that all of us can benefit from the tremendous opportunities it has to offer.

The National Academy of Medicine is launching a Global Grand Challenge for Healthy Longevity - a worldwide movement to increase physical, mental, and social well-being for people as they age. The initiative will have two components: a prize competition to catalyze breakthrough innovations from any field, and an evidence-based report authored by an international commission.

Johnson & Johnson Innovation today announced the signing of a sponsorship agreement with the National Academy of Medicine (NAM) to be the principal corporate partner of the Healthy Longevity Catalyst Awards in the United States. Part of the Healthy Longevity Global Grand Challenge1 founded by the NAM, the Catalyst Awards are a global prize competition to launch later this year, designed to stimulate innovation to transform the field of healthy longevity. The program will culminate in one or more Healthy Longevity Grand Prizes for major breakthroughs in increasing human healthspan.

The NAM Grand Challenge will roll out over three distinct phases and employ a tiered model of awards and prizes to stimulate new research and solutions around healthy longevity. Under the agreement, Johnson & Johnson Innovation will provide funding for the foundational Healthy Longevity Catalyst Awards in the U.S., to identify innovative, entrepreneurial proposals that have the greatest chance of being translatable into solutions to prevent, intercept and/or cure disease or deficits related to aging. "We envision a world in which widespread disease is a historical artifact and people enjoy longer, healthier lives, promoted by technological and medical advances. To achieve this, we need to shift the paradigm from today's widespread focus on 'disease care' - where we wait for people to get sick, to only then do something about it - towards true health care, by keeping people well in the first place, eliminating disease and restoring people to full health."

Can you tell us what kind of things Ichor Therapeutics is going to be doing?

One of the challenges in the aging space is that the kind of underlying discovery work that usually drives translational pipelines is really lacking, because the space is just so new. If you're looking at molecular targets of cardiovascular disease, cancer, or things like that, a lot of these targets have been thoroughly vetted by academic institutions in the peer-reviewed literature, and you have some level of confidence that the thing that you're going after is actually an appropriate target. But, because the aging space is so new, there's lots of new targets that are being discovered, but there hasn't really been enough time for academia to properly vet those targets. Some of them are very good real targets that we should be going after, and others are artifacts and might not actually be real or as impactful as we think.

So, at Ichor, we started doing, a while ago, a lot of contract work to try to help other companies that need to bring industrial-grade rigor to basic science and to early discovery and then move from that early-stage discovery work into full-on development programs, which are more akin to a traditional pharmaceutical pipeline. That contract work has grown; we've helped a lot of companies and worked with a lot of clients, and we've run into a need to have dedicated teams for project management and really making sure that all of the client projects get plugged into the pipeline to get our best efforts and everything else, and that's where Huda's coming in and spinning out all of our contract research into Icaria Life Sciences.

Why is Alkahest focusing on plasma proteins as a promising area for rejuvenation therapies?

Our founding science demonstrated that there are certain proteins present in plasma that can confer effects on biological function in aging. Their relation to the processes of aging is supported by the observation that many of these functional proteins increase or decrease with age - we have termed these functional plasma proteins chronokines. There are beneficial chronokines known to decline with age that we can increase and thus delay the onset of aging-related disorders, and there are detrimental chronokines which increase with age that we can inhibit for this purpose. We have therefore focused on deeply understanding the plasma proteome as a source of therapies, both plasma-based and traditional pharmaceutical modalities like small molecule inhibition.

Why use rapalogs rather than just rapamycin? Is there actually good data showing that rapamycin in moderate doses is harmful to humans?

Our lead program is determining if TORC1 inhibition improves the function of the aging immune system and thereby decreases the incidence of respiratory tract infections (RTIs) in elderly humans. In a Phase 2a clinical trial, we found that RTB101, a catalytic site mTOR inhibitor (not a rapalog), led to a greater reduction in infection rates than the rapalog everolimus. We used very low doses of both RTB101 and everolimus in this trial, and both drugs were safe and well tolerated at these low doses.

When do you anticipate finishing clinical trials and being able to offer commercially available therapies for RTIs and other diseases that resTORbio is targeting?

We anticipate finishing two Phase 3 clinical trials, which will determine if RTB101 decreases the incidence of respiratory illness in people age 65 and older, in 2020. If the Phase 3 trials are successful, we anticipate submitting a New Drug Application.

What do you think is the best method of measuring telomeres?

We call the most sensitive assay TeSLA, for telomere shortest length assay. Most scientists use a qPCR assay that is not very reliable but easy to use. It is well established that it is the shortest telomeres that leads to replicative senescence. There are thousands of published papers using the qPCR making extraordinary claims based on very small differences in average telomere length. Other methods include TRF and Q-FISH, and these are intermediate in their ability to see some but not all the shortest telomeres.

What are your thoughts on restoring telomere length using transient telomerase induction as a therapeutic approach to aging?

It is a reasonable idea, and we are currently doing such experiments. Initially, it will be done ex vivo, e.g. in the cell culture lab, to prove it works and does no harm. We can then give individuals back their own cells, potentially with slightly elongated telomeres.

The largest study to date of cardiorespiratory fitness in healthy people found that moving more is linked to living longer, regardless of age, sex, and starting fitness level. "People think they have to start going to the gym and exercising hard to get fitter. But it doesn't have to be that complicated. For most people, just being more active in daily life - taking the stairs, exiting the metro a station early, cycling to work - is enough to benefit health since levels are so low to start with. The more you do, the better."

The study included 316,137 adults aged 18-74 years who had their first occupational health screening between 1995 and 2015 in Sweden. Cardiorespiratory fitness was measured using a submaximal cycle test and expressed as maximal oxygen uptake (VO2 max) in ml/minute/kg body weight. This is the maximum amount of oxygen the heart and lungs can provide the muscles during exercise. You can estimate your VO2 max using either submaximal cycle tests, treadmill tests, or walking tests. Swedish national registries were used to obtain data on all-cause mortality and first-time cardiovascular events (fatal and non-fatal myocardial infarction, angina pectoris, or ischaemic stroke) during 1995-2015. The risk of all-cause mortality and cardiovascular events fell by 2.8% and 3.2%, respectively, with each millilitre increase in VO2 max.

Power depends on the ability to generate force and velocity, and to coordinate movement. In other words, it is the measure of the work performed per unit time (force times distance); more power is produced when the same amount of work is completed in a shorter period or when more work is performed during the same period. Climbing stairs requires power - the faster you climb, the more power you need. Muscle power gradually decreases after 40 years of age. "We now show that power is strongly related to all-cause mortality. But the good news is that you only need to be above the median for your sex to have the best survival, with no further benefit in becoming even more powerful."

The study enrolled 3,878 non-athletes aged 41-85 years who underwent a maximal muscle power test using the upright row exercise between 2001 and 2016. The average age of participants was 59 years, 5% were over 80, and 68% were men. During a median 6.5-year follow-up, 247 men (10%) and 75 women (6%) died. Median power values were 2.5 watts/kg for men and 1.4 watts/kg for women. Participants with a maximal muscle power above the median for their sex (i.e. in quartiles three and four) had the best survival. Those in quartiles two and one had, respectively, a 4-5 and 10-13 times higher risk of dying as compared to those above the median in maximal muscle power.

Researchers examined data from a total of 12,658 men from the Health Professionals Follow-Up Study, tracking them from 2008 to 2012. The team used criteria from the Alternate Healthy Eating Index-2010 to assess the quality of each of the men's diets and assign an individual score. These criteria included six food categories for which higher intake is better (vegetables, fruit, whole grains, nuts and legumes, long-chain omega-3 fatty acids and polyunsaturated fatty acids); one food category for which moderate intake is better (alcohol), and four categories for which lower intake is better (sugar-sweetened beverages and fruit juice, red and processed meats, trans fatty acids and sodium).

Researchers found that higher diet scores (meaning better diet quality) were strongly associated with decreased odds of physical impairment, including a 25 percent lower likelihood of developing impairment in physical function with aging. An overall healthy diet pattern was more strongly associated with better physical function than an individual component or food. But the team did see that greater intake of vegetables, nuts, and lower intake of red or processed meats and sugar-sweetened beverages each modestly lowered risk of impairment.

Elevated proinflammatory cytokines in aging animals, including humans, have been shown to contribute to various organ dysfunctions and human diseases. Indeed, extensive studies in vitro have shown that proinflammatory cytokines can induce senescence of a number of tissue culture cells. For example, either overexpression of CXCR2 in human primary fibroblasts or treatment of these cells with IL-1α or TNF-α induces cellular senescence. These proinflammatory cytokines can also reinforce cellular senescence in other primary tissue culture cells triggered by forced oncogene expression. Despite these studies, however, the cell/tissue source of age-associated inflammation and whether such inflammation disrupts structural proteins and thus contributes to organ aging remain unclear in any organism.

Considering the varied environments different tissues/organs reside in and the different functions they perform, it is highly likely that the inflammatory causes and consequences are different in different tissues and organisms. Cellular senescence triggered by inflammation has been implicated in aging and organ degeneration in mammals. The multitudes of senescence-associated cellular changes have, however, made it difficult to pinpoint which of these changes makes a key contribution toward age-associated organ dysfunction. Additionally, vertebrate organs often contain complex cell types, which makes it challenging to identify the cell sources and targets of inflammation that contribute to organ aging. Among many organs, the vertebrate thymus has a relatively simple stromal cell population called thymic epithelial cells (TECs) that are essential for thymic development, organization, and function. The TECs can thus serve as a relatively simple model to understand how inflammation and cellular senescence could influence structural proteins and in turn contribute to organ aging.

As a primary lymphoid organ, the thymus produces naïve T cells essential for adaptive immunity. Differentiated from the Foxn1-positive progenitors, the TECs consist of cortical TECs (cTECs) and medullary TECs (mTECs) that make up the cortical and medullary compartments of the thymus, respectively. The age-associated thymic involution or size reduction is known to contribute to the dysfunction of the immune system. Studies in mice have shown that thymic involution can be separated into two phases. The first phase occurs within ~6 weeks after birth and is characterized by a rapid reduction of thymic size. This phase is referred to as the developmentally related involution and it does not negatively affect the immune system. The second phase of thymic involution occurs during the process of organism aging and is manifested as a gradual reduction of thymic size and naïve T-cell production. Foxn1 reduction in TECs soon after birth appears to contribute to the first developmental phase of thymic involution, but the cause of the second age-associated phase of involution is unknown.

Among the structural proteins, lamins, the major component of the nuclear lamina that forms a filamentous meshwork in the nucleus has been implicated in proper organogenesis. Interestingly, reduction of lamin-B1 is found in the aging human skins, Alzheimer's disease patient brains, and various Drosophila organs, but the cause of such reduction and its impact on organ function, especially in mammals, remain poorly understood. We show that of the three lamins, only lamin-B1 is required in TECs for the development and maintenance of the spatially segregated cortical and medulla compartments critical for proper thymic function. We identify several proinflammatory cytokines in the aging thymus that trigger TEC senescence and TEC lamin-B1 reduction. Importantly, we report the identification of 17 adult TEC subsets and show that lamin-B1 reduction in postnatal TECs contributes to the age-associated TEC composition change, thymic involution, reduced naïve T-cell production, and lymphopenia.

What is the founding story and motivation behind the Party for Health Research?

In 2012 I learned that we have a chance to develop effective medicine against all diseases of old age in the near future. Because I think that this is so very important, I decided to make it to my life´s purpose to help with this development. The question I asked myself was, how I could most effectively do that. There are already non-profit organisations in this area, to which people can donate money to help this research directly and they do advocacy. I decided to also do advocacy, because in my opinion much more advocacy is needed. The more people know about this, the more support the movement will get. I decided to found a single-issue party with others, the German Party for Health Research (German name: Partei für Gesundheitsforschung).

The party is not only a very good way to do advocacy, but it also gives people an additional easy option, to support this cause by voting for the party in elections, by giving a support signature for the party's participation in the elections and by joining the party. One goal of our party is, that the big parties will also include our issue more into their program and they will probably only do that, if they would get votes for that. So the more votes we get the more likely it is. Unfortunately, our issue is ignored by most people, both by politicians and by the general public. Almost nobody actively demands more government investments in this field, e.g. there are no big demonstrations for more research against age-related diseases. By doing advocacy, we try to change that.

Why did you choose single-issue politics as the political action to follow in terms of battling aging-related diseases?

In my opinion, we need to educate much more scientists and have much more people doing research in this field to hasten the development of effective medicine against the diseases of old age significantly. All other political optimizations will not have the desired effect without this one. Our party only covers this one issue and no other issues. If a small party, who covers all issues, gets 2% and a big party gets 20%, the big party will have no reason to include the demands of the small party more into their program, because they would probably lose more votes than they would win. But if we manage to get 2% with our single issue, the big parties would have a very good reason to include our demand into their program, because almost nobody opposes more research against the diseases of old age, so they wouldn't lose any votes with that, only potentially win over some of our voters. With a single issue, everyone knows exactly, why people voted for us, and how extremely important our demand is for them.

What are the main points of your programme for the EU election?

We only have one point: We demand, that an additional 30 billion per year of the EU budget are invested into the development of effective medicine against the diseases of old age. To my knowledge at the moment only about 1 billion per year of the EU-budget are invested in the whole area of health research with no aim of the big parties yet to increase this amount significantly.

A new study adds evidence that Alzheimer's disease (AD) pathology makes nearby cells senescent. Scientists now report that in both people and animals, oligodendrocyte precursor cells (OPCs) surrounding amyloid-β (Aβ) plaques stop differentiating into myelin-repairing oligodendrocytes. Instead, they release inflammatory molecules into their environment and leave damaged axons bare of myelin. Drugs that clear senescent cells - known as senolytics - eliminated senescent OPCs and reduced neuroinflammation, microgliosis, and Aβ load in transgenic mouse models of AD, all the while improving their learning and memory. The results tap senolytic drugs as a potential therapy for Alzheimer's disease.

Senescent cells are proliferative cells that have stopped dividing with age, usually after a certain number of divisions. They remain metabolically active, however, releasing proinflammatory cytokines. Senescent cells have been found to contribute to peripheral disorders, including diabetes, cancer, and atherosclerosis. Scientists have started asking whether senescent cells accumulate in the brain. Researchers found that neurons containing tangles had entered a senescent state in both postmortem AD brain tissue and rTg4510 mice. They reported that tau pathology caused senescence of astrocytes and microglia in PS19 mice. Both sets of researchers found that clearing away the aged cells prevented or slowed neurodegeneration and cognitive deficits in mice.

Do Aβ plaques bring about senescence in the brain? In the current study, researchers examined human postmortem tissue. In samples of the inferior parietal cortices of eight AD patients, eight with mild cognitive impairment, and eight age-matched controls, they used antibodies to label Aβ plaques, microglia, astrocytes, and OPCs. OPCs occur throughout the brain - even in gray matter where there are fewer myelinated axons than in white matter - and they migrate to sites of neurodegeneration to repair myelin there. In AD patients, OPCs co-localized with markers of senescence, namely tumor-suppressor proteins p16 and p21, in 80 percent of the plaques. Astrocytes and microglia did not appear to be senescent.

What if the researchers cleared senescent OPCs from mouse brains? Zhang treated APPPS1 mice with two FDA-approved senolytic compounds. Dasatinib and quercetin (D+Q) eliminate senescent cells from tissues by transiently inhibiting tyrosine kinases that suppress apoptosis, thus killing only senescent cells. Because it takes time for healthy, dividing OPCs to become senescent, the drugs can be given intermittently. In this way, treating 5-month-old APPPS1 mice for nine days halved OPC senescence. Once-weekly treatments for 11 weeks beginning at 3.5 months old almost eliminated senescent OPCs in the hippocampi of APPPS1 mice. These animals better remembered which arm they had previously explored in a Y maze and where the hidden platform was in a water maze. D+Q treated mice accumulated about one-third the Aβ plaque load and half the level of inflammatory cytokines in the hippocampus and entorhinal cortex, as untreated controls.

Most cancers contain epigenetic and genetic alterations, but how they work together to cause cancer was not well understood. Researchers have found that epigenetic alterations characterized by changes in DNA methylation - a process by which cells add a tiny methyl group to a beginning region of a gene's DNA sequence, often silencing the gene's activation - are a key component of cancer initiation. In their laboratory model, known cancer-driving gene mutations did not cause colon cancers to form unless epigenetic methylation changes to the DNA were also present.

Cancer is primarily a disease of aging, with the majority of cancers occurring in people over age 60. To study colon cancer in the setting of aging, researchers used a mouse colon organoids derived from six- to eight-week old mice. Organoids are lab-grown cells that clump together and resemble specific normal organs, such as the colon in this case, and can grow indefinitely. The researchers compared colon organoids with and without mutations in the BRAFV600E, a known cancer-driving gene mutation common particularly to human right sided colon cancer. As the organoids aged, they remained genetically stable but became epigenetically unstable, even without the BRAF mutation being introduced. The scientists found that acquired DNA methylation during "aging" of the organoids, silenced cancer protective genes in a pattern similar to human aging that associates with risk for colon cancer by decade.

The team engineered the colon organoids to contain a transgenic BRAF mutation they could activate on demand. In all of the BRAF-activated organoids, DNA methylation was necessary for the mutation to initiate tumor development. Without this epigenetic change, the mutation did not initiate cancer in mice. "Essentially, we 'aged' young cells to become old, methylation-wise. In general, the risk of cancer increases with age, but if we can shift the epigenetic landscape through lifestyle changes to limit the impact of methylation fluctuations, we might be able to prevent cancer from developing. Although these studies were done to examine BRAFV600E-mediated tumorigenesis, we believe our findings apply to the cancer driver roles of other oncogenic mutations."

The link between brain dysfunction and chronic kidney disease (CKD) was first noted in 1930, so it is not a new finding. Experts spoke of "dialysis dementia" or "uremic encephalopathy". What is new, however, is the finding that mild cognitive impairment (MCI) may already be present in earlier stages of CKD, affecting approximately one in two CKD patients (prevalence varies in studies between 30% and 60%). In contrast to "normal" dementia, CKD-related MCI is not age-related, meaning the cognitive impairment exceeds that expected of the normal aging process. It usually worsens with declining glomerular filtration rate (GFR) of patients - the lower the GFR, the higher the risk of being affected by cognitive impairments.

The pathogenesis appears complex, involving a variety of factors besides vascular disease - the most frequent trigger for "standard" dementia in elderly people. Dialysis does not help or stop the process of cognitive decline, thus experts believe that factors which are not corrected completely by dialysis, for example the clearance of middle molecules, uncontrolled secondary hyperparathyroidism and anemia, may further the process of cognitive impairment. One interesting finding, though, is that kidney transplantation appears to slow cognitive decline.

The paucity of intervention strategies is the reason why there is no routine screening for MCI in CKD patients. Cognitive decline is one of many manifestations of brain damage that clearly accompany the decline of kidney function. Other manifestations include sleep disorders and depression, both of which are also common in CKD patients. "Chronic kidney disease is an illness that obviously affects the body and the brain. The latter has been neglected by research, but new tools in neuroscience, such as tractography or two-photon microscopy hold out the promise of gaining further insights in the pathogenesis of MCI so that we might identify therapy targets and be able to treat it one day. Until then, we have to be aware that CKD is a severe disease which affects not only the kidneys, but also other organs systems and the brain - even in early stages. This is why we should strengthen CKD prevention strategies and raise awareness for this illness that is much more severe than most people think."

Disability-adjusted life years (DALYs) are used globally to quantify the number of healthy years of life lost from the presence of a disease, disability, or injury. The burden of chronic, non-fatal health loss and early mortality is evaluated separately and compared across populations. More studies are needed for understanding how aging is linked with disease. Calculating the years lived with a disease (YLDs) and years of life lost (YLLs) from premature mortality will provide insights into the burden of common health conditions for the growing aging adult population. This information can help to identify which health conditions contribute most to the number of healthy years of life lost for aging adults, thereby informing how healthcare providers and interventions prioritize treatment and prevention efforts. The purpose of this study was to determine the burden of 10 common health conditions for a nationally-representative sample of middle-aged and older adults in the United States.

The principal findings of this investigation revealed that over 1-million years of healthy life were lost for middle-aged and older Americans from the 10 health conditions evaluated over the 16 year study period. Although aging adults were impacted by each health condition, hypertension accounted for the greatest burden; whereas, hip fractures had the lowest number of DALYs. There were 30,101 participants included. Sex stratified DALY estimates ranged from 4092 (fractured hip) to 178,055 (hypertension) for men and 13,621 (fractured hip) to 200,794 (hypertension) for women. The weighted overall DALYs were: 17,660 for hip fractures, 62,630 for congestive heart failure, 64,710 for myocardial infarction, 90,337 for COPD, 93,996 for stroke, 142,012 for cancer, 117,534 for diabetes, 186,586 for back pain, 333,420 for arthritis, and 378,849 for hypertension. In total, there were an estimated 1,487,734 years of healthy life lost from the 10 health conditions examined over the study period.

Researchers have demonstrated that electrostimulation can improve the working memory of people in their 70s so that their performance on memory tasks is indistinguishable from that of 20-year-olds. The research targets working memory - the part of the mind where consciousness lives, the part that is active whenever we make decisions, reason, recall our grocery lists, and (hopefully) remember where we left our keys. Working memory starts to decline in our late 20s and early 30s, as certain areas of the brain gradually become disconnected and uncoordinated. By the time we reach our 60s and 70s, these neural circuits have deteriorated enough that many of us experience noticeable cognitive difficulties, even in the absence of dementias like Alzheimer's disease.

Researchers asked a group of people in their 20s and a group in their 60s and 70s to perform a series of memory tasks that required them to view an image, and then, after a brief pause, to identify whether a second image was slightly different from the original. At baseline, the young adults were much more accurate at this, significantly outperforming the older group. However, when the older adults received 25 minutes of mild stimulation delivered through scalp electrodes and personalized to their individual brain circuits, the difference between the two groups vanished. Even more encouraging? That memory boost lasted at least to the end of the 50-minute time window after stimulation - the point at which the experiment ended.

Coupling occurs when different types of brain rhythms coordinate with one another, and it helps us process and store working memories. Slow, low-frequency rhythms - theta rhythms - dance in the front of your brain, acting like the conductors of an orchestra. They reach back to faster, high-frequency rhythms called gamma rhythms, which are generated in the region of the brain that processes the world around us. But when the theta rhythms lose the ability to connect with those gamma rhythms to monitor them, maintain them, and instruct them, then the melodies within the brain begin to disintegrate and our memories lose their sharpness. Meanwhile, synchronization, when theta rhythms from different areas of the brain synchronize with one another, allows separate brain areas to communicate with one another. This process serves as the glue for a memory, combining individual sensory details to create one coherent recollection. As we age, our theta rhythms become less synchronized and the fabric of our memories starts to fray.

The present work suggests that by using electrical stimulation, we can reestablish these pathways that tend to go awry as we age, improving our ability to recall our experiences by restoring the flow of information within the brain. And it's not just older adults that stand to benefit from this technique: it shows promise for younger people as well. In the study, 14 of the young-adult participants performed poorly on the memory tasks despite their age - so the researchers called them back to stimulate their brains too. "We showed that the poor performers who were much younger, in their 20s, could also benefit from the same exact kind of stimulation. We could boost their working memory even though they weren't in their 60s or 70s. Coupling and synchronization exist on a continuum. On one end of the spectrum, someone with an incredible memory may be excellent at both synchronizing and coupling, whereas somebody with Alzheimer's disease would probably struggle significantly with both. Others lie between these two extremes-for instance, you might be a weak coupler but a strong synchronizer, or vice versa."

Even to the untrained eye it has always been apparent that different people age differently. Subjective evaluation of age rather accurately assesses the ravages of time and coincides quite adequately to more objective metrics. Nevertheless, we would like to be able to reference such objective measures to examine in greater detail the dimensions of aging. The dimensions of aging encompass at least three different aspects. The first incorporates prediction of survival or mortality. In other words, we want to be able to relate a process, aging, to an outcome, longevity. This has long been a domain of aging research, and it continues to engage biodemographers. The second attempts to relate an aging process to the ability to function. So-called healthy aging derives from this approach. Finally, the need to evaluate potential therapies or interventions to extend this healthspan is yet another dimension.

Deficit indices, also known as frailty indices, constitute an uncomplicated way in which to describe the behavior of a complex aging system. Deficit indices have a long history in human aging research and in geriatrics. A deficit index is constructed from a number of signs, symptoms, marks, and manifestations. The number can be relatively small, about twenty, or much larger, as long as it is statistically sufficient. These deficits should encompass many different body or physiological systems. The deficit index arises by summing the deficits counted and dividing by the total number of deficits assessed. Increasing the number of deficits scored improves deficit index performance.

Recently, the deficit index has acquired a strong theoretical underpinning. The deficits are represented by the components of a network, in which they can be damaged or undamaged (deficits per se). By definition, the components are connected by edges. Some of them have more edges than others, performing a more critical role in the network. Damage in this network, whether partial or complete, is propagated across the network or system because of the edges. This rational, systems biology-based nature of the deficit index distinguishes it from other quantitative measures of biological age. In addition, the deficit index is uncomplicated mathematically, as opposed to most of the other measures, and it predicts mortality without the incorporation of chronological age as one of its items.

We have constructed a deficit index we call frailty index-34 (FI34), consisting of 34 health and function variables. The reference to frailty in the name stresses the relevance of the index as a measure of relative health. FI34 is a good predictor of mortality, so it is a measure of biological age. It increases exponentially with calendar age, as we would expect of a predictor of mortality. Moreover, it distinguishes different patterns of aging, and it is heritable. FI34 also captures the individual variability or heterogeneity of aging among individuals. Although constantly increasing with chronological age across a population, it shows variation among individuals in cross-section and longitudinally.

The decline in muscle strength is one of the most striking phenotypes of aging, which is only partially accounted for by a reduction in muscle mass, suggesting a loss of cellular and molecular integrity of muscle tissue, and/or impairment of neuromuscular control with aging. Low muscle strength is a powerful, independent predictor of slow gait, mobility disability, and early mortality. No interventions are currently available that can prevent or attenuate the decline in muscle strength with aging except exercise, especially resistance training. In spite of this evidence, the percentage of people who regularly exercise is still low and this percentage declines with aging.

It has been suggested that people who have an active lifestyle in daily life have a slower decline of muscle mass and strength with aging. Understanding how physical activity in daily life affects muscle physiology in older persons might help in developing new interventions that, by targeting the same mechanisms triggered by physical activity, could prevent the development of muscle impairment with aging. Numerous studies have investigated the impact of a sedentary lifestyle and low physical activity on health outcomes in both younger and older individuals. Physical inactivity, either long or short-term, negatively affects muscle performance and is associated with diminished aerobic capacity, as well as reduced insulin sensitivity and basal metabolic rate. Furthermore, physical activity alone has been shown to improve and regulate metabolic homeostasis and metabolic efficiency.

Overall, an active lifestyle could be conceptualized as a mixture of aerobic and resistance exercise, but the intermittent, and variable mixture of these activities make it difficult to study. Endurance and resistance training elicit both common and specific metabolic/morphologic adaptations in muscle, some of which are common between tissues. In general, the stress that is induced by exercise challenges energy homeostasis in myocytes, shifting the cellular environment towards an oxidative state. This induces microdamage that stimulates both transcriptional and posttranscriptional responses, which then promotes synthesis of specific proteins that seek to reestablish a different homeostatic equilibrium. Endurance training maximally stimulates mitochondrial biogenesis, enhances aerobic metabolism and fatty acid utilization, and produces change in muscle fiber composition. In contrast, heavy resistance training stimulates the synthesis of contractile proteins, leading to muscle hypertrophy, and increases in maximal contractile force speed and output. Whether an active lifestyle is sufficient to activate the same biological mechanisms triggered by endurance and resistance training is unknown.

In recent years, a handful of studies have examined the protein composition of human muscle cell types and tissues including proteomic differences between old and young muscle, athletes and non-athletes, exercise in extreme conditions, and physical activity and metabolic disorders. These studies have helped to characterize the physiological adaptations of healthy human muscle to different types of exercise. Most of these studies focused on the acute and immediate effects of short bouts of high intensity exercise in either human or mice/rat models, as well as long-term effects of exercise. However, very little research has focused on assessing the association of daily physical activity with the muscle proteome in healthy community-dwelling individuals.

To verify whether an active lifestyle is associated with detectable changes in skeletal muscle and to start to characterize these changes, we performed a quantitative, mass spectrometry-based proteome analysis of muscle specimens from a group of well-characterized healthy individuals with a wide age-range (20-87 years) and who self-reported different levels of physical activity. Independent of age and technical covariates, we found that high levels of physical activity (versus low levels) were associated with an overrepresentation of mitochondrial proteins, tricarboxylic acid (TCA) cycle enzymes, chaperone proteins, and proteins associated with genome maintenance. In contrast, proteins related to the spliceosome and transcription regulation, immune proteins, apoptosis proteins, DNA damage proteins, and senescent proteins were underrepresented in muscle of participants who reported higher physical activity. Differences observed were mostly opposite to those observed with skeletal muscle aging.

Generation of thick vascularized tissues that fully match the patient still remains an unmet challenge in cardiac tissue engineering. Here, a simple approach to 3D-print thick, vascularized, and perfusable cardiac patches that completely match the immunological, cellular, biochemical, and anatomical properties of the patient is reported. To this end, a biopsy of an omental tissue is taken from patients. While the cells are reprogrammed to become pluripotent stem cells, and differentiated to cardiomyocytes and endothelial cells, the extracellular matrix is processed into a personalized hydrogel. Following, the two cell types are separately combined with hydrogels to form bioinks for the parenchymal cardiac tissue and blood vessels.

In recent years, the strategy of 3D tissue printing evolved, allowing the creation of vasculature within hydrogels. However, in most of the studies, the endothelial cells (ECs) that form the blood vessels were printed without the parenchymal tissue, which was later on casted on top of the vessels. In other pioneering works, the researchers were able to print ECs together with thin surrounding tissues. However, the obtained tissues were not thick, the ECs did not form open blood vessels and perfusion through them was not demonstrated. Different strategies include printing of the parenchymal tissue with open, a-cellular channels in between, followed by external perfusion of ECs to form the blood vessels. Finally, decellularized hydrogels were also used for printing nonvascularized tissues. Therefore, to the best of our knowledge, the aforementioned studies did not demonstrate printing of a full, thick vascularized patch in one step.

Here, we report on the development and application of advanced 3D printing techniques using the personalized hydrogel as a bioink. In this strategy, when combined with the patient's own cells, the hydrogel may be used to print thick, vascularized, and perfusable cardiac patches that fully match the immunological, biochemical and anatomical properties of the patient. Furthermore, we demonstrate that the personalized hydrogel can be used to print volumetric, freestanding, cellular structures, including whole hearts with their major blood vessels

There is considerable between-person variation in the rate of ageing, and individual differences in their susceptibility to disease and death. The identification of individuals at greatest risk of age-related diseases and death would provide important opportunities for targeting prevention and intervention. There is thus great interest in molecular targets as clinical biomarkers which accurately predict the risk of age-related diseases and mortality. These biomarkers, which include cellular senescence, genomic instability, telomere attrition, and mitochondrial dysfunction, appear to capture pivotal aspects of biological age and have been associated with a number of age-related diseases and mortality.

It is well established that as individuals age, there is a raft of molecular changes that occur within the cells and tissues. Changes in DNA methylation patterns have been shown to occur with ageing, and thus may be a fundamental mechanism that drives human ageing. Epigenetic biomarkers of ageing, otherwise known as the epigenetic clock, have been developed using DNA methylation measurements. Referred to specifically as 'DNA methylation age' (DNAmAge), they provide an accurate estimate of age across a range of tissues, and at different stages of life, and are some of the most promising biomarkers of ageing. DNAmAge has also permitted the identification of individuals who show substantial deviations from their actual chronological age, and this 'accelerated biological aging' has been associated with unhealthy behaviours, frailty, cancer, diabetes, cardiovascular diseases, dementia, and mortality risk.

An increasing number of studies have investigated the association between DNAmAge, longevity, age-related disease, and mortality, with a total of 23 studies included in this systematic review and all published from 2015 onwards. Our primary finding is that there is sufficient evidence to support an association between accelerated DNAmAge and an increased risk of all-cause mortality. However, it remains unclear whether these methylation changes at specific CpGs are driving ageing or are consequences of the ageing process (cellular ageing, underlying disease processes.