The SENS Research Foundation funding has been critical to our work studying and developing methods to reverse the effects of advanced glycation end-products (AGEs) in aging. AGEs are non-enzymatic modifications that build up on proteins as people age, leading to inflammation and tissue damage. Early on, our lab focused significant effort on developing the first total synthesis of glucosepane - a major AGE cross-link found in human tissues - but we were unable to find funding from any of the traditional sources. The SENS Research Foundation came to our aid, and supported this research for over 5 years. In 2015, our glucosepane synthesis efforts were published in Science, and lay a foundation for developing drugs capable of detecting and reversing tissue damage in aging. We are deeply grateful to the SENS Research Foundation and Fight Aging! for all of their support and look forward to exciting, life-extending work to come!

A 14-year-old girl who said before dying of cancer that she wanted a chance to live longer has been allowed by the high court to have her body cryogenically frozen in the hope that she can be brought back to life at a later time. The court ruled that the teenager's mother, who supported the girl's wish to be cryogenically preserved, should be the only person allowed to make decisions about the disposal of her body. Her estranged father had initially opposed her wishes. During the last months of her life, the teenager, who had a rare form of cancer, used the internet to investigate cryonics. She sent a letter to the court: "I have been asked to explain why I want this unusual thing done. I'm only 14 years old and I don't want to die, but I know I am going to. I think being cryo-preserved gives me a chance to be cured and woken up, even in hundreds of years' time. I don't want to be buried underground. I want to live and live longer and I think that in the future they might find a cure for my cancer and wake me up. I want to have this chance. This is my wish."

The judge wrote: "I was moved by the valiant way in which she was facing her predicament. The scientific theory underlying cryonics is speculative and controversial, and there is considerable debate about its ethical implications. On the other hand, cryopreservation, the preservation of cells and tissues by freezing, is now a well-known process in certain branches of medicine, for example the preservation of sperm and embryos as part of fertility treatment. Cryonics is cryopreservation taken to its extreme." The judge said the girl's family was not well off but that her mother's parents had raised the money. A voluntary UK group of cryonics enthusiasts, who were not medically trained, had offered to help make arrangements. Co-operation of a hospital was required. The hospital trust in the case was willing to help although it stressed it was not endorsing cryonics. "On the contrary, all the professionals feel deep unease about it," the judge said.

The Human Tissue Authority (HTA), which regulates organisations which remove, store and use human tissue, had been consulted but said it had no remit to intervene in such a case. "The HTA would be likely to make representations that activities of the present kind should be brought within the regulatory framework if they showed signs of increasing," the judge said. The HTA said: "We are gathering information about cryopreservation to determine how widespread it is currently, or could become in the future, and any risks it may pose to the individual, or public confidence more broadly. We are in discussion with key stakeholders on the possible need for regulatory oversight." The government may need to intervene in future, the judge said: "It may be that events in this case suggest the need for proper regulation of cryonic preservation in this country if it is to happen in future."

Vital interrogation of the science behind cryogenically freezing humans is being stifled because scientists fear being ostracised and ridiculed, according to a leading researcher in the field. The cryobiologist Ramon Risco said scientists risked damaging their careers and being excluded from scientific societies if they worked on cryonics, the controversial science used last month to freeze the body of a 14-year-old cancer victim. "There is an enormous 'stigma bias' to the conversation about cryonics among scientists. For scientists who would like to discuss it open-mindedly it tends to significantly hurt their career - in fact can potentially even get them kicked out of their scientific societies."

Prof Anders Sandberg, a research fellow at the Future of Humanity Institute at Oxford University, said scientists reliant on grants and looking for tenures might exercise self-censorship. "Many young scientists are afraid to hurt their careers. Talking about the future can be very career-limiting. Being seen to be eccentric in the wrong way is frowned upon." Cryonics enthusiasts argue that the stigma surrounding the area could leave people vulnerable to unscrupulous companies ready to fill the void left by science. Tim Gibson of the non-profit group Cryonics UK, which prepared the 14-year-old's body for transportation to the freezing facility in Michigan, said the group, all of whose staff are volunteers, would welcome regulation. "The danger for us is that as the idea gets more publicity, companies wanting to make a profit could spring up and damage us by [taking advantage of clients]."

Those interested in the area who were hopeful that scientific developments could see the reanimation of humans who had been cryogenically frozen would continue to work under the radar, said Risco. He added that "unconventional concepts" such as in vitro fertilisation, space travel and organ transplantation had all suffered "initial bias". "We don't need to start making a big polemic. We will keep on working on organ cryopreservation, no one will call us crazy and eventually we will end up with a solution for the whole body."

Honestly, these cryonics stories are driving me mad. As someone with terminal cancer (and ignoring the fact that I find the description in your articles of people like myself as "cancer victims" to be teeth-grindingly irritating) I feel everyone is ignoring the fact that a young woman looked into her future and saw the denial of everything she was promised. She was denied boyfriends, university, a job, marriage, children, life... and she was not ready to give up on those promises. She didn't want to die. None of us does. I'm grateful that the judge had the good sense to realise this was not about whether cryonics worked, but her own hopes for the future. Reading some pieces lately it seems that while we'll arrange bungee-jumping days out for the terminally ill, how one disposes of one's own corpse is a step too far in giving the dying what they're asking for.

Aging is associated with a general decline in immune function, contributing to a higher risk of infection, cancer, and autoimmune diseases in the elderly. Such faulty immune responses are the result of a profound remodeling of the immune system that occurs with age, generally termed as immunosenescence. While the number of naïve T cells emerging from the thymus progressively decreases with age as a result of thymic involution, the memory T cell pool expands and exhibits significant changes in the phenotype and function of antigen-experienced T cells, particularly evident in the CD8+ T cell compartment. Chronic immune activation due to persistent viral infections, such as cytomegalovirus (CMV) and Epstein-Barr virus (EBV), is one of the main drivers contributing to the accumulation of highly differentiated antigen-specific CD8+ T lymphocytes that have characteristics of replicative senescence. In combination with the depletion of the peripheral pool of naïve T cells, the accumulation of these terminally differentiated T cells with age skews the immune repertoire and has been implicated in the impaired immune responses to new antigens and vaccination in the elderly

Natural killer cells and αβCD8+ T lymphocytes are the two major cell lineages with constitutive cytotoxic activity and have a crucial role in the recognition and killing of abnormal cells. However, the paradigm for the recognition of target cells is fundamentally different between these two cell types: conventional αβCD8+ T cells rely on the T cell receptor (TCR) to recognize specific peptides presented by major histocompatibility complex class-I (MHC-I) molecules, whereas NK cells use a repertoire of germ line-encoded receptors to detect "missing self" or "altered-self" antigens and directly kill abnormal cells, without prior sensitization. Besides antigen specificity, the development of immunological memory is conventionally another distinctive feature between NK and T cells, categorizing them into distinct arms of the immune system and the innate and adaptive immune system, respectively.

Nevertheless, accumulating evidence supports the existence of NK cell memory, as well as evidence for TCR-independent responses mediated by αβCD8+ T lymphocytes, suggesting that the conventional limits between the innate and adaptive arms of the immune system may be not as distinct as first thought. NK and T lymphocytes have a common origin from a lymphoid progenitor cell in the bone marrow, and recent comparative proteomic and transcriptomic studies have demonstrated a remarkably close proximity between effector αβCD8+ T lymphocytes and NK cells, reiterating an evolutionary ancestry and shared biology between the two cell lineages.

An increasing body of literature reveals the existence of subsets of T cells with features that bridge innate and adaptive immunity. These cells typically co-express a TCR and NK cell lineage markers, distinguishing them from NK cells and other innate lymphoid cells, which lack the expression of a TCR or somatically rearranged receptors. Functionally, innate-like T cells respond to TCR ligation but are also able to respond rapidly to danger signals and pro-inflammatory cytokines, independently of TCR stimulation, resembling innate cells. Recently, subsets of conventional αβCD8+ T cells expressing NK cell markers and intraepithelial T cells have been included in this vaguely defined group of innate-like T cells. Despite the similarities in phenotype and function, there are clear differences in ontogeny and tissue distribution between them.

In this review, we will discuss recent evidence that aging is associated with the expansion of a subset of conventional αβCD8+ T cells with phenotypic, functional, and transcriptomic features that resemble NK cells. Such innate-like αβCD8+ T cells have the characteristics of terminally differentiated T cells, and the acquisition of functional NK receptors is most likely part of a general reprograming of the CD8+ T cell compartment during human aging, to ensure broad and rapid effector functions. We propose that innate-like αβCD8+ T cells share important features with other innate-like T cells; however, fundamental differences in origin and development separate them from truly innate cells. Interestingly, these cells are also differentially affected by aging, suggesting distinct roles in immune responses at different times of life. Evidence indicates that chronological aging is associated with accumulation of cells combining features of both the innate and adaptive arms of the immune system, most likely to compensate for functional defects of conventional NK and CD8+ T cells with age. We propose that senescent CD8+ T cells should not be seen as a dysfunctional population but instead a functionally distinct subset, which uses recently acquired NK cell machinery to maintain rapid effector functions throughout life. Contrary to the classic paradigm that peripheral TCR ligation is essential for T cell activation, this subset of highly differentiated T cells has impaired TCR responsiveness and may be non-specifically activated by inflammatory cytokines or after ligation of innate receptors. The switch to an innate mode of function may shed light on the mechanisms that allow highly differentiated CD8+ T cells to maintain functionality, despite the loss of TCR signal functions.

Our understanding of the physiological significance of the expression of NKRs on T cells is still incomplete, and the identification of the molecular mechanisms and the transcriptional regulators underpinning the development of innate features in T cells is essential. Most importantly, it will be important to understand how the intersection between innate and adaptive immune features may be manipulated to enhance immune function and to use this information to develop new approaches to improve immunity in the elderly.

Visceral obesity is associated with chronic low-grade inflammation in visceral adipose tissue (VAT) and a sustained whole-body proinflammatory state, which may underlie metabolic and cardiovascular diseases. VAT inflammation associated with obesity involves a complex network of responses of immune cell components, including acquired immune cells such as various subsets of T cells and B cells and innate immune cells such as macrophages. Among these cells, CD4+ T cells have been recognized as a central regulator of chronic VAT inflammation. The number of CD4+ T cells in VAT increases as the tissue expands in obesity. Factors that drive CD4+ T cell expansion and into proinflammatory effectors in VAT during the development of high-fat diet-induced (HFD-induced) obesity may include MHC class II-associated antigens, possibly self-peptides, because the T cell receptor (TCR) repertoire of CD4+ T cells in VAT is limited, and deficiency of MHC class II protects mice from high fat diet (HFD)-induced VAT inflammation and insulin resistance. However, the obesity-associated immune background underlying chronic inflammation in VAT remains elusive.

Significant changes occur in the overall T cell populations with age. In CD4+ T cells, proportions of naive (CD44loCD62Lhi) cells sharply decline in ontogeny, with an age-dependent increase in cells of the memory phenotype (CD44hiCD62Llo). Among CD44hiCD4+ T cells, a unique population expressing programmed cell death 1 (PD-1) and CD153 actually increases with age in mice. The CD153+PD-1+CD44hiCD4+ T cell population shows compromised proliferation and regular T cell cytokine production on T cell receptor (TCR) stimulation but secretes large amounts of proinflammatory cytokines, such as osteopontin. These CD4+ T cells also show signatures of cell senescence, including a marked increase in senescence-related gene expression and nuclear heterochromatin foci, and are termed senescence-associated T cells (SA-T cells). Notably, the age-dependent development of SA-T cells, which may include autoreactive cells, is dependent on B cells. As such, the increase in SA-T cells is suggested to be involved in part in immune aging phenotypes such as impaired acquired immune capacity, increased proinflammatory traits, and high risk for autoimmunity.

In the present study, we demonstrate that CD153+PD-1+CD44hiCD4+ T cells are remarkably increased and preferentially accumulated in the VAT of HFD-fed mice in a B cell-dependent manner and that these CD4+ T cells show functional and genetic features strongly resembling SA-T cells that increase in secondary lymphoid tissues with age. We also indicate that the CD153+PD-1+CD44hiCD4+ T cells play a crucial role in inducing chronic VAT inflammation and metabolic disorder via secretion of large amounts of osteopontin. We demonstrated that adoptive transfer of CD153+PD-1+CD44hiCD4+ T cells, but not other CD4+ T cells, from HFD-fed spleens into VAT of ND-fed mice recapitulates the features of VAT inflammation, including a striking increase in CD11chiCD206lo macrophages and expression of proinflammatory cytokine genes. It is noteworthy that CD153+PD-1+CD4+ T cells in VAT of HFD-fed mice show features indistinguishable from those of CD153+ SA-T cells, which gradually increase systemically with age. The age-dependent increase in CD153+ SA-T cells may partly underlie the immune aging, including a reduction in acquired immunity and an increase in the inflammatory trait and autoimmunity risk. Obesity is also associated with diminished resistance against infection, chronic low-grade inflammation, and a greater susceptibility to autoimmunity. It has been suggested that the increase in CD153+ SA-T cells in chronological aging and systemic autoimmunity is attributable to a robust, homeostatic T cell proliferation, but the precise mechanism underlying the accumulation of these T cells in VAT of HFD-fed mice remains to be investigated. Nonetheless, it is an intriguing possibility that the predisposition often associated with obesity may partly be a systemic manifestation of the premature increase in CD153+ SA-T cells in VAT, since adipose tissues can constitute up to 50% to 60% of total BW in severe obesity.

The prospect of creating artery "banks" available for cardiovascular surgery, bypassing the need to harvest vessels from the patient, could transform treatment of many common heart and vascular ailments. But it's a big leap from concept to reality. Patients needing bypass surgeries would benefit from a better source for arteries. Replacement tissue currently comes from another part of the patient's body, and suitable tissue can't be found for many patients. Current synthetic alternatives also fail at a high rate. Diseases of blood vessels - including coronary artery disease - kill more people worldwide than any other single cause.

"Tissue engineering for blood vessels is a pretty mature field. But there are still two major problems: One is the time it takes to make the vessels, and the other is the source of the cells to grow them." For example, taking induced pluripotent (iPS) stem cells from an individual patient, growing the relevant cells and assembling them into an artery would overcome the problem of transplant rejection. However, it would be cost-prohibitive and take months to complete - too long to be clinically useful to a patient. The promising alternative is to create tissue with cells banked from a unique population of people who are genetically compatible donors, based on rare alleles that circumvent rejection. It has been estimated that about 100 different cell lines from this rare population would be enough to cover a majority of the U.S. population.

A new effort covers four phases and addresses key questions about the feasibility of this approach. The model for the project is designed around treating critical limb ischemia, a debilitating condition that restricts blood flow to limbs and often leads to amputation or death. Researchers are working to create the optimal cellular building blocks of the artery - endothelial and smooth muscle cells - that will be most suitable for transplantation and continue to grow and remodel in the patient. In tandem, a different team will develop scaffolds from natural and synthetic materials to provide structure and shape for the artery. Other researchers will build a bioreactor that provides an environment in which the arterial cells can grow around the scaffolding. The transplant surgery and resulting immune response will then be tested using a monkey limb ischemia model. Having a primate model is important to produce results more relevant to human health than those from mice or other short-lived animals. Finally, there is the production of arterial cells that meet FDA standards for human clinical trials, paving the way for potential treatments for limb ischemia in humans. If the entire process works, researchers estimate that potential human therapies remain about 10 years away.

Dry eye syndrome (DES) is a frequent eye disorder affecting many people worldwide, especially at an old age. DES is a multifactorial disorder of the ocular surface unit and results in eye discomfort, visual disturbances, and tear film instability with potential damage to the ocular surface and often poor quality of life. Current therapies for DES are only palliative, focusing on replacement of tear fluid to reduce the symptoms. Thus, there is a need for drugs that directly address the causes of DES. Clinical and basic studies have shown that the age-related decline of lacrimal-gland functions decreases the ability to synthesize and secrete proteins. These alterations may cause aqueous tear deficiency in DES. Approximately 80% of the lacrimal gland is acinar cells: highly differentiated epithelial cells specialized for the synthesis, storage, and secretion of tear fluid components, such as water, proteins, glycoproteins, and electrolytes. During aging, the synthesis and secretion of proteins decrease in lacrimal glands, and acinar cells start to produce and secrete a mucous product. The latter causes aberrations in the tear film of the eyes.

Researchers have compared ultrastructure of mitochondria in acinar cells of 6- and 12-month-old ad libitum fed Fischer 344 rats and uncovered occasional mitochondrial swelling, disorientation, shortening, and disorganization of cristae in the 12-month-old animals. Mitochondria, when dysregulated, are a major source and target of oxidative stress. Mitochondrial dysfunction strongly promotes aging and the pathogenesis of age-related diseases including eye diseases. Some authors demonstrated a connection of age-related alterations in the lacrimal gland with oxidative stress. Other authors showed the possibility of interventions (e.g., calorie restriction) aimed at reducing excessive production of reactive oxygen species (ROS) to prevent disturbances in the mitochondrial ultrastructure of acinar cells in the lacrimal gland. Changes in signaling pathways associated with age-related upregulation of oxidative stress have been detected in the aging lacrimal gland. Increased oxidative stress can result from reductions in insulin secretion and parasympathetic signaling accompanied by an increase in hormone resistance and by accumulation of advanced glycation end products in the aging lacrimal gland.

Thus, an increasing body of evidence suggests that prevention of upregulation of mitochondrial ROS is important for possible therapeutic strategies to delay age-associated alterations and to prevent age-related disorders in humans. Despite the disappointing effects of antioxidants in clinical trials, there is growing evidence of beneficial effects of mitochondria-targeted antioxidants during aging and in age-related diseases. Previously, we showed that mitochondria-targeted antioxidant 10-(6′-plastoquinonyl) decyltriphenyl phosphonium cation (SkQ1) ameliorates the signs of aging and inhibits the development of such age-related diseases as cataract, age-related macular degeneration, and glaucoma in rats. SkQ1 (under the brand name Visomitin) in the form of eye drops is already manufactured and has been successfully used since 2012 for treatment of DES in Russia. Nevertheless, the link between SkQ1's effects and its suppression of age-related aberrations in the lacrimal gland has not been explored. The aim of this study was to examine the effects of long-term dietary supplementation with SkQ1 on age-related deterioration of lacrimal-gland ultrastructure Wistar rats.

Here we demonstrated that dietary supplementation with SkQ1 (250 nmol/[kg body weight] daily) starting at age 1.5 months significantly alleviated the pathological changes in lacrimal glands of Wistar rats by age 24 months. By this age, lacrimal glands underwent dramatic deterioration of the ultrastructure that was indicative of irreversible disturbances in these glands' functioning. In contrast, in SkQ1-treated rats, the ultrastructure of the lacrimal gland was similar to that in much younger rats. Morphometric analysis of electron-microscopic specimens of lacrimal glands revealed the presence of numerous secretory granules in acinar cells and a significant increase in the number of operating intercalary ducts. Our results confirm that dietary supplementation with SkQ1 is a promising approach to healthy ageing and to prevention of aberrations in the lacrimal gland that underlie dry eye syndrome.

Mitochondria are membrane-bound organelles present in many copies in most eukaryotic cells. The circular mitochondrial genome (mtDNA) encodes proteins necessary for oxidative phosphorylation, which generates the bulk of ATP in most cells. Individual mitochondria contain multiple copies of mtDNA, each of which is packaged into a structure known as a nucleoid, with primarily a single mtDNA per nucleoid. This multiplicity of genomes per cell, in conjunction with mtDNA's high mutation rate and limited repair capacity, often results in cells carrying mtDNA of different genotypes, a condition known as heteroplasmy. Recent studies suggest that 90% of individuals have some level of heteroplasmy, with 20% harbouring heteroplasmies that are implicated in disease. If the frequency of such a mutation reaches a threshold, pathology results. Heteroplasmy for deleterious mtDNA can also arise in somatic tissues during development and in adulthood. It accumulates throughout life, and is thought to contribute to diseases of aging. These observations emphasize the importance of devising ways to reduce heteroplasmy in vivo.

Mitochondria-targeted site-specific nucleases provide one way to decrease the levels of heteroplasmy. In this approach, a site-specific nuclease is engineered so as to bind and cleave a specific mutant version of the mtDNA genome, promoting its selective degradation. This approach has recently been used to decrease the levels of heteroplasmy in patient-derived cell lines, in oocytes and in single cell embryos. However, these methods are likely to be challenging to implement in the adult, as the nuclease being expressed is a non-self protein; many cells must be targeted without off target cleavage effects; and individuals may be heteroplasmic for multiple deleterious mutations. Here we seek to promote cell biological processes that normally regulate mtDNA quality as an alternative approach to decreasing heteroplasmy in adults.

Mitophagy serves as a form of quality control that promotes the selective removal of damaged mitochondria. In one important pathway, dysfunctional mitochondria are eliminated through a process dependent on PTEN-induced putative kinase 1 (PINK1) and Parkin, loss of which lead to familial forms of Parkinson's disease. Regardless, the fact that mutant mtDNA accumulates in individuals wild type for PINK1 and parkin during aging indicates that if PINK1- and Parkin-dependent mitophagy and/or other pathways promote mtDNA quality control, they are often not active or effective. To identify ways of reducing the mutant mtDNA load in somatic tissues, systems are needed in which a specific deleterious heteroplasmy can be induced in vivo and followed over time, ideally in post-mitotic cells so as to eliminate potential confounding effects associated with stochastic segregation during cell division, and differential cell proliferation and/or cell death. Current in vivo models are cumbersome and limited, but we describe the generation and use of a transgene-based system of heteroplasmy in post-mitotic muscle to identify conditions that result in the selective removal of mutant mtDNA.

We demonstrate that the load of deleterious mtDNA can be decreased through several different interventions. Genetic and chemical screens using such a model should prove useful in identifying molecules that can cleanse tissues of a deleterious genome, via known and unknown mitochondrial quality control pathways. The many tools for regulated spatial and temporal control of gene expression in Drosophila will allow such screens to be carried out in a variety of tissues and environmental contexts, including aging. Our results show that adult muscle has a significant but limited ability to remove mutant mtDNA utilizing genes required for autophagy, and that mutant mtDNA removal can be greatly stimulated in several ways: by limiting the ability of mitochondrial fragments to re-fuse with the network (decreasing Mfn levels), by limiting their ability to undergo repolarization through ATP synthase reversal (ATPIF1 expression), by increasing the tagging of mtDNA-bearing fragments (increasing PINK1 or Parkin levels), and by increasing the frequency with which these tagged fragments are degraded (activation of autophagy). These observations have important implications for new therapies for mitochondrial disease and diseases of aging.

Dementia, a decline in memory and other cognitive functions that leads to a loss of independent function, is a common and feared geriatric syndrome that affects an estimated 4 to 5 million older adults in the United States and has a large social and economic impact on patients, families, and government programs. Although the number of older adults with dementia in the United States and around the world is expected to grow up to 3-fold by 2050 owing to the large increase in the size of the elderly population, recent studies suggest that the age-specific risk of dementia may have actually declined in some high-income countries over the past 25 years, perhaps owing to increasing levels of education and better control of key cardiovascular risk factors, such as hypertension, diabetes, and hypercholesterolemia. For instance, the incidence of dementia among older participants in the Framingham Heart Study declined by about 20% per decade between 1977 and 2008, and the decline in risk was seen only among those with at least a high school education. If confirmed in representative populations, a decline in age-specific risk for dementia would have important implications for public health and public policy. For instance, a recent population-based study of dementia in England found a 24% decline in the expected number of cases of dementia between 1991 and 2011 (a 6.5% prevalence among older adults in 2011, compared with 8.3% in 1991), which translates to more than 200,000 fewer cases of dementia.

There have been changes over the past 2 to 3 decades in both the prevalence and treatment of cardiovascular risk factors that also influence the risk for dementia. For instance, 23% of US adults were obese in 1990 compared with 35% in 2012; among adults 65 years or older, the prevalence of diabetes increased from 9% to 21%. However, intensity of treatment for diabetes, hypertension, and high cholesterol level has increased with more patients achieving treatment goals, and a significant decline in the vascular complications of diabetes such as heart attack, stroke, and lower-extremity amputations, suggesting that there could be a "spill-over" benefit of a decline in the vascular-related risk for dementia. Rising levels of education among US adults over the past 25 years may also have contributed to decreased dementia risk. The proportion of adults 65 years or older with a high school diploma increased from 55% in 1990 to 80% in 2010, while the proportion with a college degree increased from 12% to 23%. More years of formal education is associated with a reduced risk of dementia, likely through multiple causal pathways, including a direct effect on brain development and function (i.e., the building of "cognitive reserve"), health behaviors, as well as the general health advantages of having more wealth and opportunities.

In a large nationally representative survey of older Americans we found that, among those 65 years or older, the prevalence of dementia decreased from 11.6% to 8.8% between 2000 and 2012, representing an absolute decrease of 2.8 percentage points, and a relative decrease of about 24%. Educational attainment increased significantly, with those 65 years or older in 2012 having nearly 1 additional year of education compared with the 2000 cohort. After controlling for the socioeconomic factors of education, wealth, and race/ethnicity, controlling for changes in the prevalence of cardiovascular risk factors did not explain much of the additional difference in dementia risk across the two cohorts. Our findings are consistent with those of a number of recent studies that also found declines in dementia incidence or prevalence in high-income countries around the world and also suggest that the trend toward a declining prevalence of cognitive impairment or dementia in the United States that we found between 1993 and 2002 using earlier data has continued through 2012, even with significant increases in the prevalence of cardiovascular risk factors that may increase dementia risk.

A new study found that tissue health and repair dramatically decline in young mice when half of their blood is replaced with blood from old mice. The study argues against the rejuvenating properties of young blood and points to old blood, or molecules within, as driving the aging process. "Our study suggests that young blood by itself will not work as effective medicine. It's more accurate to say that there are inhibitors in old blood that we need to target to reverse aging." In 2005, researchers found evidence for tissue rejuvenation in older mice when they are surgically joined to younger mice so that blood is exchanged between the two. Despite remaining questions about the mechanism underlying this rejuvenation, media coverage of the study fixated on the potential of young blood to reverse the aging process, and on comparisons to vampires, which was not the takeaway from the study. In the years since the 2005 study, scientists have spent millions to investigate the potential medical properties of youthful blood with enterprises emerging to infuse old people with young blood. "What we showed in 2005 was evidence that aging is reversible and is not set in stone. Under no circumstances were we saying that infusions of young blood into elderly is medicine."

While the experimental model used in the 2005 study found evidence that some aspects of aging may be reversed, the techniques used in the study do not allow scientists to precisely control the exchange of blood, which is necessary to dig deeper into blood's effect on aging. When two mice are sutured together, a technique called parabiosis, blood is not the only thing that is exchanged in this setup; organs are also shared, so old mice get access to younger lungs, thymus-immune system, heart, liver and kidneys. In surgical suturing it takes weeks to a month for the effects of blood to take place and the precise timing is not actually known. Nor is the precise amount of the exchanged blood. In the new study, researchers developed an experimental technique to exchange blood between mice without joining them so that scientists can control blood circulation and conduct precise measurements on how old mice respond to young blood, and vice versa. In the new system, mice are connected and disconnected at will, removing the influence of shared organs or of any adaptation to being joined. One of the more surprising discoveries of this study was the very quick onset of the effects of blood on the health and repair of multiple tissues, including muscle, liver and brain. The effects were seen around 24 hours after exchange.

With the new experimental setup, the research team repeated the experiments from 2005. In each test, blood was exchanged between an old mouse and a young mouse until each mouse had half its blood from the other. The researchers then tested various indicators of aging in each mouse, such as liver cell growth as well as liver fibrosis and adiposity (fat), brain cell development in the region that is needed for learning and memory, muscle strength and muscle tissue repair. In many of these experiments, older mice that received younger blood saw either slight or no significant improvements compared to old mice with old blood. Young mice that received older blood, however, saw large declines in most of these tissues or organs. The most telling data was found when researchers tested blood's impact on new neuron production in the area of the brain where memory and learning are formed. In these experiments, older mice showed no significant improvement in brain neuron stem cells after receiving younger blood, but younger mice that received older blood saw a more than twofold drop in brain cell development compared to normal young mice. The researchers think that many benefits seen in old mice after receiving young blood might be due to the young blood diluting the concentration of inhibitors in the old blood.

Many lower forms of life on earth exhibit an extraordinary ability to regenerate tissue, limbs, and even organs - a skill that is lost among humans and other mammals. Now, researchers have used the components of the cellular "scaffolding" of a zebrafish to regenerate heart tissues in mammals, specifically mice, as well as exhibiting promising results in human heart cells in vitro. The researchers found that a single administration of extracellular matrix (ECM) material from zebrafish hearts restored the function of the heart and regenerated adult mouse heart tissues after acute myocardial infarction. The study also found that the zebrafish ECM protected human cardiac myocytes - specialized cells that form heart muscle - from stresses.

ECM are the architectural foundations of tissues and organs; not only do they provide a "scaffolding" on which cells can grow and migrate, they assist in the signaling necessary for the organ to develop, grow, or regenerate. In mammals, the heart quickly loses the ability to regenerate after the organism is born, except for a brief period after birth. In lower animals, such as zebrafish, the heart retains that ability throughout their lives: up to 20 percent of a zebrafish's heart can be damaged or removed, and within days the heart's capacity has been fully restored. The researchers first separated the ECM from the cells so that the recipient heart would not reject the treatment. They did this by freezing the zebrafish cardiac tissue, causing the cell membranes to burst and allowing the researchers to retrieve the ECM, a process called decellularization. They then injected the ECM into the hearts of mice with damaged heart muscles and watched the hearts repair themselves. It is difficult to inject foreign cells into a body because the body will recognize them as foreign and reject them. That's not the case with ECM because it is composed of collagen, elastin, carbohydrates and signaling molecules and has no cell surface markers, DNA or RNA from the donor, and so the recipient is less likely to reject the treatment.

Restored function starts almost immediately, and healing is noticeable as early as five days after treatment; within a week, his team could see the heart beating more strongly than the hearts of the untreated animals. The researchers tested the effectiveness of ECM from normal zebrafish and from zebrafish with damaged hearts, in which the ECM had already begun the healing process. They found that while both types of ECM were effective in repairing damage to the mice hearts, the ECM obtained from the zebrafish hearts that were healing were even more potent in restoring heart function in the mice. The researchers are now working on a process to regenerate nerves in mammals using the same process and hope to expand the heart treatments to larger animals in a future study.

Scientists report using human pluripotent stem cells to grow human intestinal tissues that have functioning nerves in a laboratory. The paper puts medical science a step closer to using human pluripotent stem cells (which can become any cell type in the body) for regenerative medicine and growing patient-specific human intestine for transplant. "One day this technology will allow us to grow a section of healthy intestine for transplant into a patient, but the ability to use it now to test and ask countless new questions will help human health to the greatest extent." This ability starts with being able to model and study intestinal disorders in functioning, three-dimensional human organ tissue with genetically-specific patient cells. The technology will also allow researchers to test new therapeutics in functioning lab-engineered human intestine before clinical trials in patients.

Researchers started out by subjecting human pluripotent stem cells to a biochemical bath that triggers their formation into human intestinal tissue in a petri dish. The process was essentially the same as that used in a 2010 study, which reported the first-ever generation of three-dimensional human intestinal organoids in a laboratory. Intestinal tissues from the initial study lacked an enteric nervous system, which is critical to the movement of waste through the digestive tract and the absorption of nutrients. The gastrointestinal tract contains the second largest number of nerves in the human body. When these nerves fail to work properly it hinders the contraction of intestinal muscles. To engineer a nervous system for the intestinal organoids already growing in one petri dish, researchers generated embryonic-stage nerve cells called neural crest cells in a separate dish. The neural crest cells were manipulated to form precursor cells for enteric nerves. The challenge at this stage was identifying how and when to incorporate the neural crest cells into the developing intestine. "We tried a few different approaches largely based on the hypothesis that, if you put the right cells together at the right time in the petri dish, they'll know what do to. It was a long shot, but it worked." The appropriate mix caused enteric nerve precursor cells and intestines to grow together in a manner resembling developing fetal intestine.

A key test for the engineered intestines and nerves was transplanting them into a living organism - in this case laboratory mice with suppressed immune systems. This allowed researchers to see how well the tissues grow and function. Study data show the tissues work and are structured in a manner remarkably similar to natural human intestine. They grow robustly, process nutrients and demonstrate peristalsis - series of wave-like muscle contractions that in the body move food through the digestive tract.

People worldwide are living longer, healthier lives. A new study of mortality patterns in humans, monkeys and apes suggests that the last few generations of humans have enjoyed the biggest life expectancy boost in primate history. The gains are partly due to advances in medicine and public health that have increased the odds of survival for human infants and reduced the death toll from childhood illness. Yet males still lag behind females - not just in humans but across the primate family tree, the researchers find. "The male disadvantage has deep evolutionary roots."

An international team compiled records of births and deaths for more than a million people worldwide, from the 18th century to the present. The data included people in post-industrial societies such as Sweden and Japan, people born in pre-industrial times, and modern hunter-gatherers, who provide a baseline for how long people might have lived before supermarkets and modern medicine. The researchers combined these measurements with similar data for six species of wild primates that have been studied continuously for three to five decades, including sifaka lemurs, muriqui monkeys, capuchins, baboons, chimpanzees and gorillas. The data confirm a growing body of research suggesting that humans are making more rapid and dramatic gains than ever before seen in the primate family tree. For example, in the last 200 years life expectancy in Sweden has jumped from the mid-30s to over 80, meaning that a baby born today can hope to live more than twice as long as one born in the early 19th century. The data show that today's longest-lived human populations have a similar 40- to 50-year advantage over people who live traditional lifestyles, such as the Hadza hunter-gatherers of Tanzania and the Aché people of Paraguay.

In contrast, these modern hunter-gatherers - the best lens we have into the lives of early humans - live on average just 10 to 20 years longer than wild primates such as muriquis or chimpanzees, from which human ancestors diverged millions of years ago. "We've made a bigger journey in lengthening our lifespan over the last few hundred years than we did over millions of years of evolutionary history." One indicator of healthcare improvement is infant mortality, which strikes fewer than 3 in 1000 babies born in Sweden or Japan today. But it was more than 40 times higher for those born two centuries ago, and is still high among hunter-gatherers and wild primates.

The researchers also studied lifespan equality, a measure similar to income equality that indicates whether longevity is distributed evenly across society, or only enjoyed by a few. They found that, for both humans and wild primates, every gain in average lifespan is accompanied by a gain in lifespan equality. That is, for a population to be very long-lived, everyone must benefit more or less equally, with fewer individuals left behind. The researchers were surprised to find that the longevity of human males has yet to catch up with females, and the improvements in males aren't spread as evenly. A girl born in Sweden in the early 1800s could expect to outlive her male counterparts by an average of three to four years. Two hundred years later, despite Swedes adding 45 years to their average lifespan, the gulf that separates the sexes has barely budged. The life expectancy gender gap isn't just true for humans. Females outlived males in almost every wild primate population they looked at.

The results of many genome-wide association studies (GWAS) of complex traits suffer from a lack of replication. Differences in population genetic structures among study populations are considered to be possible contributors to this problem. One aspect of population structure - the differences in genetic frequencies among subgroups of individuals comprising the population - was traditionally linked with the effects of population stratification. Another one - the presence of linkage disequilibrium (LD) in many parts of the human genome including those that contain causal single-nucleotide polymorphisms (SNPs) - was actively exploited in GWAS of complex traits. Methods of fine mapping following the "discovery" phase are used for evaluating causal SNPs. One could expect that the non-replication problem due to differences in LD patterns among study populations in GWAS would disappear if the detected marker SNP is a causal one, i.e., if it contributes to the variability of a trait. It turns out that the differences in LD levels around a functional SNP may still contribute to the non-replication problem.

The estimated associations in this case depend on whether the detected functional SNP is in LD with another functional SNP, the effects of these SNPs on the trait in the absence of LD (pure effects), and on the level of LD between corresponding SNP loci. This property has important consequences for interpretation of the results of genetic analyses of complex traits. In the presence of LD the estimated effects of a causal SNP may be spurious and may incorrectly characterize the biological relationships between the SNP and the trait. In contrast the pure effect of a given causal SNP estimated in the absence of LD with other such SNPs may correctly characterize the biological connections between the SNP and the trait. Therefore, for example, performing genetic analyses of African populations (that have lower levels of LD patterns for many SNP pairs than populations of European origin) has the potential to reduce bias in the estimated effects of functional SNPs on a trait caused by the presence of LD between functional loci. This condition is, however, not sufficient because of the possible presence of hidden gene/gene interaction effects, gene/environment correlations, and gene/environment interaction effects.

Human lifespan and many other aging, health and longevity related traits are multifactorial phenotypes, that is, they are affected by many genetic and non-genetic factors. The relationships between genes and these phenotypes have special features that distinguish them from other complex traits, influence methods of their genetic analyses, and affect the interpretation of the research results. The genetic variants that influence aging, health, and longevity related traits generate age dependent changes in the population genetic structure, i.e., changes in the frequencies of genetic variants and in the levels of linkage disequilibrium (LD) among them. This feature has important implications for studies focused on the replication of GWAS research findings: independent populations involved in such studies often have different genetic structures, due in part to the differences in the population age distribution at the time of biospecimen collection. As a result, the frequencies of the genetic variants associated with these traits and their LD patterns may differ even if the genetic structures in the corresponding population cohorts were the same at birth.

Detecting statistically significant associations of genetic variants with complex traits is not the end of the genetic analyses. One reason is that the relationship between a detected marker SNP and the complex trait of interest is not, necessarily, a causal one. More often these relationships serve as proxies for the real effect of some unobserved causal SNPs (due to linkage disequilibrium (LD) between the marker and causal SNPs), and, hence, do not have a direct biological effect on the phenotype. To generate insights about the biological mechanisms responsible for the trait's variability one has to identify the causal SNPs responsible for the association signal. To identify such SNPs a number of efficient fine-mapping procedures have been recommended. The main limitation of existing methods is that they seek to identify a single causal variant which is independent of (not in LD with) other causal variants. Since this is not sufficiently realistic, a new approach that allows for efficient detection of multiple causal variants has been proposed. The case where two or more causal SNPs are in LD creates additional problems for interpretation of the results of genetic association studies.

In this paper we show that the estimates of the effects of a causal SNP on lifespan depend on the genetic structure of the population under study (e.g., the level of LD of the SNP with other causal SNPs). Genetic association studies of this trait using data from populations with different LD levels are likely to produce different results. We show that differences in population genetic structures can explain why genetic variants favorable for longevity in one population appear as harmful risk factors in another population. Population structure may also be responsible for the age-specific effects of genetic variants on mortality risk. Differences in genetic structures in distinct populations may be responsible for the low level of replicability of GWAS of human aging, health, and longevity related traits.

Of all mammals, bats possess some of the most unique and peculiar adaptations that render them as excellent models to investigate the mechanisms of extended longevity and potentially halted senescence. They are considered the 'Methusalehs' among mammals due to their exceptional and surprising longevity given their body size and metabolic rate. Typically mammals that are small have a high metabolic rate (e.g. shrews) and do not live for a long time. However, despite their small size and high metabolic rate bats can live for an exceptionally long time, with the oldest recorded Brandt's bat (wild caught as an adult) ever recaptured being more than 41 years old with a body weight of 7 grams. Indeed, to get a positive correlation between longevity and body size in mammals, bats must be removed from the analyses. By comparing the ratio of expected longevity to that predicted from the 'non-bat placental mammal' regression line (longevity quotient - LQ) only 19 species of mammals are longer lived than man, one of these species being the naked mole rat and the other 18 are bats. This suggests that bats have some underlying mechanisms that may explain their exceptional longevity.

MicroRNA (miRNA) are a subset of short endogenous non-coding RNA that play a significant role in post-transcriptional regulation, via repression of translation. Since the first miRNA was discovered in 1993, a multitude of miRNA have subsequently been identified, and implicated in the regulation of the vast majority of biological pathways including cell cycle regulation, metabolism, tumorigenesis, as well as immune response. However, the role of miRNA regulation in mammalian ageing and the onset of age-related diseases has only recently been established. In mammals, various miRNA have been shown to be differentially expressed during ageing, most of which appear to be generally tissue-specific. In addition to tissue-specific ageing, it is increasingly evident that many miRNA regulate gene expressions in well-known ageing pathways, most notably in the p53 tumor suppressor pathway and insulin-like growth factor signaling pathway.

Despite being the second largest order of mammals (~1200 species), there is a scarcity of genomic and transcriptomic bat resources. To date, only five well-annotated bat genomes are publically available. Phylogenomic studies of bat genomes and other mammalian species reveal that a number of genes are under positive selection in bats. These genic adaptations have been correlated with traits such as echolocation, powered flight, hibernation, immunity and longevity. For example, specific non-synonymous mutations in GHR and IGF1R, key ageing-related genes, were detected in several long-lived vespertilionid bats (M. brandtii, M. lucifugus and Eptesicus fuscus), while a large proportion of genes involved in DNA repair (RAD50, KU80, MDM2, etc.) and the NF-кB pathway (c-REL and ATM2, etc.) were reported to be under positive or divergent selection in M. davidii and P. alecto. These results suggest bats may better detect and repair DNA damage. Intriguingly, positive selection was also detected in mitochondrial-encoded and nuclear-encoded oxidative phosphorylation genes in bats, which may explain their efficient energy metabolism necessary for flight. Apart from comparative genome analysis, only a small number of transcriptomic studies on bats using have been carried out, focused primarily on the characteristics of hibernation, immunity, echolocation and phylogeny. However, the molecular mechanisms of adaptations affecting longevity are still far from understood, especially with respect to gene regulation.

In the present study, we sequenced six small RNA libraries from whole blood sampled from wild-caught greater mouse-eared bats (Myotis myotis) and for the first time made genome-wide comparisons of both miRNomes and mRNA transcriptomes between bat and non-bat mammalian species (human, pig and cow). The profiling of the M. myotis blood miRNome showed a large number of bat-specific miRNA involved in regulating important pathways related to immunity, tumorigenesis and ageing. Comparative analyses of both miRNomes and transcriptomes also revealed distinctive longevity mechanisms in bats. Several up-regulated miRNA possibly act as tumor suppressors. Gene Ontology (GO) enrichment analysis of differentially expressed protein-coding genes showed that up-regulated genes in bats compared to other mammals were mainly involved in mitotic cell cycle and DNA damage repair pathways while a high number of down-regulated genes were enriched in mitochondrial metabolism. The results and data presented here show unique regulatory mechanisms for protection against tumorigenesis, reduced oxidative stress, and robust DNA repair systems, likely contribute to the extraordinary longevity of bats.