The list of diseases humankind has managed to defeat is impressive. But throughout history, humans have suffered from a condition that they have never been able to escape - ageing. As we get older, our cells stop working as well and can break down, leading to conditions like cancer, heart disease, arthritis and Alzheimer's disease. Together, ageing-related diseases are responsible for 100,000 deaths per day and billions are spent around the world trying to slow their steady march on our bodies.

Some researchers, however, believe we may be thinking about these conditions in the wrong way. They say we should start treating ageing itself as a disease - one that can be prevented and treated. Their hopes are founded on recent discoveries that suggest biological ageing may be entirely preventable and treatable. From a biological perspective, the body ages at different rates according to genetic and environmental factors. Tiny errors build up in our DNA and our cells begin developing faults that can accumulate into tissue damage. The extent of these changes over time can mean the difference between a healthy old age or one spent housebound and afflicted by chronic diseases.

The scientists who hope to do this sit on the fringes of the mainstream medical landscape. But there are now a number of research centres around the world that have made identifying ways of preventing biological ageing a priority. Studies in animals have shown that it is indeed possible to dramatically extend the lifespan of certain species, giving hope that it could also be possible in humans. One of the leading figures in human longevity research, Aubrey de Grey, is the chief science officer at the Strategies for Engineered Negligible Senescence (SENS) Research Foundation, a California-based regenerative medicine research foundation focused on extending the healthy human lifespan. Their goal is to develop a suite of therapies for middle-aged and older people that will leave them physically and mentally equivalent to someone under the age of 30. They want "to fix the things we don't like about the changes that happen between the age of 30 and the age of 70". There are seven biological factors de Grey argues are predominantly responsible for cellular damage that accompanies ageing and underlies ageing-related diseases.

De Grey doesn't think that it will be possible stop ageing altogether with these types of approaches, but they may give patients an extra 30 years or so of life. He envisages a future where "rejuvenation technologies" can be administered to old people in order to revert their cells to what they were like when they were in their youth, buying them extra time. The idea is that someone who is treated at the age of 60 will be biologically reverted to 30. But because the therapies are not permanent fixes, their cells will end up becoming 60 years old again in another 30 years time. By then de Grey hopes the therapies could be reapplied as "version 2.0" to revert the same individuals once again to become younger in their cells. As a result, that person's cells wouldn't become 60 again until they're about 150 years old.

And he is not alone in believing ageing-related diseases can be solved. George Church, a geneticist at Harvard Medical School, told us that while some of his colleagues argue many age-related diseases are so complex that they simply can't be treated, he finds such thinking to be incorrect. "If you can control both the environment and the genetics, you can get people that live youthful healthy lives for exceptionally much longer than others. In industrialised nations, most of the diseases are due to age-related diseases and I think those too can be handled."

But regardless of how it is achieved, extending human lifespans by decades or even hundreds of years will present us with some difficult social realities. There could be major societal impacts if we all start living longer. There are some that fear greater longevity could lead to swelling populations and raise doubts that our planet could support such numbers. Aubrey de Grey has little time for such questions and believes that other technologies - such as artificial meat, desalination, solar energy and other renewables - will increase the carrying capacity of the planet, allowing more people to live longer lives. But this rationale suffers from a dependence on uncertain techno-fixes that may not alleviate suffering in an equally distributed manner. Yet, if concerns like these had paralysed the early pioneers of vaccination and antibiotics, it is unlikely many of us today could expect to live much beyond the age of 40-years-old. Advances in medicine over the last two centuries have taught us that we have the power to defeat the diseases that afflict us. Perhaps if we apply ourselves, then we can beat ageing too.

Nearly 50 percent of all dementias, including Alzheimer's, begins with the breakdown of the smallest blood vessels in the brain and their protective "gatekeeper cells," according to a new study. That catastrophe causes a communications failure called small vessel disease. Many people with that disease also have white matter disease, the wearing away of fatty myelin that allows neurons to transfer messages within the brain network. In an animal model, researchers found that brain deterioration associated with dementia may start as early 40 in humans.

For more than 25 years, scientists have known that white matter disease impedes a person's ability to learn or remember new things, slows thinking and causes people to fall more often due to balance issues. They identified a link between crippled small blood vessels in the brain and white matter disease but didn't know what started that process until now. "Many scientists have focused their Alzheimer's disease research on the buildup of toxic amyloid and tau proteins in the brain, but this study and others from my lab show that the problem starts earlier - with leaky blood vessels in the brain. The collapse of pericytes - gatekeeper cells that surround the brain's smallest blood vessels - reduces myelin and white matter structure in the brain. Vascular dysfunctions, including blood flow reduction and blood-brain barrier breakdown, kick off white matter disease."

The study explains that pericytes play a critical role in white matter health and disease via fibrinogen, a protein that circulates in blood. Fibrinogen develops blood clots so wounds can heal. When gatekeeper cells are compromised, an unhealthy amount of fibrinogen slinks into the brain and causes white matter and brain structures, including axons (nerve fibers) and oligodendrocytes (cells that produce myelin), to die. The researchers are the first to show that fibrinogen is a key player in non-immune white matter degeneration. The protein enters the brain through a leaky blood-brain barrier. The study found about 50 percent fewer gatekeeper cells and three times more fibrinogen proteins in watershed white matter areas in postmortem Alzheimer's brains of humans compared to healthy brains.

To confirm that fibrinogen proteins are toxic to the brain, researchers used an enzyme known to reduce fibrinogen in the blood and brain of mice. White matter volume in mice returned to 90 percent of their normal state, and white matter connections were back to 80 percent productivity. "Our study provides proof that targeting fibrinogen and limiting these protein deposits in the brain can reverse or slow white matter disease. It provides a target for treatment, but more research is needed. We must figure out the right approach. Perhaps focusing on strengthening the blood-brain barrier integrity may be an answer because you can't eliminate fibrinogen from blood in humans. This protein is necessary in the blood. It just happens to be toxic to the brain."

Diffuse white-matter disease associated with small-vessel disease and dementia is prevalent in the elderly. The biological mechanisms, however, remain elusive. Using pericyte-deficient mice, magnetic resonance imaging, viral-based tract-tracing, and behavior and tissue analysis, we found that pericyte degeneration disrupted white-matter microcirculation, resulting in an accumulation of toxic blood-derived fibrin(ogen) deposits and blood-flow reductions, which triggered a loss of myelin, axons, and oligodendrocytes. This disrupted brain circuits, leading to white-matter functional deficits before neuronal loss occurs.

Fibrinogen and fibrin fibrils initiated autophagy-dependent cell death in oligodendrocyte and pericyte cultures, whereas pharmacological and genetic manipulations of systemic fibrinogen levels in pericyte-deficient, but not control mice, influenced the degree of white-matter fibrin(ogen) deposition, pericyte degeneration, vascular pathology and white-matter changes. Thus, our data indicate that pericytes control white-matter structure and function, which has implications for the pathogenesis and treatment of human white-matter disease associated with small-vessel disease.

T cells develop from hematopoietic stem cells as part of the lymphoid lineage and have the ability to detect foreign antigens and neoantigens arising from cancer cells. In the thymus, lymphoid progenitors commit to a specific T cell receptor and undergo selection events that screen against self-reactivity. Cells that pass these selection gates then leave the thymus, clonally expanding to form the patrolling naive T cell pool.

The vast majority of vertebrates experience thymic involution (or atrophy) in which thymic epithelial tissue is replaced with adipose tissue, resulting in decreasing T cell export from the thymus. In humans, this is thought to begin as early as 1 year of age. The rate of thymic T cell production is estimated to decline exponentially over time with a half-life of ∼15.7 years. Declining production of new naive T cells is thought to be a significant component of immunosenescence, the age-related decline in immune system function. With the recent successes of T cell-based immunotherapies, it is timely to assess how thymic involution may affect cancer and infectious disease incidence.

It is clear from epidemiological data that incidence of infectious disease and cancer increases dramatically with age, and, specifically, that many cancer incidence curves follow an apparent power law. The simplest model to account for this assumes that cancer initiation is the result of a gradual accumulation of rare "driver" mutations in one single cell. Furthermore, the fitting of this power law model (PLM) can be used to estimate the number of such mutations. Exponential curves have also been used to fit cancer incidence data, resulting in worse fits than the PLM overall. Nevertheless, it is worth noting that exponential rates close to the declining curve for thymic T cell production can be seen to emerge from the incidence data, indicating the relevance of the thymic involution timescale. While the PLM fits well, it does not account for changes in the immune system with age. To better determine the processes underlying carcinogenesis, we asked whether an alternative model, based only on age-related changes in immune system function, might partly or entirely explain cancer incidence.

Our model outperforms the power law model with the same number of fitting parameters in describing cancer incidence data across a wide spectrum of different cancers, and provides excellent fits to infectious disease data. Our hypothesis and results add to the understanding of infectious disease and cancer incidence, suggesting in the latter case that immunosenescence, rather than gradual accumulation of mutations, serves as the predominant reason for an increase in cancer incidence with age for many cancers. For future therapies, including preventative therapies, strengthening the functionality of the aging immune system appears to be more feasible than limiting genetic mutations, which raises hope for effective new treatments.

The scarcity of human donor organs in terms of availability for transplants is a renowned problem. The high request of organs moves toward an increased use of marginal donors, including organs from old or very old donors usually transplanted into younger recipients. Within the context of orthotopic liver transplants, clinical evidence suggests that livers from aged donors (≥ 70 years) do have function and duration comparable to those achievable with livers from younger donors. Paradigmatic are the cases of 26 octogenarians livers being transplanted between 1998 and 2006, 15 patients out of 26 are currently alive and 2 of those organs being centenarians.

Our team was deeply involved in an Italian national project to collect biological data to answer the question - why livers from old donors may be successfully used for transplants. The first evidence was a relative low grade of aging signs of liver donors at histological and cytological level, also including the three major proteolytic activities of proteasome, comparing young and old livers. Further, we tried to investigate the epigenetic age-related modifications in terms of liver microRNAs (miRs). We discovered that at 60-70 years of chronological age, three miRs start to increase their expression level, i.e. miR-31-5p; miR-141-3p; miR-200c-3p, and we assumed such an increase as markers of aging in human liver. When a relatively young liver was transplanted into a relatively older recipient (Δ age-mismatch average: +27 years) the expression of these miRs significantly increased in the organ (follow up after graft at 15 ± 7 months). It is interesting that we were not able to document the reverse. Indeed, when a relatively old liver was transplanted into a relatively young recipient (Δ age-mismatch average: -17 years), the expression of the three above-mentioned miRs did not change (follow up after graft at 10 ± 2 months).

On the whole, these observations suggest that in the setting of liver transplantation the aging phenotype can be "transmitted/propagated" more easily than the young phenotype via the body microenvironment. Recently, we studied the above mentioned miRs using single-miR real time-RT qPCR on blood serum samples from 34 recipients stratified on the basis of donor liver chronological age. No difference was observed, thus suggesting that the phenomenon previously found was tightly related to the organ itself without miR-specific exocytosis and changes at circulating level, at least for the identified miRs.

The biological effect of donor and recipient age-mismatch is a topic rather neglected despite its great potential, biological and clinical interest. The possibility that a centenarian liver can still function properly may suggest not only the intrinsic peculiarity of this organ (slowed down ageing; regeneration phenomena), but also the interaction with the younger recipients. This interaction was previously demonstrated in heterochronic parabiosis experiments in mice models, but deep analyses need specifically in humans, aiming at explain the reason of the variability associated with the duration of transplant.

For the first time, researchers have regenerated patients' damaged lungs using autologous lung stem cell transplantation in a pilot clinical trial. In 2015, the researchers identified p63+/Krt5+ adult stem cells in a mouse lung, which had potential to regenerate pulmonary structures including bronchioles and alveoli. Now they are focusing on lung stem cells in humans rather than mice. The researchers found that a population of basal cells labeled with an SOX9+ marker had the potential to serve as lung stem cells in humans. They used lung bronchoscopy to brush off and amplify these lung stem cells from tiny samples.

In order to test the capacity of lung stem cells to regenerate lung tissue in vivo, the team transplanted the human lung stem cells into damaged lungs of immunodeficient mice. Histological analysis showed that stem cell transplantation successfully regenerated human bronchial and alveolar structures in the lungs of mice. Also, the fibrotic area in the injured lungs of the mice was replaced by new human alveoli after receiving stem cell transplantation. Arterial blood gas analysis showed that the lung function of the mice was significantly recovered.

The team launched the first clinical trial based on autologous lung stem cell transplantation for the treatment of bronchiectasis. The first two patients were recruited in March 2016. Their own lung stem cells were delivered into the patients' lung through bronchoscopy. One year after transplantation, two patients described relief of multiple respiratory symptoms such as coughing and dyspnea. CT imaging showed regional recovery of the dilated structure. Patient lung function began to recover three months after transplantation, which maintained for one year.

Kidney glomeruli - constituent microscopic parts of the organ - were generated from human embryonic stem cells grown in plastic laboratory culture dishes containing a nutrient broth known as culture medium, containing molecules to promote kidney development. They were combined with a gel like substance, which acted as natural connective tissue - and then injected as a tiny clump under the skin of mice. After three months, an examination of the tissue revealed that nephrons: the microscopic structural and functional units of the kidney - had formed.

Tiny human blood vessels - known as capillaries - had developed inside the mice which nourished the new kidney structures. However, the mini-kidneys lack a large artery, and without that the organ's function will only be a fraction of normal. So, the researchers are working with surgeons to put in an artery that will bring more blood the new kidney. "We have proved beyond any doubt these structures function as kidney cells by filtering blood and producing urine - though we can't yet say what percentage of function exists. What is particularly exciting is that the structures are made of human cells which developed an excellent capillary blood supply, becoming linked to the vasculature of the mouse. Though this structure was formed from several hundred glomeruli, and humans have about a million in their kidneys - this is clearly a major advance. It constitutes a proof of principle - but much work is yet to be done."

Researchers have created a new lab-grown blood vessel replacement that is composed completely of biological materials, but surprisingly doesn't contain any living cells at implantation. The vessel, that could be used as an "off the shelf" graft for kidney dialysis patients, performed well in a recent study with nonhuman primates. It is the first-of-its-kind nonsynthetic, decellularized graft that becomes repopulated with cells by the recipient's own cells when implanted.

The researchers generated vessel-like tubes in the lab from post-natal human skin cells that were embedded in a gel-like material made of cow fibrin, a protein involved in blood clotting. Researchers put the cell-populated gel in a bioreactor and grew the tube for seven weeks and then washed away the cells over the final week. What remained was the collagen and other proteins secreted by the cells, making an all-natural, but non-living tube for implantation.

To test the vessels, the researchers implanted the 15-centimeter-long (about 5 inches) lab-grown grafts into adult baboons. Six months after implantation, the grafts grossly appeared like a blood vessel and the researchers observed healthy cells from the recipients taking up residence within the walls of the tubes. None of the grafts calcified and only one ruptured, which was attributed to inadvertent mechanical damage with handling. The grafts after six months were shown to withstand almost 30 times the average human blood pressure without bursting. The implants showed no immune response and resisted infection.

Researchers have developed the first blood test to detect amyloid-β protein buildup in the brain, one of the earliest hallmarks of Alzheimer's disease. The findings show that measurements of the protein and its precursors in the blood can predict neural amyloid-β deposition and could pave the way for a cheap and minimally invasive screening tool for the disease. "This study has major implications. It is the first time a group has shown a strong association of blood plasma amyloid with brain and cerebrospinal fluid."

Current methods to identify amyloid-β buildup in living people are limited to costly and sometimes highly invasive procedures, such as brain imaging with a PET scanner and spinal cord fluid extraction. So researchers set out to test whether the same information could be obtained from a blood sample. Using immunoprecipitation and mass spectrometry, the team isolated and characterized amyloid proteins in the blood from a cohort of 121 people in Japan spanning a range of cognitive function, from normal to developed Alzheimer's. They showed that blood test results could predict amyloid-β levels in the brain with about 90 percent of the accuracy achieved using PET scanning. A repeat of the approach with a validation cohort of 252 people in Australia confirmed the blood test's performance.

Such a test could one day be used to detect early signs of Alzheimer's in people with no obvious symptoms. "I can see in the future, five years from now, where people have a regular checkup every five years after age 55 or 60 to determine whether they are on the Alzheimer's pathway or not. If a person knows they are on this pathway well before the onset of any cognitive impairment some would want to alter their lifestyles. It's good to see this type of study advance, as we desperately need noninvasive and low-cost markers for Alzheimer's disease. But still, at this point it is not ready for prime time."

Mortality, life expectancy, and age-at-death are all strongly socially structured. Despite economic growth, welfare state provisions, modern medicine and a fundamental change in disease panorama, we find a negative social gradient in mortality generation after generation. Because education, occupation, and income all predict health and survival we should also expect such characteristics in the parental generation to predict the next generation's health prospects, resulting in "inheritance of longevity". It is possible, however, that this influence from previous generations is considerably broader than that working through the children's own education, occupation, and income. Variation in mortality risk within social groups is great. To understand "inheritance of longevity" we need a conceptual framework that also identifies those within-class influences.

Already in 1934 it was suggested that the first 15 years of life could determine your mortality risk during the entire lifecourse. Similarly, the so-called DOHaD (Developmental Origins of Health and Disease) theory suggests that early life experiences is an important determinant of adult health and disease. DOHaD theory has focused on specific aetiologies and influences, such as that of foetal growth restriction on blood pressure and circulatory disease. Another, earlier school of thinking argued for more general disease-causing mechanisms. Concepts like frailty, general susceptibility, or differential vulnerability refer to individual differences in the ability to survive hardship.

Demographic concepts like frailty, epidemiological ones like general susceptibility, and psychological ones like resilience all refer to the same real-life-phenomenon: a general rather than specific vulnerability to disease. Some have stressed its social roots, while others perhaps assumed it to have a more genetic basis. Resilience, in turn, may be related to both views. It could be thought of as the opposite extreme to susceptibility/frailty on the same underlying dimension. In this study, we argue that resilience is acquired early and maintained throughout life. Resilience should therefore influence the ability to survive up to a high age and be linked to longevity, as a number of studies indeed suggest.

"Inheritance of longevity" has been discussed at length in the literature. Its precise nature is somewhat elusive. Studying the entire Icelandic population, researchers concluded that longevity was inherited within families, probably because of shared genes. Other groups, looking at twin data, concluded that genetic influences on the lifespan were minimal before age 60 and only increase after that age. On the other hand, other work has rejected any idea that mortality in old age is genetically programmed. Consistent with that view, a Swedish study of men born in 1913, found that a number of social and behavioural factors measured at age 50, but not their parents' survival, predicted longevity.

Evolutionary theorists have debated whether there is any evolutionary pressure to promote survival into old age. Nevertheless, we observe a steady lifespan extension in modern societies, especially among women, partly based on falling mortality rates across their long post-reproductive period. That children tend to live longer than their parents is likely to be determined both by what experience parents brings to the next generation, and by the improved life circumstances of the children themselves in their childhood and adult life. The importance of genetic factors for longevity, we suggest, may lie in their interaction with other factors, perhaps especially if this interaction takes place at an early age.

Aging is one of the most intricate and complex biological phenomenon. One physiological system that shows marked changes during aging is the immune system. The interest of the immune system in aging is related to the fact that this is an interacting master regulatory system that keeps the organism free of invaders, either internal or external. Since the introduction of the notion of immunosenescence, many scientists have questioned the justification for unidirectional implication of the immune system and its decreased efficiency associated with aging. Whereas some functions are indeed decreased, others are increased. Therefore; changes are not as uniform as the designation would suggest.

Accordingly, we can propose a new paradigm for dynamic immune changes with aging. We suggest that aging leads to modified/modulated responses of the immune system, making it more adapted to cope with challenges (pathogens) in a given (local) environment, and not just to an eventually terminal deterioration of the immune system. From an evolutionary perspective, this is a simple optimization of the resources of the aging body, even if it ultimately leads to pathologies and death. Immunosenescence may be necessary for an adequate response to known antigens, but detrimental for responses to new antigens in most circumstances. From this perspective, many or most age-related changes in the immune system may be desirable adaptations to the aging process, and thus no need for rejuvenation seems to be necessary.

In conclusion, most experimental data on immune changes with aging show a decline in many immune parameters when compared to young healthy subjects. The bulk of these changes is termed immunosenescence. Immunosenescence has been considered for some time as detrimental because it often leads to subclinical accumulation of pro-inflammatory factors and inflammaging. Together, immunosenescence and inflammaging are suggested to stand at the origin of most of the diseases of the elderly, such as infections, cancer, autoimmune disorders, and chronic inflammatory diseases. However, an increasing number of gerontologists have challenged this negative interpretation of immunosenescence with respect to its significance in aging-related alterations of the immune system.

If one considers these changes from an evolutionary perspective, they can be viewed preferably as adaptive or remodeling rather than solely detrimental. Whereas it is conceivable that global immune changes may lead to various diseases, it is also obvious that these changes may be needed for extended survival/longevity. Recent cumulative data suggest that, without the existence of the immunosenescence/inflammaging duo (representing two sides of the same phenomenon), human longevity would be greatly shortened.

Researchers analyzed blood samples from nearly 10,000 people to find that genetic markers in the gene responsible for keeping telomeres (tips of chromosomes) youthfully longer, did not translate into a younger biologic age as measured by changes in proteins coating the DNA. DNA methylation age is a biomarker of chronological age and predicts lifespan, but its underlying molecular mechanisms are unknown.

In this genome-wide association study, researchers found gene variants mapping to five loci associated with intrinsic epigenetic age acceleration (IEAA) and gene variants in three loci associated with extrinsic epigenetic age acceleration. Variants in the gene called Telomerase Reverse Transcriptase (TERT) on chromosome 5 that were associated with older IEAA were also associated with longer telomeres indicating a critical role for TERT in regulating the epigenetic clock, in addition to its established role of compensating for cell replication-dependent telomere shortening.

"We calculated the epigenetic aging rate for each person using a previously described epigenetic clock method. Next, we related the epigenetic aging rate to millions of genetic locations (SNPs) across all of the chromosomes. Then we studied the SNPs that had very significant associations with epigenetic aging rates. To our surprise, one of these locations was the TERT locus. The finding is surprising because this was not a study of telomere length. TERT is a subunit of the enzyme telomerase, which is widely known because it has been touted as an anti-aging enzyme. Our study highlights the error in the notion that activation of telomerase (as advocated by some) will cure aging. Instead, our study shows that an anti-aging therapy based on telomerase expression would be accompanied by continued aging."

Cellular senescence prevents the proliferation of cells exposed to potentially oncogenic stresses, such as DNA-damaging reagents, irradiation, telomere shortening, and oncogene activation. Mutations in genes essential for the senescence-induced cell cycle arrest predispose cells to immortalization and shorten lifespan by increasing cancer incidence. However, cellular senescence not only arrests the cell cycle but also changes how the cell impacts its microenvironment. The way in which senescent cells influence their microenvironment is highly context dependent. It promotes tumor development in many cases, but can also be tumor suppressive in certain circumstances. Removal of senescent cells that accumulated in the body during aging alleviates atherosclerosis, hepatic steatosis, tumor development, and functional declines of heart, kidney, and fat tissues, resulting in prolonged healthspan and lifespan. These effects may be attributable to so-called , whereby cells secrete high levels of inflammatory cytokines, chemokines, growth factors, and metalloproteinases.

Although the involvement of typical secretory proteins in the non-cell-autonomous effects of senescent cells has been well studied, the functions of membrane-enclosed vesicles secreted by senescent cells have not been studied until recently. These extracellular vesicles (EVs) were once thought to be cellular trash, but now it is clear that they are critical mediators in intercellular communication. Emerging evidence indicates that EVs also play important roles in cellular senescence and aging. This field is rapidly advancing especially since it was reported that EVs deliver functional RNA to the recipient cells. Extracellular vesicles contain a huge variety of proteins and nucleic acids in a cell type-dependent manner.

Senescence-associated increase in EV secretion seems to be a general feature of cellular senescence and has been observed in fibroblasts, epithelial cells, and cancer cells. This increase is at least partially mediated by p53 and one of its targets, TSAP6, although the mechanism whereby TSAP6 regulates EV secretion is not well understood. It is known that EV secretion contributes to the clearance of harmful molecules in cells, such as cytoplasmic DNA. It has been shown that EV-mediated removal of cytoplasmic DNA is essential for the survival of senescent cells, which may explain why EV secretion is increased in senescent cells.

Recent findings implicate senescent cell EVs in cancer development, vascular calcification, and age-related decline in bone formation. Increased secretion of EV-associated DNA from senescent cells is likely to be pro-inflammatory and may contribute to age-related chronic inflammation. Whether senescent cell EVs promote or suppress cancer development may be context dependent. Despite this progress, it should be noted that the functions of senescent cell EVs are still understudied, at least partially due to inadequate understanding of EVs themselves. This research field is immature and the methods used are not sufficiently standardized yet. Nevertheless, EVs are now shown to be critical players in cellular senescence and aging, and more functions will be revealed in the future as the EV research field matures.

The human brain's ventricular system is essential for the movement of nutrient-rich cerebrospinal fluid (CSF) throughout the central nervous system. A special epithelial lining along the ventricle walls composed of ependymal cells allows for the movement of CSF nutrients into the brain parenchyma as well as clearance of proteins and metabolites from the interstitial fluid (ISF). This ependyma-mediated bidirectional CSF-ISF exchange, as well as the formation of a cell barrier to prevent movement of proteins and metabolites from the CSF back into the ISF, relies on the presence of an intact ependymal cell monolayer. Pathological conditions in humans that are characterized by ependymal cell stretching and/or loss, including hydrocephalus, typically result in decreased CSF turnover rates and impaired clearance of proteins and metabolites resulting in a harmful buildup of these substances in brain parenchymal tissue.

Longitudinal magnetic resonance imaging (MRI)-based studies have established that expansion of the brain's fluid-filled lateral ventricles (LVs), or ventriculomegaly, is a defining feature of the aging brain. Ventricle expansion rates correlate strongly with declining cognitive performance and the rate of ventricle volume increase has been linked to an increase in Alzheimer's disease (AD)-related amyloid-beta (Aβ) plaques and tau neurofibrillary tangles, as well as alterations in CSF biomarker composition. Together, these point towards defective CSF-ISF exchange and impaired clearance mechanisms that are characteristic of AD.

Degeneration of periventricular brain tissue and declines in associated white matter tract integrity are common with normal aging and the extent of periventricular tissue abnormalities has been linked to dementia and AD. Periventricular hyperintensities (PVH), as measured using MRI, are indicative of fluid accumulation, or edema, often located in the parenchymal tissue directly adjacent to the frontal and occipital horns of the LV. The precise etiology of PVH is not clear; however, studies have implicated impaired drainage of ISF from the periventricular white matter resulting in aberrant fluid accumulation.

In previous studies, we found that enlarged ventricles from aging humans exhibited regional gliosis in the place of functional ependymal cell coverage. We predict that replacement of the ependymal lining with stratified layers of astrocytes at the ventricle surface adversely affects CSF/ISF bulk flow mechanisms, leading to fluid accumulation or edema and harmful buildup of proteins and metabolites in the periventricular space. Due to the rarity of longitudinal MRI data sets and associated subject-matched periventricular tissue biospecimens, this has never been directly demonstrated.

Using data from the Alzheimer's Disease Neuroimaging Initiative (ADNI) and the Baltimore Longitudinal Study of Aging (BLSA), we investigated the relationships among the following variables: ventricle expansion, PVH, periventricular white matter tract integrity, and degree of cognitive impairment. We also investigated the histopathological correlates of these measures, including LV wall gliosis and periventricular protein accumulation. We found that both LV and PVH volumes increase with age, and this expansion is more rapid and dramatic in cognitively impaired (CI) subjects. We also found a direct relationship between LV volume and PVH volume increase. Case studies from the BLSA allowed us to link ventricle expansion with regional gliosis, where an intact ependymal cell monolayer was replaced with stratified layers of astrocytes in regions of LV expansion. Additionally, adjacent parenchymal regions exhibited edema (as indicated by PVH), white matter deterioration, decreased vascular integrity, and harmful buildup of proteins including Aβ and tau.

With their large buck teeth and wrinkled, hairless bodies, naked mole rats won't be winning any awards for cutest rodent. But their long life span - they can live up to 30 years, the longest of any rodent - and remarkable resistance to age-related diseases, offer scientists key clues to the mysteries of aging and cancer. That's why researchers studied naked mole rats to see if the rodents exhibit an anticancer mechanism called cellular senescence.

Previous studies indicated that when cells that had undergone senescence were removed from mice, the mice were less frail in advanced age as compared to mice that aged naturally with senescent cells intact. Researchers therefore believed senescence held the key to the proverbial fountain of youth; removing senescent cells rejuvenated mice, so perhaps it could work with human beings. But is eliminating senescence actually the key to preventing or reversing age-related diseases, namely cancer?

Researchers compared the senescence response of naked mole rats to that of mice, which live a tenth as long - only about two to three years. Their unexpected discovery? Naked mole rats do experience cellular senescence, yet they continue to live long, healthy lives; eliminating the senescence mechanism is not the key to their long life span. The researchers found that although naked mole rats exhibited cellular senescence similar to mice, their senescent cells also displayed unique features that may contribute to their cancer resistance and longevity.

The cellular senescence mechanism permanently arrests a cell to prevent it from dividing, but the cell still continues to metabolize. The researchers found that naked mole rats are able to more strongly inhibit the metabolic process of the senescent cells, resulting in higher resistance to the damaging effects of senescence. "In naked mole rats, senescent cells are better behaved. When you compare the signals from the mouse versus from the naked mole rat, all the genes in the mouse are a mess. In the naked mole rat, everything is more organized. The naked mole rat didn't get rid of the senescence, but maybe it made it a bit more structured."

We urgently need to better understand the mechanisms of the aging process, with a view to improving the future quality of life of our aging populations. Most aging studies have been carried out in shorter-lived laboratory model species, given the ease of manipulation, housing, and length of life span. Although they are excellent study species, it is difficult to extrapolate experimental findings in these short-lived laboratory species to long-lived, outbred species such as humans. Therefore, it has been argued that long-lived, outbred species such as bats may be better models to investigate the aging processes of relevance to people.

Only 19 species of mammal are longer-lived than humans in proportion to their body size, and 18 of these species are bats. Bats are the longest-lived mammals relative to their body size, with the oldest bat recaptured (Myotis brandtii) being more than 41 years old, weighing ~7 g, and living ~9.8 times longer than predicted for its size. Although an excellent model species to study extended healthspan, logistically, it is difficult to study aging in bats because they are not easily maintained in captivity. Here, uniquely drawing on more than 60 years of cumulative long-term, mark-recapture studies from four wild populations of long-lived bats, we determine whether telomeres, a driving factor of the aging process, shorten with age in Myotis myotis (n = 239; age, 0 to 6+ years), Rhinolophus ferrumequinum (n = 160; age, 0 to 24 years), Myotis bechsteinii (n = 49; age, 1 to 16 years), and Miniopterus schreibersii (n = 45; age, 0 to 17 years).

We show that telomeres shorten with age in Rhinolophus ferrumequinum and Miniopterus schreibersii, but not in the bat genus with greatest longevity, Myotis. As in humans, telomerase is not expressed in Myotis myotis blood or fibroblasts. Selection tests on telomere maintenance genes show that ATM and SETX, which repair and prevent DNA damage, potentially mediate telomere dynamics in Myotis bats. Twenty-one telomere maintenance genes are differentially expressed in Myotis, of which 14 are enriched for DNA repair, and 5 for alternative telomere-lengthening mechanisms. These results, coupled with differential expression of ATM, SETX, MRE11a, RAD50, and WRN across all tissues in the genus Myotis compared to other mammals, suggest a potential role for alternative lengthening of telomeres (ALT) mechanisms in the maintenance of telomeres in these species. If telomeres are maintained by ALT mechanisms in Myotis species, then these genes may represent excellent therapeutic targets given that cancer incidence in bats is rare.

One of the common features of aging is low-level chronic inflammation, termed sterile inflammation or inflammaging. Even though all the sources of inflammaging are unclear, it likely derives at least partly from senescent cells. Mammalian cells undergo senescence in response to stressful stimuli. An important feature of senescent cells is the secretion of a myriad of biologically active factors, termed the senescence-associated secretory phenotype (SASP).

The SASP is similar between mice and humans, and comprises inflammatory cytokines such as IL-6 and IL-8. The SASP can disrupt the surrounding microenvironment and normal cell functions, and stimulate malignant phenotypes in nearby cells. Senescent cells can also promote tumor growth in mice. Because senescent cells increase with age and are frequently found within hyperplastic and degenerative tissues, the SASP may be a major cause of inflammaging. Compounds that modulate the SASP hold promise for ameliorating a number of diseases of aging, including cancer.

Nutlins were originally identified as potent small molecules that inhibit the interaction between p53 and MDM2, which promote p53 degradation. Nutlin therefore stabilizes p53, thereby promoting the apoptotic death of cancer cells. Importantly, in cancer cells, nutlin-3a inhibits the activity of NF-κB, a potent transcriptional stimulator of genes encoding inflammatory cytokines, in a p53-dependent manner. The clinical importance of small-molecule MDM2 inhibitors like nutlin-3a spurred the discovery of similar compounds, such as MI-63, which are more efficient inhibitors of the MDM2-p53 interaction.

We investigated the effects of small-molecule MDM2-p53 interaction antagonists on senescent phenotypes, including the SASP, of primary human fibroblasts and epithelial cells. We used nutlin-3a, as well as the non-peptide small molecule inhibitor of MDM2, MI-63. We compared these compounds for their ability to induce a growth-arrested state, whether quiescence or senescence, in human cells, and evaluated their ability to modulate the SASP. We found that both compounds trigger selected markers of a senescent-like state, but the growth arrest was reversible, and both significantly suppressed the SASP, suggesting potential utility as therapeutic agents.

Normal functioning of the central nervous system (CNS) requires a continuous, tightly controlled supply of oxygen and nutrients as well as washout of harmful metabolites through uninterrupted cerebral blood flow (CBF). The energetic demands of neurons are very high, yet the brain has very little energetic reserves. During periods of intense neuronal activity, there is a requirement for adjusting oxygen and glucose delivery to local neuronal activity through rapid adaptive increases in CBF. This is ensured by a mechanism known as neurovascular coupling (NVC). The resultant functional hyperemia is a vital mechanism to maintain optimal microenvironment of cerebral tissue and thereby ensuring normal neuronal function.

There is an increasing appreciation that (micro)vascular contributions to cognitive impairment and dementia in elderly patients are critical. Importantly, neurovascular coupling responses are impaired both in elderly patients and aged laboratory animals. Experimental studies support this concept, showing that pharmacologically induced neurovascular uncoupling in mice mimics important aspects of age-related cognitive impairment. On the basis of these findings, we proposed that novel therapeutic interventions should be developed to rescue functional hyperemia in elderly patients to prevent/delay cognitive impairment. Previous studies demonstrate that aging exacerbates generation of reactive oxygen species (ROS) in the cerebromicrovascular endothelial cells, which contribute to age-related neurovascular uncoupling in aged mice by promoting endothelial dysfunction. We hypothesize that pharmacological treatments, which attenuate endothelial oxidative stress, will have the capacity to improve neurovascular coupling in aged individuals.

The mitochondrial free radical theory of aging posits that mitochondria-derived ROS (mtROS) production and related mitochondrial dysfunction are a critical driving force in the aging process. In support of this theory, it was demonstrated that attenuation of mitochondrial oxidative stress (by mitochondria-targeted overexpression of catalase) increases mouse lifespan. There is particularly strong evidence that mitochondrial oxidative stress is implicated in cardiovascular aging processes. Yet, although drugs that improve mitochondrial function have been shown to exert beneficial effects both on the vasomotor function of peripheral arteries, their potential protective effects on the aged cerebral microvasculature has not been investigated.

This study was designed to test the hypothesis that pharmacological attenuation of mtROS can restore cerebromicrovascular endothelial function and thus improve neurovascular coupling in aged mice. To achieve this goal, in aged mice mitochondrial oxidative stress was manipulated by treatment with the mitochondrial-targeted peptide SS-31. We found that neurovascular coupling responses were significantly impaired in aged mice. Treatment with SS-31 significantly improved neurovascular coupling responses by increasing cerebromicrovascular dilation, which was associated with significantly improved spatial working memory, motor skill learning, and gait coordination. These findings are paralleled by the protective effects of SS-31 on mitochondrial production of reactive oxygen species and mitochondrial respiration in cultured cerebromicrovascular endothelial cells derived from aged animals.