People at an older age mainly die of three causes, accounting for 85% of them: cardiovascular disease, cancer, and respiratory system diseases. Although infection constitutes only a secondary cause of death in that group, happening mainly during the winter periods because of influenza infection and pneumonia disease, it is a major threat for aging adults in cluster environments like rest homes or health care facilities. People from that age group arriving in hospitals with a secondary diagnosis of infection monopolize the beds for a long period, recover badly and remain weak when leaving the health care facility. This results in a long-term poor overall health condition with a high cost for society.

Healthcare systems will have to deal with increasing numbers of ageing adults with severe infections, not only because of the higher number of individuals living longer but also because of the decline in their immune response, called immunosenescence, which makes them more vulnerable to pathogens. Ageing adults may thereby also become a new source of infection. However, an effective medical act to safeguard individuals and populations against infectious diseases is vaccination, which has proven its effectiveness in children and young adults. The ambition is to achieve a similar level of infectious disease control in ageing adults. This would be fundamental for enhancing healthy ageing. However, many recommended vaccines for ageing adults do not maintain an effective and/or sustained immune response, as is the case for influenza, pneumococcal disease or pertussis, for example.

Therefore, there is a need to better understand the aetiology of the major infectious diseases affecting this population. There is also a need to decipher the mechanisms underlying immunosenescence, which should lead to improved vaccine effectiveness and to the development of more efficient vaccination strategies for this age group (whom to vaccinate, when, where, how frequently, and at what price). Finally, there is a need to provide dedicated educational programs to healthcare professionals. Over the next decade, local decision makers will need to have a clear view on this healthcare problem, with access to effective tools to manage the growing healthcare burden they need to control.

UNITY Biotechnology, Inc., a biotechnology company developing therapeutics to extend healthspan by slowing, halting or reversing diseases of aging, today announced the 12-week results from the Phase 2 study of UBX0101, a p53/MDM2 interaction inhibitor, in patients with moderate-to-severe painful osteoarthritis (OA) of the knee. There was no statistically significant difference between any arm of UBX0101 and placebo at the 12-week endpoint for change from baseline in WOMAC-A, an established measurement of pain in OA. Given these results, UNITY does not anticipate progressing UBX0101 into pivotal studies and will narrow the company's near-term focus to its ongoing ophthalmologic and neurologic disease programs.

"Developing novel treatments that selectively eliminate or modulate senescent cells is at the heart of what we do, and we have generated valuable data that will enable us to learn from this study and inform future studies in diseases of aging. While these are not the results we had hoped for, the evidence that senescent cells contribute to diseases of aging remains compelling, and we are excited to advance UBX1325 for retinal diseases, which inhibits Bcl-xL, a distinct senolytic target. Diabetic macular edema and diabetic retinopathy are attractive not only because of the strength of underlying biology, but also because of the sensitive, quantitative, and objective clinical assessments available. The burden of senescent cells in various diseases of aging is increasingly evident, which together with our research gives us great conviction in our science and the future of our pipeline."

Aging is a major risk factor for the higher incidence and prevalence of chronic conditions, such as cardiovascular diseases, metabolic diseases, and neurodegenerative diseases. Chronic systemic sterile inflammation is crucially involved with the etiology and progression of these conditions. In the elderly, these conditions are often presented with multimorbidity and may finally lead to organ failure and death. With the advance of immunosenescence (aging of the immune system), older adults also become more susceptible to infectious diseases and cancer. Of note, T cell aging and low-grade inflammation (inflammaging) are implicated with several age-related conditions. The expansion of late-differentiated T cells (CD28-), regulatory T cells, increased serum levels of autoantibodies, and pro-inflammatory cytokines were implicated with morbidities during aging. Features of accelerated immunosenescence can be identified in adults with chronic inflammatory conditions, such as rheumatoid arthritis, and are predictive of poor clinical outcomes. Therefore, there is an interplay between immunosenescence and age-related diseases.

First of all, it is important to differentiate acute from chronic inflammatory processes. Acute inflammation is a transient and useful process aiming the elimination of pathogens and tissue regeneration, orchestrated by cells of the innate immunity. It is a self-regulated process with alarm, leukocyte mobilization, and resolution phases. But aging starts a chronic inflammatory process, known as "inflammaging", with persistent and non-resolved production of pro-inflammatory mediators (cytokines, chemokines, and acute phase proteins) that increases the risk for age-related morbidity and mortality.

Although there are many sources of inflammaging, some evidence indicates the presence of overt infections during life to fuel inflammaging. Age-related intrinsic factors may also contribute to the inflammaging. When cells reach senescence, they produce cytokines, chemokines, growth factors, proteases, and angiogenic factors that characterize a senescence-associated secretory phenotype (SASP). As senescent cells accumulate during aging, SASP may also contribute to inflammaging. Inflammaging can be therefore interpreted as the complex result of the interplay between SASP, lifestyle factors, and of dysregulated innate immune cell functions with aging.

Not surprisingly, immunosenescence and SASP have been observed in older adults and during the developmental course of many immune-mediated conditions. Age-related diseases such as neurodegenerative diseases, rheumatoid arthritis, cardiovascular diseases, metabolic disorders, and cancer share common features of immunosenescence. Adverse effects of chronic low-grade inflammation increase the risk for the early appearance of diseases associated with age, suggesting that both aging and chronic (immune-mediated) diseases are interconnected states with common characteristics.

Dave Asprey, 48, is the founder of the Bulletproof wellness empire and a vocal champion of the movement to extend human life expectancy beyond 100 years. He's made millions by experimenting on his own body and packaging his home-brewed discoveries into books, a podcast, consulting services and consumer products (you may have even tried his butter-laced coffee). Thanks to a recent explosion of advances in longevity medicine, Asprey's vision of living healthfully into his second century might not be so crazy. In fact, for people in middle age right now, a handful of therapies in clinical trials have the potential, for the first time in human history, to radically transform what "old age" looks like. If the life extensionists are right, a person who's 40 today might reasonably expect to still be downhill skiing, running a 10K or playing singles tennis at 100.

It might be an exaggeration to say BioViva CEO Liz Parrish believes death is optional, but for her, Asprey's goal of living to 180 shows a distinct lack of ambition. "If you can reach homeostasis in the body, where it's regenerating itself just a little bit faster than it's degrading, then what do you die of? An accident or natural disaster, probably. There's no expiration date at 90 or 100 years old." Like Asprey, she has received criticism from the longevity research community for becoming "patient zero" in her own experimental drug trial, aimed at halting aging at the cellular level. In 2015, Parrish underwent telomerase and follistatin gene therapies in Bogotá, Colombia. The procedures involved receiving around a hundred injections of a cocktail of genes and a virus modified to deliver those new genes into her body's cells.

Humans have always aspired to find the fountain of youth, so "people might be skeptical about the fact that anti-aging technologies are working now," says British investor and businessman Jim Mellon. "But the fact is that this is finally happening, and we need to seize the moment." Mellon cofounded Juvenescence, a three-year-old pharmaceutical company that's investing in multiple technologies simultaneously to increase the odds of bringing winning products to market. Mellon, 63, has made his fortune betting on well-timed investment opportunities, and he predicts that a new "stock-market mania" for life extension is just around the corner. "This is like the internet dial-up phase of longevity biotech. If you'd invested in the internet in the very early days, you'd be one of the richest people on the planet. We're at that stage now, so the opportunity for investors is huge." One of Mellon's bets is on a class of drugs called senolytics, which destroy senescent cells. Senescent cells harm the body by secreting compounds that cause inflammation in surrounding tissues. Many age-related conditions - arthritis, diabetes, Alzheimer's, cancer - have an inflammatory component, and studies suggest that a buildup of senescent cells is a large part of the problem.

Eric Verdin, 63, is president and CEO of the Buck Institute, a globally renowned center for aging research just outside San Francisco in Marin County. Verdin is bullish on the promise of living healthfully to at least 100. Today. But 180? Don't count on it. "My prediction, based on everything we know today, is that getting to 120 is about the best we can do for the foreseeable future. I'll bet my house we're not going to see anyone live to 180 for another 200 years, if ever. But making everyone a healthy centenarian, this is something we can do today. And that's something to be excited about." Verdin's own lab at the Buck Institute studies the aging immune system and how it's affected by lifestyle factors, such as nutrition and exercise. Take, for instance, rapalogs, a class of drugs derived from rapamycin that interact with a protein called mTOR, which serves as a linchpin for multiple critical biological processes, including cell growth and metabolism. Rapalog drugs tamp down mTOR, possibly preventing age-related diseases such as diabetes, stroke, and some cancers. One of the many effects of rapamycin is that it mimics the mechanisms of calorie restriction. As Verdin's lab and others have shown, fasting provides a number of anti-aging benefits, including insulin regulation, reduced inflammation and, to put it colloquially, clearing out the gunky by-products of metabolism.

Perhaps you hope that the U.S. government will be able to accelerate COVID-19 vaccine development with its 10 billion program 'Operation Warp Speed'. Maybe it will. However, if these are your primary concerns, then getting funding for aging research should be a top priority, especially if you are an older adult, or if you have friends or family that are elderly. As you are probably aware, the COVID-19 pandemic disproportionately affects older adults. In fact, 80% of hospitalizations from Covid-19 are adults older than 65 years of age. Although the novel coronavirus may be your top concern at this time, I suggest you turn your attention to an underlying disease process ubiquitous in humans that receives far less attention: aging. If we could treat aging itself, the effects of this pandemic would certainly be muted.

To an outside observer, aging has a fairly obvious phenotype: hair graying and thinning, and skin wrinkling beginning in our third and fourth decades of life, some loss of height, tooth decay and the need for glasses in our fourth, fifth, and sixth decades of life, and age spots, loss of muscle tone and strength, diminished height, and aches and pains in the decades after that. We all know that these unwanted changes occur as we age, and yet we do not talk about aging as though it is a disease. If you walk into a doctor's office at the age of 65 and complain that you are old with a laundry list of age-related problems, the doctor may be able to help with some of your symptoms, but will have nothing to offer you to treat their underlying cause.

Appropriate funding and attention should be given to research in gerontology, the study of aging, but instead the issue is being sidelined while it continues to wreak havoc on humanity. Aging should be treated like any other disease, since the biological underpinnings of aging are becoming better understood every day and potential therapies are being investigated, albeit slowly.

Scientists and aging researchers have garnered a great deal of knowledge regarding the biological mechanisms of aging in recent years. However, there is still much to learn about the drivers of aging, especially in regards to how the nine hallmarks of aging affect one another. The more we know about the biology of aging, the easier it will be to develop therapies that target the specific causes of aging. With the knowledge we have, scientists at universities and in the private sector are already at work developing potential treatments for aging.

Recent research suggests that aging is treatable and potentially reversible. The identification of the nine inter-related hallmarks of aging in the 2013 review paper "The Hallmarks of Aging" brought the notion that aging could be addressed therapeutically into the mainstream and spawned a flurry of research into the aging process. At the time of this writing "The Hallmarks of Aging" has been cited over six thousand times. Additionally, the advent of new technologies for genetic programming, such as CRISPR-Cas9 in 2013, discoveries in the field of stem cells, most notably the discovery of Yamanaka factors, to generate Induced Pluripotent Stem Cells (IPSCs) from somatic cells in 2006, and technological advancements in the field of proteomics such as more precise and efficient microscopy, histology, and mass spectrometry, have given scientists the tools necessary to attempt to target the hallmarks of aging and repair them. Advances such as these have led to several anti-aging breakthroughs in recent years, with a central theme being that targeting just one hallmark of aging usually confers benefits to multiple other hallmarks.

Federal funding for aging research comes from the National Institute on Aging (NIA). The NIA is a division of the National Institutes of Health (NIH), which is the largest biomedical research agency on Earth, and the medical research arm of the U.S. department of Health and Human Services (HHS). The NIA is requesting 3.2 billion for fiscal year (FY) 2021, a decrease of about 10% from FY 2020. The NIA will only allocate 10% of its budget, 322.6 million, to its Division of Aging Biology (DAB), which "supports research to determine the basic biochemical and genetic mechanisms underlying the processes of aging at the cell, tissue, and organ levels and the ways these are communicated among cells and tissues of the body."

The research done by the DAB is arguably closest to what we mean in regards to research on the biology of aging, yet it receives only 10% of the NIA budget. The NIA's requested budget for FY 2021 is only 0.24% of the United States proposed discretionary budget for 2021, and the NIA's DAB budget is only 0.024% of the United States discretionary budget. Aging research is far too valuable to only account for less than a quarter of a percent of discretionary funding. And research on the biology of aging through the DAB, which includes research on treating aging with therapies such as senolytics, is receiving a negligible amount of funding given the enormous potential of such therapies to slow or reverse aging.

Age-associated systemic, chronic inflammation is partially attributed to increased self (auto)-reactivity, resulting from disruption of central tolerance in the aged, involuted thymus. This involution causally results from gradually decreased expression of the transcription factor FOXN1 in thymic epithelial cells (TECs), while exogenous FOXN1 in TECs can partially rescue age-related thymic involution. Given the findings that TECs induced from FOXN1-overexpressing embryonic fibroblasts can generate an ectopic de novo thymus under the kidney capsule and intra-thymically injected naturally young TECs can lead to middle-aged thymus regrowth, we attempted to extend these two findings by combining them as a novel thymic rejuvenation strategy with two types of promoter-driven FOXN1-reprogrammed embryonic fibroblasts (FREFs).

We engrafted these two-types of FREFs directly into the aged murine thymus. We found significant regrowth of the native aged thymus with rejuvenated architecture and function in both males and females, exhibiting increased thymopoiesis and reinforced thymocyte negative selection, along with reduced senescent T cells and auto-reactive T cell-mediated inflammation in old mice. Therefore, this strategy has preclinical significance and presents a strategy to potentially rescue decreased thymopoiesis and perturbed negative selection to significantly, albeit partially, restore defective central tolerance and reduce subclinical autoimmune symptoms in the elderly.

Since the discovery in the early 1930s that reduced food intake extends the life span of rats, caloric restriction (CR), defined as a reduction in calorie intake without causing malnutrition, has been shown to extend the life span of a range of species. While the effect on life span for humans remains to be determined, studies in nonhuman primates indicate that CR confers health benefits and possibly extends life span in rhesus monkeys, and short-term CR studies in humans evoke metabolic health benefits.

While the life span phenotype of CR was first observed in laboratory rats, much of the insight into molecular mechanisms has derived from simpler model organisms including the budding yeast Saccharomyces cerevisiae. Budding yeast has been a canonical model for aging research due to its short replicative life span (defined as the number of daughter cells produced by a mother cell prior to senescence) and ease of genetic manipulation. In addition, yeast cells can grow on synthetic media of precisely controlled composition, making it possible to isolate the effect of an individual nutrient on life span. For example, CR has been implemented by simply reducing the glucose concentration of the media without affecting other nutrients.

In this work, we investigate the molecular mechanism of life span extension by glucose restriction (GR) in yeast, using an approach that combines global gene expression profiling, microfluidics-based single-cell analysis, and candidate-based genetic manipulations. Using ribosome profiling and RNA-seq, we systematically compared the translational and transcriptional profiles of cells grown in GR and normal media, uncovering groups of functionally related genes that are up- or down-regulated. We observed a cross-talk from glucose sensing to the regulation of intracellular methionine: methionine biosynthetic enzymes and transporters were significantly down-regulated by GR, leading to the decreased intracellular methionine level, and external supplementation of methionine cancels the life span extension by GR without affecting the life span in the normal media. With additional evidence from systematic manipulations of methionine pathway genes and bioinformatic analyses of other long-lived mutants, we were able to place intracellular methionine at a central position for life span regulation.

Tiny factories float inside our cells and provide them with almost all the energy they need: the mitochondria. Their effectiveness decreases when we get older. Mitochondria are almost like cells within the cell. Like their host, they have a membrane that protects their genetic material and, above all, filters exchanges with the outside. The difference in electrical charge between the inside and the outside of the mitochondria, called "membrane potential", allow certain molecules to go through, while others remain at bay. As between the two poles of a used electric battery, the membrane potential of the mitochondria can sometimes drop. For scientists, this is an unmistakable clue that its functions are impaired.

We know how to measure the phenomenon on cultured cells. But until now, you couldn't really see it on live animals. Now researchers have found a way to study the phenomenon in live mice. They use animals that are genetically modified to express luciferase - an enzyme that produces light when combined with another compound called luciferin. This is how fireflies sometimes light up our summer evenings. Scientists have developed two molecules that, when injected into the rodent, pass into the mitochondria, where they activate a chemical reaction. The mitochondria then produce luciferin and eject it outwards. Luciferin combines with luciferase in mouse cells to produce light.

Researchers need only measure light intensity to get a clear picture of how well the mitochondria are functioning. When they function less well, their membrane lets in less chemical compounds. The production of luciferin decreases, and therefore the luminosity too. To demonstrate the potential of their method, the researchers carried out several experiments. For example, they observed that older rodents produce significantly less light. This drop in light reflects a drop in the activity of mitochondria - their membrane potential is much lower than in younger rodents. The team also tested a chemical known to rejuvenate mitochondria: nicotinamide riboside. This molecule is non-toxic and commercially available as a dietary supplement. Mice given this compound produced more light, a sign of increased mitochondrial activity.

Frailty is a late life phenotype, which is associated with low physiologic reserve and increased vulnerability to adverse outcomes such as disability, hospitalization, and death. Frailty is a multidimensional construct and involves several components, including physical, psychological, cognitive, and social domains. The complexity of this clinical syndrome has made it difficult to elucidate its biology. Although both genetic and proteomic approaches have been applied, previous studies have been inconclusive regarding the biology of frailty. To date, no large-scale proteomic study has been carried out in regard to frailty. An additional challenge is to distinguish the biological antecedents of frailty from aging. Since frailty is strongly associated with chronological age, both may share a common biological signature.

To elucidate the proteomic signature associated with frailty, 4265 proteins were measured in plasma of older adults, of which 55 were positively associated and 88 were negatively associated with frailty. The proteins most strongly associated with frailty were fatty acid-binding proteins, including FABP and FABPA, leptin, and ANTR2. Pathway analysis with the top 143 frailty-associated proteins revealed enrichment for proteins in pathways related to lipid metabolism, musculoskeletal development and function, cell-to-cell signaling and interaction, cellular assembly, and organization. A frailty prediction model utilizing 110 proteins demonstrated a correlation between predicted frailty and observed frailty. Predicted frailty was also more strongly correlated with chronological age than observed frailty.

The major aim of stroke therapies is to stimulate brain repair and to improve behavioral recuperation after cerebral ischemia. Despite remarkable advances in cell therapy for stroke, stem cell-based tissue replacement has not been achieved yet, stimulating the search for alternative strategies for brain self-repair using the neurogenic zones of the brain, the dentate gyrus and the subventricular zone (SVZ). However, during aging, the potential of the hippocampus and the SVZ to generate new neuronal precursors, declines. We hypothesized that electrically stimulation of endogenous neurogenesis in aged rats could increase the odds of brain self-repair and improve behavioral recuperation after focal ischemia.

Following stroke in aged animals, the rats were subjected to two sessions of electrical non-convulsive stimulation using ear-clip electrodes, at 7- and 24 days after injury. Animal were sacrificed after 48 days. We report that electrical stimulation (ES) stimulation of post-stroke aged rats led to an improved functional recovery of spatial long-term memory (T-maze), but not on the rotating pole or the inclined plane, both tests requiring complex sensorimotor skills. Surprisingly, ES had a detrimental effect on the asymmetric sensorimotor deficit.

Histologically, there was a robust increase in the number of doublecortin-positive cells in the dentate gyrus and SVZ of the infarcted hemisphere and the presence of a considerable number of neurons expressing tubulin beta III in the infarcted area. Among the genes that were unique to ES, we noted increases in the expression of seizure related 6 homolog like, which is one of the physiological substrate of the β-secretase BACE1 involved in the pathophysiology of Alzheimer's disease, and Igfbp3 and BDNF receptor mRNAs which has been shown to have a neuroprotective effect after cerebral ischemia. However, ES was associated with a long-term down regulation of cortical gene expression after stroke in aged rats suggesting that gene expression in the peri-infarcted cortical area may not be related to electrical stimulation induced-neurogenesis in the subventricular zone and hippocampus.

In contrast to the steady pace of chronological age, the pace of biological age varies among individuals and may predict distinct aspects of aging at different life stages. As chronological age does not sufficiently represent fundamental aging processes, methods to measure biological aging have been developed, which is important for assessing strategies to slow down biological aging and extend healthspan. Technical breakthroughs have led to the discovery of several molecular markers of aging, including epigenetic biomarkers.

Among biomarkers of aging, such as telomere length (TL), metabolomic, transcriptomic, and proteomic variations, the most promising are based on the DNA methylation (DNAm) of cytosines at CpG dinucleotides, representing one of the key epigenetic mechanisms altering gene expression or splicing. The cumulative assessment of DNAm levels at age-related CpGs could be used as a DNAm clock, which may mirror biological aging. Although some clinical biomarkers outperform DNAm clocks in reflecting morbidity and mortality, the advantage of DNAm clocks is their ability to measure either multitissue or cell-/tissue-specific aging. DNAm clocks could help explain why some individuals stay healthy, whereas others develop age-related neurodegenerative diseases.

Several studies support the link between DNAm clocks and biological age. DNAm-age acceleration (difference between DNAm-age and chronological age) was associated with major neurodegenerative diseases. Similarly, HIV-infected individuals exhibit premature aging based on methylome-wide changes. Furthermore, individuals with Werner syndrome or Down syndrome also display accelerated DNAm clocks. In contrast, DNAm-age in centenarians is on average 9 years younger than their chronological age. However, it is mostly unclear what the underlying molecular mechanisms of DNAm clocks are. Do they reflect similar aspects of the aging process? What is their capacity to predict risk of decline before disease onset and therapeutic effectiveness aiming to extend healthspan? Various confounders may influence the outcome of these age predictors, including genetic and environmental factors, as well as technical differences in the selected DNAm arrays. These factors should be taken into consideration when interpreting DNAm clock predictions.

Immunotherapy has revolutionized cancer treatment by stimulating the patient's own immune system to attack cancer cells, yielding remarkably quick and complete remission in some cases. But such drugs work for less than a quarter of patients because tumors are notoriously adept at evading immune assault. Now a new study has found that the effects of a standard immunotherapy drug can be enhanced by blocking the protein TREM2, resulting in complete elimination of tumors. "An antibody against TREM2 alone reduces the growth of certain tumors, and when we combine it with an immunotherapy drug, we see total rejection of the tumor. The nice thing is that some anti-TREM2 antibodies are already in clinical trials for another disease. We have to do more work in animal models to verify these results, but if those work, we'd be able to move into clinical trials fairly easily because there are already a number of antibodies available."

T cells, a kind of immune cell, have the ability to detect and destroy tumor cells. To survive, tumors create a suppressive immune environment in and around themselves that keeps T cells subdued. A type of immunotherapy known as checkpoint inhibition wakes T cells from their quiescence so they can begin attacking the tumor. But if the tumor environment is still immunosuppressive, checkpoint inhibition alone may not be enough to eliminate the tumor. A protein called TREM2 is associated with underperforming immune cells in the brain in the context of Alzheimer's disease. Researchers realized that the same kind of immune cells, known as macrophages, are found in tumors, where they produce TREM2 and promote an environment that suppresses the activity of T cells.

Researchers injected cancerous cells into mice to induce the development of a sarcoma. The mice were divided into four groups. In one group, the mice received an antibody that blocked TREM2; in another group, a checkpoint inhibitor; in the third group, both; and the fourth group, placebo. In the mice that received only placebo, the sarcomas grew steadily. In the mice that received the TREM2 antibody or the checkpoint inhibitor alone, the tumors grew more slowly and plateaued or, in a few cases, disappeared. But all of the mice that received both antibodies rejected the tumors completely. The researchers analyzed immune cells in the tumors of the mice treated with the TREM2 antibody alone. They found that suppressive macrophages were largely missing and that T cells were plentiful and active, indicating that blocking TREM2 is an effective means of boosting anti-tumor T cell activity. Further experiments revealed that macrophages with TREM2 are found in many kinds of cancers.

Although human life expectancy has increased over the past two decades, individuals in most countries do not appear to be living healthier. Disease prevalence, disability, and the number of years spent with disease or disability have all increased. Yet, in contrast, many centenarians do not follow this trend. Rather, exceptional longevity is associated with a reduced risk of morbidity and, on average, a delay in the onset of age-associated diseases including cancer, cardiovascular disease, stroke, and dementia. Throughout older adulthood, in comparison to their peers who do not survive to 100 years, centenarians have fewer diseases and limitations in performing activities of daily living and are less likely to be hospitalized. Moreover, living to extreme ages has been associated with compression of morbidity and disability, or shortening the proportion of life spent with disease and disability toward the end of life. In fact, supercentenarians, individuals aged 110+ years, spend only 5% of their lives on average with an age-related disease in comparison to 18% for younger controls with many maintaining functional independence up to the age of 100 years.

The exceptionality of centenarians (i.e., their extreme survival), is the reason that they are a powerful cohort among which to examine genetic contributions to longevity and healthy aging. The sensitivity of a genetic risk model to correctly classify individuals as long-lived increased with increasing age exceptionality (i.e., 71% specificity in classifying individuals aged older than 102 years and 85% specificity in classifying individuals aged older 105 years) indicating that the genetic contribution to longevity becomes stronger when looking at older ages. The ability to reach exceptional ages without an age-related disease is also considered an extreme phenotype which can increase the power to identify genetic variants associated with a reduced risk of disease. Using centenarians as extreme controls against cases with specific age-related diseases has been shown to increase the power to detect associations between genetic variants and risk of disease.

Unexpectedly it seems that centenarians do not achieve their exceptional longevity due to the absence of genetic variants associated with disease, as centenarians have been found to have variants related to increased risk of cancer, cardiac disease, and even neurodegenerative diseases. Rather, it seems that centenarians are enriched with protective genes, including variants related to a reduced risk of cardiovascular disease and hypertension as well as enhanced immunity and metabolism. Genetic comparisons with centenarians may also be helpful in evaluating the clinical significance of genetic variants found to be associated with disease as those that are present in centenarians clearly do not preclude long survival.

Previous research had shown that maintaining supplies of adenosine, known to nourish the chondrocyte cells that make cartilage, also prevented osteoarthritis in similar animal models of the disease. In a new study, researchers injected adenosine into the joints of rodents whose limbs had been damaged by inflammation resulting from either traumatic injury, such as a torn ligament, or from massive weight gain placing pressure on joints. The biological damage in these cases is similar to that sustained in human osteoarthritis. The study rodents received eight weekly injections of adenosine, which prompted regrowth rates of cartilage tissue between 50 percent and 35 percent as measured by standard laboratory scores.

Among the study's other key findings was that a cell-signaling pathway, known as transforming growth factor beta (TGF-beta) and involved in many forms of tissue growth, death, and differentiation, was highly active in cartilage tissue damaged by osteoarthritis, as well as in cartilage tissue undergoing repair after being treated with adenosine. Additional testing in lab-grown chondrocytes from people with osteoarthritis showed different chemical profiles of TGF-beta signaling during breakdown than during growth, providing the first evidence that the pathway switched function in the presence of adenosine, from assisting in cartilage breakdown to encouraging its repair.

Despite the availability of vaccines and antibiotics, Streptococcus pneumoniae remain the leading cause of community-acquired pneumonia in the elderly. Immunosenescence, the overall decline in immunity that occurs with age, contributes to the increased susceptibility of the elderly to infection. We and others previously found that neutrophils (polymorphonuclear leukocytes or PMNs) are required for host defense against S. pneumoniae infections as they are needed for initial control of bacterial numbers upon infection.

Extracellular adenosine (EAD) is key for host resistance to pneumococcal infection. Upon tissue injury triggered by a variety of insults, including infection, ATP is released from cells and metabolized to adenosine. EAD is recognized by four G protein-coupled receptors, A1, A2A, A2B, and A3. These receptors are ubiquitously expressed on many cell types including PMNs and can have opposing effects on immune responses.

Aging is accompanied by changes in EAD production and signaling. However, the role of the EAD pathway in immunosenescence remains practically unexplored. We previously found that triggering A1 receptor signaling in old mice significantly enhanced their resistance to pneumococcal lung infection and reduced the ability of S. pneumoniae to bind pulmonary epithelial cells. The objective of this study was to explore the age-driven changes in the EAD pathway and its impact on PMN function.

PMNs from old mice failed to efficiently kill pneumococci ex vivo; however, supplementation with adenosine rescued this defect. To identify which adenosine receptors is involved, we used specific agonists and inhibitors. We found that A1 receptor signaling was crucial for PMN function as inhibition or genetic ablation of A1 impaired the ability of PMNs from young mice to kill pneumococci. Importantly, activation of A1 receptors rescued the age-associated defect in PMN function. In exploring mechanisms, we found that PMNs from old mice failed to efficiently kill engulfed pneumococci and that A1 receptor controlled intracellular killing. In summary, targeting the EAD pathway reverses the age-driven decline in PMN antimicrobial function, which has serious implications in combating infections.