We provide counterintuitive evidence for a "dark" side of B cells - they exacerbate manifestation of Alzheimer's disease (AD)-like symptoms in addition to producing potentially beneficial amyloid-β plaque-reducing immunoglobulins and expressing AD-ameliorating cytokines. Although the exacerbation in Rag-deficient APP and 5×FAD mice is linked to the loss of protective B cells and T cells, our data revealed that the genetic loss of B cells alone or their transient depletion at the onset of AD improves the disease symptoms of three different mouse models.

Unlike a recent report that linked AD progression to the reduction of anti-inflammatory B1a cells in 5×FAD mice, the numbers of B1a and B1b cells in peripheral blood, spleen, and cervical lymph nodes were either unaffected (in 5×FAD mice even when followed for 4, 7, and 12 months) or upregulated (in 3×TgAD and APP/PS1 mice). However, regardless of their numbers, we recently reported that the function of B1a cells is not static and is rather controlled by the inflammatory milieu. In the aged hosts, B1a cells lose their anti-inflammatory activity and acquire pathogenic functions, such as becoming 4-1BBL+ B1a cells (termed 4BL cells) that induce cytolytic granzyme-B+ CD8+ T cells and promote insulin resistance. In concordance, B1 cells (as well B2 cells, in some models) in AD mice also appeared to acquire an inflamed phenotype, as they upregulated expression of cytokines. Although age-associated B cells also accumulate in aging, we did not detect their involvement in our three types of mice with AD.

Consistent with a recent RNA-seq report that revealed presence of mature B cells in the brains of AD mice, our data indicate that AD increases B cells in the brain, and their IgG in the cortex and hippocampus parenchyma, which was often colocalized with amyloid-β plaques and activated microglia. As in multiple sclerosis and cognitive dysfunction following stroke, B cells in the brain presumably produce immunoglobulins and proinflammatory factors exacerbating AD-promoting neuroinflammation. Our data also indicate that the loss of B cells, thus immunoglobulin G, in the brain significantly retards the development of AD. Although the mechanism of this process is a topic of a different study, we think that brain IgG (or its immune complex) alone or in concert with B-cell cytokines exacerbates neuroinflammation in AD.

Reflecting on the realities of the past 50 years of the "war on cancer", and the reality of the prevalence of comorbidity for populations surviving to the upper limits of the human lifespan, we cannot continue on the same course originally plotted out by the National Cancer Act of 1971. Today cancer is still the second leading cause of death in America. The project of behaviour control has not successfully altered this outcome, in large part because it does not alter the most significant risk factor for cancer - age.

I am not suggesting that public health should concede the battle and abandon the important preventative measures of smoking cessation and a physically active lifestyle. Of course not. But we should have the humility to recognize that doubling down on these efforts for the next half a century is unlikely to yield a significant health dividend for today's ageing populations. Strategic innovation in preventative medicine will be required. The strategy of behaviour control must be supplemented with the strategy of rate control. In order to unify the aspirations to "save people" from cancer mortality while also ensuring they live longer and better lives, the inborn ageing process must also be targeted. To fixate on disease elimination without also aspiring to alter the rate of ageing will prove costly with diminishing health returns because it does not increase the healthspan.

The public health lessons of the 50-year campaign to defeat cancer in the USA ought to inform global public health more generally. The European Commission, for example, has recently identified cancer as a "mission area". A House of Lords "Science and Technology Select Committee" UK report was released, the catalyst of which an assessment of the feasibility of the government's Ageing Society Grand Challenge mission. Chapter 6 of this report is entitled "The Ageing Society Grand Challenge", and it sets the goal of increasing healthy life expectancy by 5 years by 2035. The World Health Organization dedicated the decade 2021-2030 as the decade of "healthy ageing". The campaign identifies four main areas of action-age-friendly environments, combating ageism, integrated care and long-term care. These are all morally laudable, but incomplete, prescriptions.

Like the EU report on defeating cancer, what is missing from the World Health Organization's action plan is undertaking the committed action to develop an applied gerontological intervention to increase the human healthspan. Geroscience is an integral element of public health for today's ageing populations. Redressing the imbalance between the research funding invested in tackling specific chronic diseases vs the most significant risk factor for chronic diseases is critical. The past half a century war on cancer reveals the limitations of continuing on the path of disease elimination for populations that are approaching the upper limits of the human lifespan.

Strategic innovations in preventative medicine are required if we hope to improve the healthspan of today's ageing populations. To make serious headway in cancer prevention, we must target the most significant risk factor - biological ageing. Despite the limits facing behaviour control, there is good reason for optimism that the development of an applied gerontological intervention could help us achieve the important goal of rate control. Age retardation would ensure we improve the quality of life for older people vs simply preventing death by helping older populations manage multi-morbidity.

When President Nixon declared a "war on cancer" nearly 50 years ago, the success of the war was equated with disease elimination. That is a noble but unrealistic goal. Waging a war against an unrealistic goal is harmful for two reasons. Firstly, it means that large investments of public funds are invested into something that is not attainable (of the 200+ types of cancer, none have been cured or eliminated). Secondly, and more importantly, that investment in disease elimination imposed a hefty opportunity cost. Had those same funds been invested elsewhere, for example, targeting the ageing process itself, it could have yielded the population a much more significant health dividend. The primary challenge for today's ageing populations is not to eradicate cancer mortality but rather to increase the human healthspan.

The two most common causes of dementia are Alzheimer's disease and white matter strokes - small strokes that accumulate in the connecting areas of the brain. Currently, there are no therapies capable of stopping the progression of white matter strokes or enhancing the brain's limited ability to repair itself after they occur. Now a new study identifies a cell therapy that can stop the progressive damage caused by the disease and stimulate the brain's own repair processes.

The cells used in the therapy are a specialized type of glial cells, which are cells that surround and support neurons in the central nervous system. Researchers evaluated the effects of their glial cell therapy by injecting it into the brains of mice with brain damage similar to that seen in humans in the early to middle stages of dementia. Upon injection, the cells traveled to damaged areas of the brain and secreted growth factors that stimulated the brain's stem cells to launch a repair response. Activating that repair process not only limited the progression of damage, but it also enhanced the formation of new neural connections and increased the production of myelin - a fatty substance that covers and protects the connections.

Astrocytes, axons, and myelin are subjected to major damage during subcortical white matter stroke (WMS), a debilitating disorder leading to cognitive and motor impairments. Previous studies have shown that immature astrocyte transplantation could promote remyelination in rodent models. Now, a team has used a model of WMS in mice to demonstrate that transplantation of glial enriched progenitor cells differentiated from human-induced pluripotent stem cells (hiPSC-GEPs) shortly after stroke matured into a mature astrocyte phenotype and had therapeutic effect on axonal damage, demyelination, and cognitive impairments more effectively than hiPSC-derived neuronal precursor cells. The results suggest that astrocyte precursors have therapeutic potential in stroke.

The regenerative capacity of intestine decreases upon aging. Organ homeostasis in the intestine is maintained by intestinal stem cells (ISCs). A decline in ISC function is a main reason for the impaired regeneration of intestinal epithelium upon aging. ISCs express the marker gene Lgr5 and are located next to differentiated Paneth cells at the base of the intestinal crypt. To function properly under homeostasis, ISCs differentiate into highly proliferative transient amplifying (TA) cells. Upon their migration from the crypt base to the villus, TA cells further differentiate into mature cell types including cells in the intestinal villus made of enterocytes, goblet cells, and enteroendocrine cells.

The small RhoGTPase Cdc42 cycles between an active, GTP-bound form (Cdc42-GTP) and an inactive, GDP-bound form. It is thought that biological activity of Cdc42 is regulated by its active form, i.e., the level of Cdc42-GTP. The relative ratio of active Cdc42 is elevated in various tissues of aged mice compared to that of young mice, whereas animals in which Cdc42 activity is increased by genetic means show diverse premature aging phenotypes. It is possible that there is a causative link between Cdc42 activity and aging, and increased Cdc42 activity has indeed been reported to be a causative stem cell intrinsic mechanism for the aging of hematopoietic stem cells (HSCs).

For ISCs, their regeneration capacity declines upon aging, and multiple mechanisms including changes in Wnt signaling could be involved in the process. We show here that an aging-associated increase in the Cdc42 activity in ISCs causes a decline in ISC function and impairs intestinal epithelial regeneration. Suppression of Cdc42 activity can ameliorate ISC regeneration in vitro, and pharmacologic targeting of Cdc42 critically enhances intestinal regeneration upon stress in vivo up on aging. Our studies imply that a tight regulation of the Cdc42 activity is critical for maintaining tissue homeostasis within the intestine during aging and that suppression of aging-related increased Cdc42 activity allows for enhanced tissue regeneration in vivo.

A new study investigates a genetic culprit behind abdominal aortic aneurysm, a serious condition that puts people at risk of their aorta rupturing - a potentially deadly event. There are no medications to directly treat the condition and prevent an aneurysm from growing. Current options include things like addressing blood pressure to lower the stress on the arteries and veins running through the body, and making lifestyle changes like quitting smoking. Most people monitor their aneurysm to see if it grows enough to eventually require endovascular or open surgical repair.

For this study, researchers investigated the role of an epigenetic enzyme called JMJD3 in the development of abdominal aortic aneurysm. They found the gene was turned on in both people and mice who had an abdominal aortic aneurysm and that the gene promoted inflammation in monocytes and macrophages. When they blocked the enzyme, it prevented an aneurysm from forming. "Targeting the JMJD3 pathway in a cell specific-manner offers the opportunity to limit abdominal aortic aneurysm progression and rupture."

Researchers have presented the first successful attempt to generate retinal cells that can integrate into the retina. Retinal ganglion cells (RGCs), commonly damaged in glaucoma, are responsible for the transmission of visual information. The scientists managed to not only grow neurons (retinal ganglion cells are considered specialized neurons), but also transplant them into the eyes of mice, achieving the correct ingrowth of artificial retinal tissue. Without treatment, glaucoma can lead to irreversible damage to the optic nerve and, as a result, the loss of part of the visual field. Progression of this disease can lead to complete blindness.

Retinal cells were grown using special organoids, with the tissue formed in a petri dish. These cells were subsequently transplanted into several groups of mice. "Our studies in mice have shed light on some of the basic questions surrounding retina cell replacement, i.e. can donor RGCs survive within diseased host retinas? Or are transplants only possible within young hosts? Using mice in which we used microbeads to artificially elevate intraocular pressure and a model of chemically induced neurotoxicity, we could show that transplanted donor cells survive in disease-like microenvironments. In addition, we could demonstrate that cells survived independent of the donor's age and the location to which the cells were delivered within the retina."

According to the authors, these cells have successfully existed inside mouse retinas for 12 months, which is a significant period for the species. Scientists confirmed that they were able to receive signals from other neurons in the retina; however, the ability of the cells to transmit signals to the brain has yet to be assessed with absolute certainty.

Researchers characterised and compared changes in the structure, function, and gene activity in skeletal muscle across the lifespan in mice. They grouped mice into four age categories - young, middle-aged, old and oldest-old - and looked at muscle weight, type of muscle fibers, whether the muscles had accumulated fat, and skeletal muscle function. Although old mice displayed mild sarcopenia, the common clinical features of sarcopenia were only present in the oldest-old mice. Next, they looked at changes in muscle gene activity and found a progressive disruption in genes known to be associated with the hallmarks of aging from the young to the oldest-old mice.

Next, they looked at whether administering Klotho to mice would have beneficial effects on the muscle healing after injury. They found that applying Klotho after muscle injury reduced scarring and increased structures associated with force production in the animals. Injured mice that received Klotho also had better muscle function - such as muscle twitch and force production - and their whole-body endurance improved two-fold.

Finally, the team looked at whether giving the mice Klotho could reverse age-related declines in muscle quality and function. They found that Klotho administration led to some improvements in the old mice: force production was improved by 17% and endurance when supporting whole body weight was 60% greater compared to mice without treatment. But this was only seen in the old mice, and not in the oldest-old animals. Further investigation showed that Klotho affected genes associated with the hallmarks of aging in all age groups, but that the oldest-old mice showed a dysregulated gene response.

Our team and others have proposed a number of potential biomarkers, such as epigenetic clocks, serum N-glycans, and GDF15, associated to aging or age-related diseases. Moreover, during the last years, our group also studied the "volatilome", i.e. a set of endogenous Volatile Organic Compounds (VOCs) resulting from body's metabolism. VOCs are low-weight carbon-based molecules detectable in sweat, exhaled breath, blood, urine, and feces, and that, except for blood, are considered non-invasive diagnostic biomarkers. VOCs are involved in different physiological processes and VOCs profile may differ with age, gender, physiological status, reflecting the metabolic conditions of an individual and represents her/his "odor-fingerprint".

We wondered whether this kind of biomarkers could be useful also to identify people's age, as suggested by previous studies. We then investigated VOCs profile in healthy aging and longevity in humans by analyzing the VOCs in both urine and feces that better mirror the endogenous metabolism of the organism. The samples derived from volunteers of different age, including centenarians and their offspring that represent a sort of "super-controls" to identify potential VOCs biomarkers of successful aging and longevity. We have reported the existence of specific patterns of urinary and fecal VOCs that can discriminate subjects of different age, from young to centenarians, and, even more interesting, centenarians' offspring from age-matched controls.

Among the different VOCs identified in our study, we found that the fecal VOCs belonging to aldehydes class are less abundant in the group of young with respect to the groups of elders, that generally display a greater susceptibility to inflammation and diseases. This finding is in agreement with literature data indicating that metabolites belonging to aldehydes class are produced during inflammatory processes and are involved in several age-related diseases, such as atherosclerosis, cardiovascular diseases, neurodegenerative diseases, and metabolic disorders. These observations suggested that the different VOCs patterns may likely reflect changes in metabolic processes associated with age and health status.

Current research findings in humans and other mammalian and non-mammalian species support the potent regulatory role of myostatin in the morphology and function of muscle as well as cellular differentiation and metabolism, with real-life implications in agricultural meat production and human disease. Myostatin null mice (mstn-/-) exhibit skeletal muscle fiber hyperplasia and hypertrophy whereas myostatin deficiency in larger mammals like sheep and pigs engender muscle fiber hyperplasia. Myostatin's impact extends beyond muscles, with alterations in myostatin present in the pathophysiology of myocardial infarctions, inflammation, insulin resistance, diabetes, aging, cancer cachexia, and musculoskeletal disease.

In this review, we explore myostatin's role in skeletal integrity and bone cell biology either due to direct biochemical signaling or indirect mechanisms of mechanotransduction. In vitro, myostatin inhibits osteoblast differentiation and stimulates osteoclast activity in a dose-dependent manner. Mice deficient in myostatin also have decreased osteoclast numbers, increased cortical thickness, cortical tissue mineral density in the tibia, and increased vertebral bone mineral density. Further, we explore the implications of these biochemical and biomechanical influences of myostatin signaling in the pathophysiology of human disorders that involve musculoskeletal degeneration.

The pharmacological inhibition of myostatin directly or via decoy receptors has revealed improvements in muscle and bone properties in mouse models of osteogenesis imperfecta, osteoporosis, osteoarthritis, Duchenne muscular dystrophy, and diabetes. However, recent disappointing clinical trial outcomes of induced myostatin inhibition in diseases with significant neuromuscular wasting and atrophy reiterate complexity and further need for exploration of the translational application of myostatin inhibition in humans.

The role of sirtuins in senescence was discovered in budding yeast, where overexpression of SIR2 increases replicative lifespan. Subsequently, It was reported that elevated sirtuin levels increase lifespan in the nematode C. elegans and the fruitfly Drosophila, indicating an evolutionarily ancient role of sirtuins in longevity assurance. Mammals contain seven sirtuins, SIRT1-7, which are categorized by their different subcellular localization, unique binding substrates, and diverse enzymatic activities. Recently the direct role of SIR2 in aging and lifespan extension has been disputed, but the overwhelming majority of significant results still support a potential role for SIRT6 in regulating mammalian lifespan.

SIRT6 was shown to extend lifespan in mammals, while deficiency of SIRT6 was associated with progeria, an accelerated aging disorder. Studies have confirmed the important roles for SIRT6 in protecting against aging and disease pathologies: SIRT6-deficient mice are small and have severe metabolic defects, and by 2-3 weeks of age, they develop abnormalities that are usually associated with aging. However, SIRT6 overexpression led to an increase in lifespan in male mice. Mechanistically, SIRT6, being a histone deacetylase, inhibits the transcription of transcription factors related to senescence, maintains the structure of telomere chromatin, prevents genomic instability after DNA damage, and protects cells from senescence.

A small clinical trial of postmenopausal women with prediabetes shows that the compound NMN (nicotinamide mononucleotide) improved the ability of insulin to increase glucose uptake in skeletal muscle, which often is abnormal in people with obesity, prediabetes or Type 2 diabetes. NMN also improved expression of genes that are involved in muscle structure and remodeling. However, the treatment did not lower blood glucose or blood pressure, improve blood lipid profile, increase insulin sensitivity in the liver, reduce fat in the liver or decrease circulating markers of inflammation as seen in mice.

Among the women in the study, 13 received 250 mg of NMN orally every day for 10 weeks, and 12 were given an inactive placebo every day over the same period. "Although our study shows a beneficial effect of NMN in skeletal muscle, it is premature to make any clinical recommendations based on the results from our study. Normally, when a treatment improves insulin sensitivity in skeletal muscle, as is observed with weight loss or some diabetes medications, there also are related improvements in other markers of metabolic health, which we did not detect in our study participants."

The remarkable beneficial effects of NMN in rodents have led several companies in Japan, China and in the U.S. to market the compound as a dietary supplement or a neutraceutical. The U.S. Food and Drug Administration is not authorized to review dietary supplement products for safety and effectiveness before they are marketed, and many people in the U.S. and around the world now take NMN despite the lack of evidence to show clinical benefits in people.

When scientists in the 1950s tried to cool hamsters to 0°C and rewarm them, it didn't go great. In 2002, things looked rosier when a scientist chilled a single rabbit kidney down to -130°C, then rewarmed it and transplanted it into a live rabbit, where it worked for 48 days. Then not much else succeeded for the next decade. Chilling and re-warming organs, it turns out, is really, really hard. Ice crystals that form during cooling and re-warming cause massive physical damage to cells and whole tissues.

To nudge the field forward, in 2014 a group of entrepreneurs formed the nonprofit Organ Preservation Alliance (OPA). In the years since, the OPA coordinated numerous conferences and publications and prompted the creation of a National Science Foundation technology roadmap for organ cryopreservation, all of which bolstered more than 100 million in new cryobiology funding from U.S. science agencies, donors, and industry. Now, in what OPA sees as a culmination of their efforts, the organization is launching a philanthropic fund to support two academic research centers focused on cryopreservation. "It's been a renaissance for the field of cryobiology. These two centers build on that momentum, and new technologies have come into sharp focus within the same timeframe."

Resarchers will focus on safely cooling tissues and organs by infusing the vasculature and surroundings with cryoprotective solutions and iron oxide nanoparticles coated with silica. After rapid cooling to a very low temperature, a process called vitrification, the organ or tissue is stored. Upon rewarming, the team activates the distributed nanoparticles via a radiofrequency field, heating the cryopreserved tissue rapidly and uniformly. Finally, the cryoprotective agents and nanoparticles can be safely removed prior to transplant or other biomedical use. "Scientists are coming back to ideas they had in the 1980s, but now with the right technology to carry them out. It's incredibly exciting. Back then, we didn't have the right tools, but now it feels like we really do. We hope we're about to make this really big step forward."

The endothelial cell (EC) monolayer forms the inner cellular lining of all blood vessels forming a critical interface between blood and tissue. Vascular endothelium is involved in physiological functions, which include regulation of blood fluidity, hemostasis and clotting, vascular tone, immune responses, inflammation, angiogenesis, and metabolism. Dysfunction of the endothelium is a major contributor to cardiovascular diseases (CVD) such as stroke, atherosclerosis, hypertension, and diabetes. Chronological aging is the dominant risk factor for CVD, cancer and neurodegenerative diseases and indeed endothelial dysfunctions including arterial stiffening, impaired neovascularization, and loss of tissue-barrier function are evident in age-related disease.

EC dysfunction is a well-accepted hallmark of age-related vascular dysfunction, with the initiation of abnormal inflammatory and thrombotic circuits, arterial stiffening and oxidative stress being central to its biology. Importantly, for our understanding of vascular aging, senescent EC accumulate in aging tissues and contribute to tissue dysfunction.

The field of senolytics, drugs that selectively eliminate senescent cells, is gaining momentum. Dasatinib and Quercetin (D+Q) were some of the first senolytics, which remove senescent cells in vitro and in progeroid mice through targeting of the anti-apoptotic pathways in senescence. Long term oral treatment of D+Q have been shown to improve vascular function in aged or atherosclerotic mice. The D+Q combination has been shown to efficiently reduce senescence cell burden in phase I trials for several senescence-related diseases such as diabetic kidney disease.

Although senescence was initially considered as an all-encompassing phenotypic change, it is now apparent that each cell type exhibits an unique and distinguishing senescence phenotype, one that may also be tissue specific. Hence our understanding of endothelial senescence is still in its infancy. Current findings have indicated that specific depletion of senescent cells reverses age-related changes and prolongs life span. However, caution should be urged as cellular senescence also plays important physiological roles such as in tissue development, wound healing, and tumor inhibition. To achieve optimal success in targeting senescence it will be imperative to have a thorough knowledge of the senescent cell type at play in disease, and their spatiotemporal expression in order to deliver the most appropriate senolytic, senomorphic or drug combination.

Substantial alterations in bone architecture occur with aging, including decreases in trabecular thickness and number, cortical bone loss and porosity, and increase in marrow adiposity. These changes reflect imbalances in bone remodeling, favoring a net loss of bone caused predominately by increased osteoclast activity in postmenopausal women, as well as both poor bone formation and increased osteoclast activity in older men and women. Cellular senescence and apoptosis of osteoblasts and osteocytes account for much of the aging phenotype in bone, although appear to be independent of estrogen-mediated effects.

There is growing evidence to suggest that cellular senescence in bone can be triggered by reactive oxygen species, DNA damage, telomere dysfunction, and heterochromatin changes, depending on the cell type. miRNAs serve to modulate critical switching points, such as those between osteogenesis and adipogenesis, and aspects of the senescence program. The senescence-associated secretory phenotype (SASP) likely mediates local and even distant deleterious effects of senescent cells, especially by myeloid cells and osteocytes. Radiation-induced bone loss provides an accelerated aging bone model that recapitulates many aspects of age-related bone loss. With both physiological and premature bone aging, genetic and pharmacologic approaches to clearing senescent cells prevent, delay, or ameliorate osteoporosis in mouse models. Senolytic compounds are currently being evaluated in interventional clinical trials.