In a series of studies over the last 15 years, researchers have shown that, when infused with blood from young mice, old ones heal faster, move quicker, think better, remember more. The experiments reverse almost every indicator of aging the teams have probed so far: It fixes signs of heart failure, improves bone healing, regrows pancreatic cells, and speeds spinal cord repair. It sounds sensational, almost like pseudoscience. It's some of the most provocative aging research in decades. These studies, which use a peculiar surgical method called parabiosis that turns mice into literal blood brothers, show that aging is not inevitable. It is not time's arrow. It's biology, and therefore something we could theoretically change.

Blood itself will not become a treatment for old age. It's too messy, too complicated, too dangerous. But because of these labs' findings, we know that somewhere swirling around in young veins are signals that awaken the natural mechanisms to repair and restore the body. These mystery factors, once researchers can identify and fine-tune them, could become precious medicine. Heterochronic parabiosis, in which researchers pair two animals at different points in the lifespan, was first used to study aging in the 1950s. But by the 1990s, it was largely forgotten - until more recent studies put it back on the map.

On the theory that blood-borne factors might orchestrate the transitions of aging, researchers turned to heterochronic parabiosis. The team's 2005 findings caused a stir. If an older mouse's leg gets frozen with a piece of dry ice, the cells in charge of muscle repair don't respond much; the number of active cells increases by just 10 percent or so. But after heterochronic parabiosis, twice as many cells activate in response to injury - a reaction like that of a young animal. Older mouse livers demonstrate a similarly sprightly cellular turnover. Longevity enthusiasts eagerly discussed the findings, even though there is little evidence that heterochronic parabiosis extends life; even in rodents, all we know for sure is that it undoes some late-in-life decay.

Meanwhile, a cottage industry began selling young plasma. Around 2016, Ambrosia, a California company, offered to infuse customers as part of a clinical trial that charged participants 8,000 to join. (So far, the team has not published any findings in the scientific literature.) Other entities and individuals launched similar efforts, such as a proposed study that would charge large sums to frail elderly people for doses of young plasma. This "therapeutic plasma exchange" is a legitimate treatment for certain rare autoimmune diseases and problems with coagulation, so these providers are not necessarily required to obtain explicit approval from the Food and Drug Administration so long as they make no unsubstantiated health claims about their regimen. But, of course, they did: Companies marketed benefits for people with memory loss, heart disease, and even Parkinson's. The FDA, now stepping into the regulatory role of the 17th-century pope, released a stern memo in 2019 that curbed the trend.

The most straightforward path to a therapy would be to pinpoint a pro-aging factor in old blood, mouse and human, that a drug could block. Many groups have identified such elements. One has found that a protein called CCL11 increases in aged humans and mice and is correlated with reduced brain cell birth. The other obvious tactic is to identify youthful plasma's secret formula and optimize it. Some research suggests the hormone oxytocin might be a candidate; other work has identified the protein GDF11. Combination therapies are also under consideration; a biotech company is exploring mixtures of hundreds of blood-borne proteins as therapies for a variety of age-related diseases.

It's also possible that the rejuvenating effects seen in experiments don't arise from one magic ingredient, or even from some combination of a dozen or a hundred compounds, but happen simply because the procedure dilutes some unknown harmful substances that accumulate in old blood. From this perspective, there's no particular need for young stuff: Any form of plasma replacement will do. It's sort of like changing the oil in your car. One research group is starting a company and are aiming for human clinical trials to determine if simply flushing out the bloodstream can help with problems like frailty and declining cognition.

Evolutionary theory allows for various types of byproduct effects that can affect late life, both negatively and positively. If pleiotropy is viewed mechanistically, molecule-based and network-based pleiotropy make late life effects likely. Research on model systems has already shown that there are a large number of mechanisms by which single mutations can affect late life, supporting the possibility that populations accumulate diverse positive and negative late life effects. It is likely that late life is subject to little selection due to rapidly decreasing population size and lack of late life reproduction in most species, making it unlikely that aging is under simple regulatory control. Instead, it could potentially be an emergent property of the many byproduct effects that affect late life (both selection-based and neutrality-based) and the accumulation of mutations primarily affecting late life. Each species will have its own constellation of byproduct effects and late acting mutations.

This will translate into a large and complex mixture of genetic variation that will distribute across the individuals in populations. Some of the mutations affecting aging may be shared between species, due to conservation of molecules or networks, while others will be species specific. Characteristic lifespans for different species would be another emergent property. Superimposed upon this pattern of aging would be physiological responses to environmental insults common to aging animals, such as stress and infection. Such responses could contribute to the aging pattern. These responses would also consist of both conserved and species-specific components. While it is unclear how age-related tissue dysfunction connects to organism mortality, tissue specific changes with age would be expected to contribute to the species-specific pattern.

One of the most prominent theories accounting for aging and age-dependent mortality rates postulates cumulative damage leading to stochastic failure of tissues and the organism. Specific mechanisms included in this theory are oxidative damage or somatic mutation. The disposability model states that repair capacities are limited by evolutionary constraints, leading to this cumulative damage. At the present time these theories cannot account for the full range of aging patterns in all species. Perhaps aging can be viewed as the net result of hundreds of byproduct effects combined with the accumulation of late-acting mutations, encompassing both positive and negative effects upon mortality and vigor.

Aging is correlated with a large number of species, tissue, and cell type specific changes at the molecular level. It is possible that aging is an emergent property of hundreds of effects, some conserved, some fixed at the species level, and some that are variable at the population level. According to this view, it would only be a modest exaggeration to say aging is all trees and no forest.

The first misconception is that hyperfunction is always an increase of function. Correctly, hyperfunction is often an unchanged function, that is still higher than optimal for longevity. Hyperfunction is a function that was not switched off upon its completion. In some cases, age-related alterations are indeed an absolute increase: hyper-secretory phenotype, pro-inflammation, hypertension, hyperlipidemia, hyperglycemia, hyperinsulinemia, hyperplasia, and hypertrophy of cells and organs (e.g., heart and prostate). In typical cases, hyperfunction is relative. It may even be a decrease of function that is still higher than optimal for longevity in the aging organism.

Using an analogy, consider a car driving 65 miles per hour (mph) on the highway with a 65 mph speed limit. This is the normal and optimal speed on this highway, or optimal functioning early in life. Early in life, during organism growth, all cellular and systemic functions are optimal for growth (not for longevity). However, if the car exits the highway to enter low-speed streets without decreasing speed (stuck accelerator) and continues at the same speed, 65 mph becomes over-speeding, or hyperfunction. The car is bound to crash on your driveway and is destroyed by over-speeding. It has no chance to be destroyed on a molecular level by rusting.

The second misconception is that the hyperfunction theory of aging denies a harmful accumulation of molecular damage. To clarify, molecular damage does accumulate. Furthermore, molecular damage would eventually kill the organism, unless the organism dies from hyperfunctional aging or, even more specifically, from mTOR-driven aging. Aging due to molecular damage and due to cellular hyperfunctions occur in parallel, but the latter is a life-limiting process, which progresses faster. How do we know that hyperfunctional aging is life-limiting and accumulation of molecular damage is not? In several dozen studies, rapamycin (mTORC1 inhibitor) prolonged lifespan in animals. Then mTOR-driven aging is life-limiting almost by definition.

The third misconception is that hyperfunction theory is primarily based on an evolutionary theory. Correctly, the hyperfunction theory is principally based on a cellular model of geroconversion. The hyperfunction theory is not just an evolutionary theory, even though it is completely in agreement with the latter and develops the notion of Antagonistic Pleiotropy (AP) further. Evolutionary perspectives in the hyperfunction theory are needed mostly to explain why hyperfunctional (quasi-programmed) aging is life-limiting and why accumulation of molecular damage is not. Otherwise, the hyperfunction theory is a mechanistic theory: an analogy of the cellular model of geroconversion in vitro. When cells proliferate, mTOR and other growth-promoting signaling pathways drive cellular mass growth, which is balanced by cell division. However, if the cell cycle is blocked by p21 or p16, then the same mTOR pathway drives "pathological growth" (geroconversion) from reversible arrest to irreversible senescence. Geroconversion is a continuation of growth - a quasi-program of growth.

The hyperfunction theory is a translation of the rules of geroconversion to the organism. Organismal aging and geroconversion can be described in similar terms, and similar signaling pathways drive geroconversion and organismal aging. It does not necessarily mean that a few senescent cells cause organismal aging. Fully senescent cells may contribute to aging, but are not required. Instead, most cells are becoming at least relatively hyperfunctional, gerogenic, producing age-related diseases.

The great increase in average life expectancy during the 20th century emerges as one of society's greatest achievements. As a matter of fact, in the last two decades, life expectancy at birth has increased by 5-10 years. Regardless of the cultural or socioeconomic context, women have lived longer than men in different countries and in every era. Nowadays, 75% and 90% of people older than 100 years and 110 years (respectively) are women, and the longest living centenarian person (122 years old) was a woman. This phenomenon occurs not only in humans, but in many species, like all Old-World monkeys, apes, short-finned pilot whales, African lions, red deer, and Wistar rats, in which female life expectancy exceeds male life expectancy by 16%.

One plausible explanation for this protection against aging is that females are endowed with higher levels of estrogens than males. Estrogens are known to have many beneficial effects: cardioprotection, skeletal homeostasis maintenance, brain function, and hematopoietic stem cell division enhancement, among others. Moreover, intramuscular estrogen levels have been recently associated with skeletal muscle strength and power. Furthermore, they act as antioxidants in vitro and also have beneficial effects against oxidative stress in vivo. Indeed, a few years ago, we reported that estrogens were able to induce antioxidant and longevity-related genes, such as glutathione peroxidase (GPx) and manganese superoxide dismutase (Mn-SOD) in rats, through a mechanism involving the ERK1-2/NFκB pathway. We thus suggested that this finding could explain why females suffer less oxidative stress than males in many species, including humans.

However, all these estrogen beneficial effects may be lost in menopause. Indeed, we observed that when mimicking postmenopausal loss of estrogens by ovariectomizing Wistar rats, their peroxide production rose, and their glutathione levels decreased. They were restored after estrogen replacement therapy. This confirmed the impact of estrogen as a causative agent for this effect and made us hypothesize that this finding could be extrapolated to humans, that is, that estrogen replacement therapy (ERT) may be useful to restore estrogen levels and thus the estrogen-related beneficial effects.

Thus, the aim of this study was to confirm the ability of estrogens to upregulate antioxidant and longevity-related genes in humans, particularly in women, after a medically induced menopause. As expected, we found that medically induced menopause significantly decreased sexual hormone (estrogens and progesterone) levels. It also lowered glutathione peroxidase (GPx), 16S rRNA, P21, and TERF2 mRNA expression and blood glutathione levels. Estrogen replacement therapy significantly restored estrogen levels and induced mRNA expression of Mn-SOD, GPx, 16S rRNA, P53, P21, and TERF2 and restored blood gluthatione levels. Progesterone replacement therapy induced a significant increase in MnSOD, P53, sestrin 2, and TERF2 mRNA expression when compared to basal conditions. These findings provide evidence for estrogen beneficial effects in upregulating antioxidant and longevity-related genes in women.

This study examines how the duodenal microbiome changes with chronological age and with the process of aging. In this article, we have used the term aging to include chronological age, the number of concomitant diseases, and the number of medications used. Our results indicate that the duodenal microbiome changes progressively and significantly in older subjects, including a decrease in microbial diversity that was driven not only by chronological age but also by increases in the number of medications used and the number of concomitant diseases. Furthermore, this decrease in diversity is associated with increases in coliform levels. Representatives from phylum Firmicutes demonstrate stability and predictability over time, but other components of the common core duodenal microbiome change significantly with chronological age. This was driven by increases in phylum Proteobacteria, which increases to the second most abundant phylum in the duodenum in adults aged 36-50 years and remains in this position throughout adulthood. In contrast, phylum Bacteroidetes progressively decreases in RA with increasing age. The increase in RA of phylum Proteobacteria results from increases in the family Enterobacteriaceae, and specifically the genera Escherichia and Klebsiella. These changes are most pronounced when comparing young adults in their 20s and 30s to adults in their 70s and beyond, and correlated with changes in predicted microbial metabolic pathways, including the ubiquinone biosynthesis pathway, which is an antioxidant pathway whose expression is increased under stress conditions, including in anoxic environments for Escherichia coli.

We identified a significant decrease in duodenal microbial diversity in older subjects, which is consistent with previous data demonstrating reductions in microbial diversity in the stool microbiome with age, coupled with shifts in the dominant species and declines in beneficial microorganisms. However, advancing chronological age is accompanied by multiple factors that complicate microbial analysis. For example, the process of aging is associated with increases in the number of concomitant diseases present in older subjects and the number of medications used, factors that were not explored in previous studies. Through multivariate analyses controlling for these factors, we found that the decrease in duodenal microbial diversity was driven by a combination of chronological age, increases in the number of concomitant diseases, and increases in the number of medications used by older subjects, rather than solely by age alone. Our culture findings indicate that this decrease in microbial diversity in the duodenum is also associated with increased levels of coliform bacteria in the duodenum. This included increased relative abundance of the genera Klebsiella and Escherichia, a finding that is also consistent with previous findings in studies using stool, but here we show that Escherichia is associated with chronological age rather than the aging process, and that Klebsiella is associated with the number of medications used.

Previous studies have shown that the stool microbiome is dominated by bacteria from the phyla Firmicutes and Bacteroidetes. We found that the common core microbiome in the duodenum is also dominated by phylum Firmicutes, including the genera Streptococcus and Veillonella which are part of the core of the duodenal microbiome, but the relative abundance of the other major phyla differ with increasing age, including decreased relative abundance of Bacteroidetes, which is consistent with recent findings from the stool microbiome. These changes appear to be driven by increases in phylum Proteobacteria, which significantly and negatively affects the relative abundance of the phyla Firmicutes and TM7. Within phylum Proteobacteria, changes in the family Enterobacteriaceae also significantly and negatively impact the duodenal microbiome, affecting both the relative abundance of other microbial families and overall microbial diversity. These increases in Enterobacteriaceae were driven by the genera Escherichia and Klebsiella, both of which are coliforms, again supporting a link between increases in duodenal coliforms and decreased microbial diversity in older adults.

Further comparisons between the youngest and oldest groups of adults (ages 18-35 and 66-80 years, respectively) revealed that the changes in some genera were solely associated with chronological age (e.g., Escherichia, family Enterobacteriaceae), whereas others were in fact associated with the number of medications used (e.g., Klebsiella, family Enterobacteriaceae) or with the number of concomitant diseases (e.g., Clostridium, family Clostridiaceae). Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis of predicted microbial metabolic pathways based on 16S data suggested enrichment of microbial genes associated with the ubiquinone biosynthesis pathway in the duodenal microbiome of older adults. Ubiquinone constitutes the first line of defense in oxidative stress and plays an essential role in respiration in E. coli, so it is not surprising that this pathway could be enriched in older subjects.

In conclusion, this study examined how age and the process of aging are associated with changes in the microbiome of the small intestine, using validated sampling and processing techniques. The most significant differences are higher relative abundance of the phylum Proteobacteria and decreased relative abundance of Bacteroidetes in older subjects when compared to the youngest group. The higher relative abundance of Proteobacteria appeared to affect other duodenal microbial taxa, leading to decreased microbial diversity and increased relative abundance of coliforms and of anaerobic bacteria. The small intestine is vital to digestion, nutrient absorption, and incretin regulation, and consequently has a critical effect on host metabolism. The small intestine microbial changes reported here may play a clinically relevant role in human health and disease throughout the aging process. Further studies are needed to understand the causes and implications of these microbial changes with advancing age.

Articular cartilage functions as a shock absorber and facilitates the free movement of joints. Currently, there are no therapeutic drugs that promote the healing of damaged articular cartilage. Limitations associated with the two clinically relevant cell populations, human articular chondrocytes and mesenchymal stem cells, necessitate finding an alternative cell source for cartilage repair. Human embryonic stem cells (hESCs) provide a readily accessible population of self-renewing, pluripotent cells with perceived immunoprivileged properties for cartilage generation.

We have developed a robust method to generate 3D, scaffold-free, hyaline cartilage tissue constructs from hESCs that are composed of numerous chondrocytes in lacunae, embedded in an extracellular matrix containing Type II collagen, sulphated glycosaminoglycans and Aggrecan. The elastic (Young's) modulus of the hESC-derived cartilage tissue constructs (0.91 ± 0.08 MPa) was comparable to full-thickness human articular cartilage (0.87 ± 0.09 MPa). Moreover, we have successfully scaled up the size of the scaffold-free, 3D hESC-derived cartilage tissue constructs to between 4.5 mm and 6 mm, thus enhancing their suitability for clinical application.

Protein quality control mechanisms decline during the process of cardiac aging. This enables the accumulation of protein aggregates and damaged organelles that contribute to age-associated cardiac dysfunction. Macroautophagy is the process by which post-mitotic cells such as cardiomyocytes clear defective proteins and organelles. We hypothesized that late-in-life exercise training improves autophagy, protein aggregate clearance, and function that is otherwise dysregulated in hearts from old vs. adult mice.

As expected, 24-month-old male C57BL/6J mice (old) exhibited repressed autophagosome formation and protein aggregate accumulation in the heart, systolic and diastolic dysfunction, and reduced exercise capacity vs. 8-month-old (adult) mice. To investigate the influence of late-in-life exercise training, additional cohorts of 21-month-old mice did (old-ETR) or did not (old-SED) complete a 3-month progressive resistance treadmill running program. Body composition, exercise capacity, and soleus muscle citrate synthase activity improved in old-ETR vs. old-SED mice at 24 months. Importantly, protein expression of autophagy markers indicate trafficking of the autophagosome to the lysosome increased, protein aggregate clearance improved, and overall function was enhanced in hearts from old-ETR vs. old-SED mice.

This data provides the first evidence that a physiological intervention initiated late-in-life improves autophagic flux, protein aggregate clearance, and contractile performance in mouse hearts.

Cardiac radiotherapy (RT) may be effective in treating heart failure (HF) patients with refractory ventricular tachycardia (VT). The previously proposed mechanism of radiation-induced fibrosis does not explain the rapidity and magnitude with which VT reduction occurs clinically. Here, we demonstrate in hearts from RT patients that radiation does not achieve transmural fibrosis within the timeframe of VT reduction. Electrophysiologic assessment of irradiated murine hearts reveals a persistent supraphysiologic electrical phenotype, mediated by increases in NaV1.5 and Cx43. By sequencing and transgenic approaches, we identify Notch signaling as a mechanistic contributor to NaV1.5 upregulation after RT.

Our study presents findings to suggest that radiation therapy, successfully used in patients with refractory VT, may increase levels of the cardiac sodium channel and improve conduction. Indeed, explanted cardiac specimens obtained from a treated patient with refractory VT revealed threefold higher NaV1.5 protein levels in the radiation-targeted region when compared to a nontargeted region of the same heart, restoring NaV1.5 to levels within the range of nonfailing myocardium. As an observation of the potential effect of RT on human physiology, we also report a non-significant decrease in mean QRS duration in the Electrophysiology-guided Noninvasive Cardiac Radioablation for Ventricular Tachycardia (ENCORE-VT) patient cohort, as well as robustly shortened QRS intervals in at least 4 of the 19 patients.

Our findings have direct relevance for patient care. Most surviving patients continue to exhibit reduced VT burden 24 months after a single RT treatment. Our results demonstrate that the functional and molecular effects of RT and Notch reactivation are persistent and expected to directly translate into long-term durability of therapy.

In addition to genetic, environmental and lifestyle factors, nutrition plays a vital role in shaping health throughout human aging. Recently, health was defined as the sum of several hallmarks, including, the ability to react to environmental and cellular stress, integrity of barriers and maintenance of cellular and organismal homeostasis, of which many cross-talk with dietary factors. While a moderate consensus has been reached on what defines an unhealthy diet, the constitution of a healthy diet remains debated and subject to different beliefs. In principle, healthy diets should have positive effects on diverse health parameters, while not evoking negative effects. Different concepts of healthy dietary plans have been developed. These indices estimate and rate the intake of 8-12 components (for instance whole grain, nuts, legumes, fruit, vegetable, alcohol, etc.) and good scores are linked to lower cardiovascular disease (CVD) incidence and cancer mortality.

Accumulating evidence suggests that caloric restriction (CR) and various forms of fasting (intermittent fasting, time restricted eating, periodic fasting), avoiding malnutrition and including an adequate intake of macro- and micronutrients, present yet additional possibilities to promote the health status by reducing CVDs and cancer, among other beneficial effects. Recently, the concept of caloric restriction mimetics (CRMs) was developed to describe pharmacologically active substances that mimic some of CR's myriads of effects. At the core of the CRM definition, we and others argue that potential CR-mimicking compounds should in principle increase life- and/or healthspan and ameliorate age-associated diseases in model organisms, thus often the simultaneous use of the term "anti-aging substances." Additionally, CRMs should be capable of inducing autophagy, a homeostasis-regulating cellular recycling mechanisms that degrades obsolete, damaged or otherwise unneeded proteins, cellular structures or organelles.

Natural CRM candidates are widely present in foods and, in most cases, inevitably consumed by humans. Given their prominent occurrence in plant-based foods (especially polyphenols and polyamines), it is conceivable that these compounds contribute to the beneficial effects of healthy diets. Nevertheless, to date, specific dietary recommendations must be read with caution as too many uncertainties remain regarding bioavailability, concentration in food, stability and optimal intake levels. Furthermore, estimations of CRM levels in healthy diet plans are largely elusive and should be evaluated in future studies, as they could add to or be responsible for some of the beneficial effects of these diets.

Overall, the promising and emerging field of dietary CRM candidates needs to be considered with scientific rigor, as large parts of evidence on their effects in humans come from epidemiological and/or small-scale studies, often conducted with plant-based extracts that contain numerous bioactive substances. Problems may also arise when translating pre-clinical and epidemiological evidence of dietary and body-endogenous substances to clinical studies. For many of the herein discussed substances important data yet need to be collected: oral bioavailability, stability throughout the intestinal tract, metabolization, cellular uptake, distribution throughout the body, organ-specific effects, interaction with body-endogenous biosynthesis pathways and bioactive levels, just to name a few. More importantly, epidemiological data on dietary components can only be as good as the underlying food databases. Unfortunately, regionally varying food compositions, quality, the influence of meal preparation techniques and storage conditions are sometimes insufficiently studied or documented.

We previously reported the neuroprotective effects of icariin in rat cortical neurons. Here, we present a study on icariin's anti-aging effect in 24-month aged mice by treating them with a single daily dose of 100 mg/kg of icariin for 15 consecutive days. Icariin treatment improved motor coordination and learning skills while lowered oxidative stress biomarkers in the serum, brain, kidney, and liver of the aged mice. In addition, icariin improved the intestinal integrity of the aged mice by upregulating tight junction adhesion molecules and the Paneth cells and goblet cells, along with the reduction of iNOS and pro-inflammatory cytokines (IL-1β, TNF-α, IL-2 and IL-6, and IL-12). Icariin treatments also significantly upregulated aging-related signaling molecules, Sirt 1, Sirt 3 and Sirt 6, Pot1α, BUB1b, FOXO1, Ep300, ANXA3, Calb1, SNAP25, and BDNF in old mice.

Through gut microbiota (GM) analysis, we observed icariin-associated improvements in GM composition of aged mice by reinstating bacteria found in the young mice, while suppressing some bacteria found in the untreated old mice. To clarify whether icariin's anti-aging effect is rooted in the GM, we performed fecal microbiota transfer (FMT) from icariin-treated old mice to the old mice. FMT-recipients exhibited similar improvements in the rotarod score and age-related biomarkers as observed in the icariin-treated old mice. Equal or better improvement on the youth-like features was noticed when aged mice were FMT with feces from young mice. Our study shows that both direct treatments with icariin and fecal transplant from the icariin-treated aged mice produce similar anti-aging phenotypes in the aged mice. We prove that GM plays a pivotal role in the healing abilities of icariin. Icariin has the potentials to be developed as a medicine for the wellness of the aged adults.

Cerebrospinal fluid (CSF) clears the brain's interstitial spaces, and disruptions in CSF flow or egress impact homeostasis, contributing to various neurological conditions. Here, we recast the human cribriform plate from innocuous bony structure to complex regulator of CSF egress with an apical role in Alzheimer's disease etiology. It includes the pathological evaluation of 70 post-mortem samples using high-resolution contrast-enhanced micro-CT and cutting-edge machine learning, a novel ferret model of neurodegeneration, and a clinical study with 560 volunteers, to provide conclusive evidence of a relationship between cribriform plate aging/pathology and cognitive impairment.

Interstitial spaces within the medial temporal lobe and basal forebrain are cleared by CSF flow that drains through olfactory structures to the olfactory bulb, directly above the cribriform plate. We characterized CSF flow channels from subarachnoid spaces under the olfactory bulb to the nasal mucosa through subarachnoid evaginations that subdivide into tiny tubules that connect to an elaborate conduit system within the cribriform plate. These conduits form an internal watershed that runs from the crista galli's vault to a bony manifold within the olfactory fossa's back wall, connecting with large apertures in between.

We found that the cross-sectional area of apertures limits CSF flux through the cribriform plate, which declines with increasing age. Subjects with a confirmed post-mortem diagnosis of Alzheimer's disease had the smallest CSF flux capacity, which reduces CSF-mediated clearance in upstream areas and leads to the accumulation of toxic macromolecules that seed AD pathology.

We surgically occluded apertures in adult ferrets and found that this manipulation induced progressive deficits in spatiotemporal memory and significant atrophy of the temporal lobe, olfactory bulbs, and lateral olfactory stria. Finally, we explored human cribriform plate aging/pathology and cognition in a clinical study with 560 participants (20-95 years old). We evaluated cribriform plate morphology with CT and Deep Learning, assessed memory with a novel touch screen platform, tested olfactory discrimination, and asked questions about family history and relevant life events, like broken noses. Deep learning algorithms effectively parsed subjects and established the feasibility of predicting Alzheimer's disease years before a clinical presentation of cognitive impairment.

A consortium of biotech founders, clinicians, and leading longevity research institutions announced today the launch of the Longevity Science Foundation. The new Swiss foundation has committed to distributing more than 1 billion over the next ten years to research, institutions and projects advancing healthy human longevity and extending the healthy human lifespan to more than 120 years. The Longevity Science Foundation will provide funding to promising longevity research institutions and groups around the world. The focus of the Foundation will be to select support projects in four major areas of healthy longevity medicine and tech - therapeutics, personalised medicine, AI, and predictive diagnostics. The Foundation is seeking to fund projects that can make a significant difference in people's lives as soon as possible - even within five years.

One of the main focuses of the Foundation is in driving longevity medicine from theoretical concepts to real-world applications. The Foundation's donations will support the transformation of scientific findings and deep technological advances into treatments and solutions that can be used in the clinic today. By identifying and funding the most promising and cutting-edge advances, the Foundation seeks to address one of the most pressing issues in the science and applicability of longevity medicine - radical inequality in accessing and understanding longevity-focused treatment. Significant funding gaps remain an obstacle to bringing longevity medicine out of the laboratory and into the real world.

As populations get older, the association between chronological age and health status becomes increasingly heterogeneous. To describe this heterogeneity in health status as we age, the concepts of biological age or frailty versus fitness spectrum have been proposed. The frailty index (FI) methodology was introduced to quantify the accumulation of people's health 'deficits' (i.e., symptoms, clinical signs, medical conditions and disabilities) at a given chronological age. This method has allowed for the establishment of potentially useful population norms and the study of influences of wider determinants of health on the variation in health status within people of a similar chronological age.

Since FI deficits increase with age, the FI has a statistically significant association with chronological age. However, on the account of population heterogeneity, the effect size of this association has been found to be small. It has been suggested that given the age-related nature of its constituent deficits, the FI should be interpreted jointly with age. Our aim was to utilize data from 8,174 wave 1 participants in The Irish Longitudinal Study on Ageing (TILDA) to conduct, separately by sex, supervised machine learning analyses of the ability of the individual items of an FI to predict 8-year mortality. To gain insights as to the importance of age in this prediction, we repeated the analyses including age as a feature.

By wave 5, 559 men and 492 women had died. In the absence of age, the FI was an acceptable predictor of mortality with area under the curve (AUCs) of 0.7. When age was included, AUCs improved to 0.8 in men and 0.9 in women. After age, deficits related to physical function and self-rated health tended to have higher importance scores. Not all FI variables seemed equally relevant to predict mortality, and age was by far the most relevant feature. Chronological age should remain an important consideration when interpreting the prognostic significance of an FI.

Although osteoathritis (OA) was considered as a non-inflammatory disease, an ever-increasing body of evidence suggests that chronic degeneration of the joint is associated with persistent long-term low-grade inflammation in the joint. The source of inflammation in OA is unknown, although it has been shown to associate with high-fat diet, mechanical injury, and aging. We have shown here that one of the sources of joint inflammation is mesenchymal stromal cells (OA-MSC) within cartilage itself. OA-MSC synthesizes pro-inflammatory cytokines and chemokines that have been implicated in OA pathogenesis. We demonstrated that the induction of such pro-inflammatory molecules occurs at both mRNA and protein levels. We have also shown that the induction of inflammation in OA cartilage occurs during the transition from normal cartilage stromal cell (NCSC) in the young to the OA-MSC in the old during aging.

In recent years, cell senescence has been shown to be closely associated with OA pathogenesis. Injection of senescent cells into the joint space led to joint degeneration. Conversely, local clearance of p16INK4a-positive senescent cells from the joint attenuated injury and aging induced OA. Although the role of senescent cells in causing joint degeneration has been established, the molecular mechanism by which a chondrocyte reaches senescence has not been well understood. The expression levels of the cell senescence marker p16INK4a and senescence-associated secretory phenotype (SASP) were elevated in the serial passages of human chondrocyte culture in vitro and in aged human and mouse cartilage in vivo. However, inactivation of p16INK4a in chondrocytes of adult mice failed to attenuate joint degeneration during aging or injury. This observation raised an important question whether senescent chondrocytes were involved in cartilage degeneration.

We have shown here for the first time that OA-MSC, but not OA chondrocytes (OAC), has elevated levels of p16INK4a and SASP. Therefore, OA-MSC, but not OAC, are the senescent cells that become a source of inflammation in the joint. Our study also provided a plausible molecular explanation to the observation that joint degeneration was not affected when the p16INK4a gene was deleted in chondrocytes. Since p16 is expressed at very low levels in the OAC, targeting OAC for p16 knockout might not affect the real source of cell senescence in OA cartilage. Our data predict that joint degeneration would be attenuated if p16 were knocked out in OA-MSC, since it would abolish the source of SASP in OA cartilage. Although this prediction remains to be tested, OA-MSC should be considered as potential target cells of senolytics and anti-inflammation therapy for OA intervention in future studies.

We demonstrated that NeuroD1-mediated in vivo direct reprogramming of astrocytes into neurons promoted their neural circuit integration and led to the visual functional recovery after ischemic injury. Our work bridged the knowledge gap between individual cellular response recovery and animal behavioral recovery, where we characterized the functional synapses formed from specific projections and assessed neuronal response to stimuli in awake mice, which are critical functional characterization at the intermediate neural circuit level. The mouse primary visual cortex is a unique model system providing an opportunity to quantify projection-specific functional connectivity and the direct visual responsiveness of the reprogrammed cells. Furthermore, the ability to record responses to different visual features such as orientation and direction provides a unique ability to quantify how well the cells mature and whether the synapses they receive are functional.

In our model system, the visual responses were drastically reduced following ischemic injury, yet they recovered following the NeuroD1 delivery. The putative excitatory neurons started to regain their visual responses 3 weeks after reprogramming, while the putative inhibitory neurons progressively integrated circuit inputs and refined their activity over a longer period of time. This delayed recovery of inhibition after reprogramming is similar to the absence of matured inhibition at an early age. Furthermore, these visual responses became more specific with time, based on our two-photon calcium imaging and extracellular recording results. The NeuroD1 converted cells gradually developed to be selective to the orientations and directions of visual stimuli, which is a typical feature of the mature visual cortical neurons. Interestingly, the reprogrammed cells at 6 weeks post-infection demonstrated higher selectivity compared to the healthy controls, which could be potentially explained by the more functionally developed synaptic inputs received by the reprogrammed cells compared to the healthy controls.

Compared to other studies, the functional recovery achieved by NeuroD1-mediated astrocyte-to-neuron conversion in vivo was similarly efficient. The local functional circuit and visual response recovery were also similar to embryonic neuronal transplantation results. Direct in vivo conversion of astrocytes into neurons removes the possibility of graft rejection and provides a viable solution for this problem, however. Our findings suggest that the NeuroD1-based in vivo direct reprogramming technology may be a promising gene therapy treatment of brain injury by replenishing the lost neurons and successfully integrating them into the existing neural circuit.