Prevention might be worth a pound of cure to the individual, but to the American healthcare innovators, cures are worth much more. It's a well-known axiom that America has a sick-care rather than a health care system. Our ultimate goal at Cambrian Bio is to develop primary preventive medicines, but the sick care system persists. So, we visited the Nation's capital. We talked to elected officials and administration experts, advocates and think tanks about the medicines Cambrian is developing and the challenges inherent in developing preventive medicines.

In policy circles, most people think of longevity science exclusively in terms of behavioral interventions. That's not terribly surprising given the popularity of shows like Limitless and the fact that medicines based on the biology of aging are just starting to make it into human trials. But even the prevention policy experts we spoke with hadn't heard about the possibility that life-extending medicines for mice could be tested in humans. Our Takeaway: We are very early. Those of us in the field need to continue talking about this work, but when we do, we need to assume our audience is starting from scratch. You'll see our policy blog go back to the basics, laying the groundwork to fill this gap.

Shifting demographics may be one of the most important reasons to invest in the prevention of aging-related diseases, but it may not be the most compelling argument in Washington ... yet. We'll keep thinking about this. In today's world, generating the data to prove effectiveness for FDA approval is essential but perhaps not sufficient. The drug development industry may need a new story to tell about how scientists, biotech, and pharma are creating more value for society with their medicines rather than just increasing healthcare costs. Granted, we're biased, but we think inexpensive preventative medicines will be a key lever to drive this point home and unlock support for future innovation. As a field, we believe we have a good story to tell and we think the time is ripe for that pivot.

The process of ageing is characterized by a progressive decline in organism functions, which leads to multimorbidity and mortality. To respond to the increase in deaths related to population ageing for the leading causes of death, ageing-related health research represents the emergent agenda. There is a battery of molecular markers of "biological age" which are explored as determinants of the rate of ageing, including the copy number of mitochondrial DNA (mtDNA-CN). Mitochondria regulate a number of cellular processes, including ATP production by oxidative phosphorylation (OXPHOS), apoptosis, β-oxidation of fatty acids and the biogenesis of iron-sulfur clusters, and are involved in the production of reactive oxygen species (ROS). Ageing is accompanied by a decay in mitochondria function, alteration in its morphology, mitochondrial content, and OXPHOS capability.

The content of mtDNA in cells and tissues is connected to metabolic activities, but how mtDNA copy number (mtDNA-CN) is adjusted to and maintained at a certain level is poorly understood. Many studies showed a reduction in mtDNA-CN in older subjects, and the estimates of an extent of decline of copies by decade have not been reported. There are facts of the association between low mtDNA-CN and all-cause and cardiovascular (CVD) mortality; however, the studies of mtDNA content in nonagenarians and centenarians have contradictory results. Referring to specific age-related outcomes, the inverse relationship between mtDNA-CN and fatal and non-fatal CVD outcomes was reported in several studies. At the same time, the estimates of potential associations between an alteration in mtDNA-CN and chronic kidney disease or cancer are rather heterogeneous depending on the cancer type and study design.

We examined a random population sample in 2003/2005 (n = 9,360, age 45-69, the HAPIEE project) and followed up for 15 years. Using a nested case-control design, we selected non-external deaths among those free from baseline cardiovascular diseases (CVD) and cancer (n = 371), and a sex- and age-stratified control (n = 785). The odds ratios (ORs) of death were 1.06 per one-decile decrease in mtDNA-CN independent of age, sex, metabolic factors, smoking, alcohol intake, and education.

The age-sex-adjusted ORs of death in the second and first tertiles of mtDNA-CN vs. the top tertile were 2.35 and 1.59; an increased risk was confined to the second tertile after controlling for smoking and metabolic factors. The multivariable-adjusted OR of CVD death was 1.92 in tertile 2 vs. the top tertile of mtDNA-CN, and for cancer-related death the ORs were 3.66 and 2.29 in tertiles 2 and 1 vs. the top tertile. In the Siberian population cohort, the mtDNA-CN was an inverse predictor of the 15-year risk of natural mortality, due to the greatest impact of CVD and cancer-related death. The findings merit attention for exploring further the role of mtDNA in human ageing and the diversity of mortality.

Women diagnosed and treated for breast cancer have increased biological aging compared to women who remain free of breast cancer, according to a new study. Among women diagnosed with breast cancer, the association with faster biological aging was most pronounced for those who received radiation therapy, while surgery showed no association with biological aging. This finding suggests that developing cancer is not what increases the aging effect.

Biological age reflects a person's cell and tissue health, and it differs from chronological age. To measure biological age, the researchers studied 417 women who had blood samples collected at two time points about eight years apart. About half of the women studied were selected because they had developed breast cancer during that time span. The participants are enrolled in the Sister Study, a research effort that seeks to identify environmental risk factors for breast cancer risk and other health conditions, led by the National Institute of Environmental Health Sciences (NIEHS), part of NIH.

The researchers used three different established "methylation clocks" to determine if there were changes in a women's biological age between the two time points. The clocks measure naturally occurring, chemical modifications to a person's DNA, known as methylation changes. Small variations in methylation patterns can help determine a person's risk of developing an age-related disease. Women diagnosed with breast cancer had faster aging rates by all three clocks, with no significant racial differences, when compared to women who did not develop breast cancer.

Next the scientists examined whether biological age was associated with specific treatment regimens, such as surgery, chemotherapy, radiation therapy, and endocrine therapy. Among women with breast cancer, aging rates varied by treatment type. "Radiation is a valuable treatment option for breast cancer, and we don't yet know why it was most strongly associated with biological age. This finding supports efforts to minimize radiation exposures when possible and to find ways to mitigate adverse health effects among the approximately 4 million breast cancer survivors living in the United States."

What are we going to do today? We're going to think differently for seven minutes about cholesterol and aging. I'm not going to mention LDL once. So! What goes wrong in this whole process?

Problem one: this is a problem of cholesterol transport. Localized excesses of cholesterol form when cholesterol transport is disrupted. If you are obese, you are disrupting everything everywhere, your body has nowhere left to put cholesterol, the situation promptly goes south. Otherwise, more subtle effects of aging operate on the cells that are needed to sustain cholesterol transport, leading to less pervasive but locally similar issues.

Problem two: oxidative stress that occurs with aging causes the creation of forms of toxic cholesterol. These are outright disruptive to tissue function, and are a problem that should be gotten rid of.

In both cases this is not really the present dogma in terms of how treatment is targeted or works for conditions related to cholesterol, which is why I'm suggesting that we need to think differently about this. Just focusing for a moment on problem one, the broken cholesterol transport system: as you may or may not know, cholesterol manufacture is expensive, energetically expensive, therefore we evolved not to do it in situ, where the cholesterol is needed. It is manufactured in the liver, largely, with a fifth of it coming from the diet, and then you have a Rube Goldberg system that transports this cholesterol everywhere it needs to be. It is needed everywhere! Every single cell in your body needs cholesterol.

When it works, great! But we can say that about everything in the young body. Aging degrades this system, and particularly the macrophages that are responsible for taking this cholesterol and removing it from where it gets stuck in your blood vessel walls. That is the real problem here, though certainly others exist due to the ability of aging to mess up everything that looks like a complex system.

A localized excess of cholesterol, however it comes about, is toxic. Cells have a limited ability to stash this excess as esterified cholesterol, or refuse to take it up. That capacity can be very easily overwhelmed by physiologically achievable levels of cholesterol - get a little bit fat, and you are causing toxic harm to yourself. Get old, and there is toxic harm taking place due to problems, such as macrophage dysfunction, that reach a tipping point and lead to accumulations of cholesterol in your blood vessel walls.

Excess intracellular cholesterol disrupts cell function and kills cells. Once the excess overwhelms the ability of the cell to esterify it, it becomes free cholesterol, and free cholesterol is explicitly toxic to cell function. This is what happens in the old body, and this is what happens in the obese body. In obesity, you get the very prevalent non-alcoholic steatohepatitis, NASH, which is a silent disease, and very problematic because it is irreversible at present. In the case of your dysfunctional macrophages in your blood vessel walls, you get atherosclerosis, which, coincidentally, is also largely irreversible at the moment. One you have developed a atherosclerotic lesion, that lesion isn't going away, and there is nothing you can do about it using the present standard of care.

These are both very large potential markets, if you can find a way to deal with this problem. But let us look at the other issue for a little bit, our problem two. The other issue is that inflammation and oxidative stress, which go hand in hand in aging, largely due to mitochondrial issues, produce altered, toxic forms of cholesterol. The more oxidative stress you have, when your dysfunctional mitochondrial produce more oxidative molecules than the body can handle, the more that those oxidative molecules are going to oxidize lipids.

That causes problems in many ways, and one of the problems that you are probably all familiar with, because of the work of Cyclarity, is the growing presence of 7-ketocholesterol. This is one of the worst of these oxidized lipids. It is implicated in a whole range of conditions in aging. One of those conditions in atherosclerosis, because 7-ketocholesterol punches above its weight, there are only small amounts of it relative to normal cholesterol, when it comes to the ability to disrupt macrophage function in arterial walls. But again, remember that an excess of normal cholesterol will achieve the same outcome without adding 7-ketocholesterol. 7-ketcholesterol is adding insult to injury on top of that.

How do we address both of these two problems? Cyclarity is addressing the second problem, and hopefully their approach produces a large effect size, something that you can add on top of statins. The way that you address both problems is by selectively clearing cholesterol. But! You can't just go into the body and clear cholesterol. It is in cell membranes. If you put enough cyclodextrins into the body for the small molecules to grab all of the cholesterol out of lesions in the blood vessel walls, the you probably also just turned that patient's blood to mush and killed them along the way, as the treatment will also grab cholesterol from cell membranes.

Thus we need something smarter, and that is what we do at Repair Biotechnologies. We have something smarter, a combination of human enzymes that act to safely break down only the excess free cholesterol inside cells - the non-esterified toxic cholesterol. It also happens to work on modified cholesterols, such as 7-ketocholesterol, when they get taken up into cells. Those molecules are also broken down. We have demonstrated that this produces very profound reversal of both NASH and atherosclerosis in animal models. Localized excess of cholesterol is the major mechanism by which these diseases operate. You have this local excess of cholesterol that produces toxic free cholesterol inside cells.

In the case of macrophages it disrupts their function, makes them foam cells, stops them doing their job, advances the tipping point to enable the growth of atherosclerotic lesions that will kill you. In the case of NASH, there is so much cholesterol in a NASH patient that it is just messing everything up: the whole liver is a toxic mess. But specifically, it is a toxic mess because of excess intracellular free cholesterol. If you can get rid of that, then everything else becomes much less of a problem.

That is this short topic in a less-than-seven-minute nutshell, Repair Biotechnologies and why you should think differently about cholesterol and aging. Why you should think differently is because if you clear free cholesterol, you observe profound reversal of conditions that cannot presently be reversed. Anyone who is interested - you know where to find us!

We have made considerable progress since presenting at Foresight last year. We work with lipid nanoparticle (LNP) / mRNA delivery systems at the moment, and we have used them to produce quite extensive reversal of NASH in animal models of the condition. On the strength of this work, we submitted an INTERACT meeting request to the FDA earlier this year, and were told to go straight to a pre-IND meeting. We plan to submit the pre-IND meeting package in, say, Q4 this year.

Started in 2021, Impetus Grants made its goal to go after ideas in the aging space that would be ignored by traditional funders. Since then, we deployed more than 24 million into science, supporting a number of aging clinical trials, biomarkers, novel tools, and model organisms. In August of 2023, we will launch a new round, together with Hevolution and Rosenkranz foundations, providing 5 Million in matching funding each. Thematically, the upcoming round will be open-ended, with a focus on high-risk high-reward kind of aging science. We are also looking to enable the following kind of research, among other things.

1.Proposals that stress-test popular theories of aging. Example: Recently, there has been published yet another study showing that eliminating senescent cells is detrimental for the organism - this time in the lungs of mice.

2.Proposals that stress-test popular protocols for extending the lifespan. Example: In the last two years reprogramming has become the central topic of many companies and research groups. However, it hasn't been rigorously investigated or reported as to what extent rejuvenating effects of partial reprogramming happen due to the depletion (death) of aged cells in the reprogramming pool.

3.Category-openers or proposals that test novel mechanisms and approaches to reversing aging. Example: In the previous round we funded a project that was deemed to be very risky by our reviewers, as it didn't have any research precedents. That work, "Extending lifespan in C.Elegans by controlling mitochondrial membrane potential with light", pioneered a concept of external energy replacement for treating aging, creating a novel branch of aging research. We are looking forward to funding more proposals that develop absolutely new paradigms and ways of thinking about geroscience, even if it comes at risks.

4. Translation of preclinical findings. We continue looking into creating greater worldwide access to improved model organisms, to make early large-animal studies less prohibitively expensive. We will also continue supporting a great number of proposals that test the context-dependence of known aging modulators.

Applications will open on the main page on August 1st and will stay open until August 31st, 2023. More guidance on writing applications can be found on our website.

Donanemab is a monoclonal antibody, like the two earlier Alzheimer's drugs, aducanumab (Aduhelm) and lecanemab (Leqembi). These drugs attack plaques in the brain that are made of a protein called amyloid. They disrupt cell function and lead to the rapid spread of another protein called tau. Both amyloid and tau contribute to the development of Alzheimer's disease.

The trial showed donanemab slowed cognitive decline by 35% compared with placebo in patients with low-to-intermediate levels of tau in the brain. These results are similar to those reported with Leqembi, which received FDA approval earlier this month. In the donanemab trial, patients also experienced a 40% lower risk of progressing from mild cognitive impairment to mild dementia, or from mild-to-moderate dementia.

Donanemab was better at removing amyloid plaques compared to Aduhelm and Leqembi. It reduced tau concentrations in the blood, but not in a key area of the brain. While these results are encouraging, an in-depth analysis still is needed to understand how these findings affect patient outcomes. Patients with more advanced disease showed little to no benefit compared to those who received the placebo. Like the two other new Alzheimer's drugs, donanemab was associated with ARIA, amyloid-related imaging abnormalities that may include brain swelling and microbleeds. Serious ARIA occurred in 3.7% of patients, including three deaths. Risks were higher among patients with the APOE4 gene, which is related to an increased risk for Alzheimer's.

Making human beings live longer in good mental, neurological and physical health would be one of the most important steps humanity has ever taken. Not only because of the suffering experienced by millions of people around the world, but also because of the massive impact it would have on society, the economy and the public policies of any state. Many countries are under the threat of unsustainable spending, due to the high cost of chronic and degenerative disease. In Spain, for example, health spending related to old age will grow by 18% over the coming decade, reaching over 100 billion annually.

We must not forget that the planet rests on a demographic time bomb. The population is aging at an unprecedented rate. It's estimated that, by 2030, there will be 1.4 billion people over the age of 60 worldwide. In 2050, this figure will top 2.1 billion, according to the World Health Organization.

Many have tried to calculate the value of the gigantic anti-aging industry. There are numerous projections, but they vary enormously, depending on the fields that are taken into account. These range from preventive medicine to the reprogramming of cells. Bankers estimate that the value of the global industry will amount to around 610 billion by 2025. Currently, the market is at around 110 billion, while the annual growth rate is at 28%. On the other hand, the projection by the Aging Analytics Agency is more ambitious and broad, even taking into account the financial services markets, such as pension plans and life insurance. It estimates that the longevity economy will reach 33 trillion by 2026.

In Europe and the United States, there are already investment funds focused exclusively on start-ups that are trying to tackle the devastating effects that the passage of time has on cells and molecules. Around 5.2 billion of funds were raised by companies at various stages of their development in the global longevity industry. A decade ago, this sector barely had half-a-billion in capital. Observers believe that investment in anti-aging research will continue to rise: "The market should be able to raise more than 15 billion by 2030 in innovative therapeutic areas such as cell programming, cell membrane restoration, and regenerative medicine."

Frailty is an intermediate and reversible geriatric syndrome that often precedes dependence. Therefore, its identification is essential to prevent dependence. Several molecules have been proposed as biomarkers of frailty, but none of them have reached clinical practice. Recently, circular RNAs have emerged as new non-coding RNAs. Their regulatory role together with their high stability in biofluids makes them good candidates as biomarkers for various processes, but, to date, no study has characterized the expression of circRNA in frailty.

We studied RNA from leukocytes of 35 frail and 35 robust individuals to determine the best circRNA combination to discriminate frail from robust. In addition, CircRNA candidates were studied in 13 additional elder donors before and after a 3-month physical intervention. We found 89 differentially expressed circRNAs with frailty. Upregulation of hsa_circ_0007817, hsa_circ_0101802 and hsa_circ_0060527 in frail individuals was validated. The combination of hsa_circ_0079284, hsa_circ_0007817 and hsa_circ_0075737 levels showed a great biomarker value with a 95.9% probability of correctly classifying frail and robust individuals. Moreover, hsa_circ_0079284 levels decreased after physical intervention in concordance with an improvement in frailty scores.

This work describes for the first time a different expression pattern of circular RNA (circRNAs) between frail and robust individuals. Moreover, the level of some circRNAs is modulated after a physical intervention. These results suggest that they could be used as minimally invasive biomarkers of frailty.

Teeth can undergo a lot of damage. In particular, when wily bacteria sneak past the protective outer layer of the tooth, they can penetrate the dental pulp that lives at its core. These unwanted residents trigger inflammation - more recognizable to us as searing pain and swelling. The teeth aren't defenseless, though. They can fight off minor infections and repair some damage. This ability to regenerate comes from stem cells buried in the dental pulp. These cells can turn into many of the different cell types required for healthy dental pulp, but they don't always have enough juice on their own to restore tissue damaged by an infection or other injury.

One way that scientists imagine repairing a damaged tooth is by delivering stem cells into the tooth and giving them the right signals to regenerate the damaged cells. The tricky part is knowing exactly which factors will lead to this outcome; after all, growing a glob of fat in a tooth socket would not be helpful. Other groups have developed 3D-printed scaffolds designed to match the shape of the damaged area. A team made scaffolds shaped like human and rat teeth out of biodegradable polymers. The scaffolds had tiny channels to deliver molecules that would steer the stem cells toward bone- and tooth-supporting cell types. After nine weeks implanted in a rat, the desired cells began to form at the base of the scaffold.

The ultimate goal for many regenerative dentists is to grow a whole human tooth for implant. However, that possibility is still far away. Teeth are complex organs, with many different components making up even the smallest incisor: dental pulp, enamel, dentin, and more. During human development, mesenchymal stem cells interact with other types of cells to generate the inner and outer layers of a tooth; this process is still poorly understood, and replicating it artificially is no small task. One challenge that continues to stump the scientists is how to get tissue engineered teeth to grow faster. The teeth still seem to follow their normal biological clocks, so they grow too slowly to make them usable on demand in the clinic.

Lewy body disease is an umbrella term for Parkinson's disease and Lewy body dementia. When movement difficulties are more dominant, the disease is called Parkinson's disease, and when cognitive impairments are dominant, the term Lewy body dementia is used. Lewy body disease is caused by the misfolding of the alpha-synuclein protein in the brain. When this happens, the protein clumps together and forms what are called Lewy bodies, which damage the nerve cells.

Until very recently, it was not possible to determine with certainty whether a person with movement difficulties or cognitive impairments had Lewy bodies in the brain until after their death. But now, with a spinal fluid test, it is possible to see if the person has the misfolded protein. Researches conducted a large study involving over 1,100 individuals, none of whom initially showed any cognitive impairments or motor difficulties. However, it turned out that nearly ten percent had Lewy bodies in their brains according to the spinal fluid test. Therefore, it is possible to detect Lewy body disease even before the first symptoms appear.

"Despite the participants not having any cognitive or neurological problems at the beginning of the study, we observed that those with Lewy bodies in the brain subsequently experienced a decline in their cognitive functions over time. They were also the ones who developed Parkinson's disease or Lewy body dementia in the coming years." An interesting finding was also that Lewy bodies are strongly associated with a reduced sense of smell even before other symptoms have developed. The sense of smell also deteriorates as the disease progresses. The correlation is so clear that it could be justified to screen individuals over 60 years of age with a smell test and then proceed with testing spinal fluid if one wants to detect Lewy body disease early

Loss of proteostasis is a hallmark of aging and Alzheimer disease (AD). Here, we identify β-hydroxybutyrate (βHB), a ketone body, as a regulator of protein solubility in the aging brain. βHB is a small molecule metabolite which primarily provides an oxidative substrate for ATP during hypoglycemic conditions, and also regulates other cellular processes through covalent and noncovalent protein interactions.

We demonstrate βHB-induced protein insolubility across in vitro, ex vivo, and in vivo mouse systems. This βHB-induced insolubility leads to misfolded protein turnover in vivo, likely via βHB communication with cellular protein degradation pathways. This activity is shared by select structurally similar metabolites, and is observable in mouse brains in vivo after delivery of a ketone ester. Furthermore, this phenotype is selective for pathological proteins such as amyloid-β, and delivery of exogenous βHB ameliorates pathology in nematode models of amyloid-β aggregation toxicity.

We have generated a comprehensive atlas of the βHB-induced protein insolubility using mass spectrometry proteomics, and have identified common protein domains within βHB target sequences. Finally, we show enrichment of neurodegeneration-related proteins among βHB targets and the clearance of these targets from mouse brain, likely via βHB-induced autophagy. Overall, these data indicate a new metabolically regulated mechanism of proteostasis relevant to aging and AD.

Mutations are not the only, or perhaps even the most important, molecular events that result from cellular proliferation. We and others have shown that DNA methylation (DNAm) is also substantially altered as a direct function of cell division. Further, the epigenome has been shown to undergo dramatic changes with aging and is implicated in establishing, driving, and maintaining many cancers.

Coincidently, the DNAm changes observed in aging, cancer, and proliferation share some notable patterns. In general, they tend to be characterized by gains in methylation at promoters - especially those marked by polycomb group (PcG) factor targets - and loss of methylation in intergenic regions and repetitive elements. Thus, one hypothesis is that as cells replicate in aging tissues, they may also take on epigenetic signatures that are more cancer-like, making the leap to oncogenic transformation progressively more likely with time.

To date, the field has linked (i) age-related epigenetic changes and cancer phenomenon and (ii) replication-related changes to cancer, but little evidence exists linking all three simultaneously. It also remains unclear whether age-related replication-based changes are tumorigenic switches, and can perhaps predate the disease, or whether they are simply outcomes of cancer and uncontrolled proliferation. To test these hypotheses, we quantified a "replication fingerprint" in DNAm data derived from extensively passaged immortalized human cells using a de novo computational training platform.

This signature, termed CellDRIFT, increased with age across multiple tissues, distinguished tumor from normal tissue, was escalated in normal breast tissue from cancer patients, and was transiently reset upon reprogramming. In addition, within-person tissue differences were correlated with predicted lifetime tissue-specific stem cell divisions and tissue-specific cancer risk. Our findings suggest that age-related replication may drive epigenetic changes in cells and could push them toward a more tumorigenic state.

Angiogenesis is the process by which new capillaries form by sprouting from pre-existing ones. Each step in angiogenesis is regulated by the extracellular matrix (ECM). This process involves the migration, proliferation, and differentiation of endothelial cells (ECs) and pericytes and results in elongation of the initial tip, followed by anastomosis with other blood vessels to form perfused vascular branches. Accumulating evidence indicates that angiogenesis is impaired in older adults, contributing to cardiovascular and cerebrovascular disease and delayed wound healing, reducing the quality of life and causing a significant burden for healthcare systems.

Evidence indicates that ageing-related changes in the ECM driven by cellular senescence lead to a reduction in neovascularisation, reduced microvascular density, and an increased risk of tissue ischaemic injury. Elucidating interactions between the ECM and cells during angiogenesis in the context of ageing is necessary to clarify the mechanisms underlying reduced angiogenesis in older adults. In this review, we summarize ageing-related changes in the composition, structure, and function of the ECM and their relevance for angiogenesis. Then, we explore in detail the mechanisms of interaction between the aged ECM and cells during impaired angiogenesis in the older population for the first time, discussing diseases caused by restricted angiogenesis.

We also outline several novel pro-angiogenic therapeutic strategies targeting the ECM that can provide new insights into the choice of appropriate treatments for a variety of age-related diseases. Based on the knowledge gathered from recent reports and journal articles, we provide a better understanding of the mechanisms underlying impaired angiogenesis with age and contribute to the development of effective treatments that will enhance quality of life.

Competition among adult brain cells has not been extensively researched. To investigate whether healthy glia can outcompete diseased human glia in the adult forebrain, we engrafted wild-type (WT) human glial progenitor cells (hGPCs) produced from human embryonic stem cells into the striata of adult mice that had been neonatally chimerized with mutant Huntingtin (mHTT)-expressing hGPCs. The WT hGPCs outcompeted and ultimately eliminated their human Huntington's disease (HD) counterparts, repopulating the host striata with healthy glia.

Single-cell RNA sequencing revealed that WT hGPCs acquired a YAP1/MYC/E2F-defined dominant competitor phenotype upon interaction with the host HD glia. WT hGPCs also outcompeted older resident isogenic WT cells that had been transplanted neonatally, suggesting that competitive success depended primarily on the relative ages of competing populations, rather than on the presence of mHTT. These data indicate that aged and diseased human glia may be broadly replaced in adult brain by younger healthy hGPCs, suggesting a therapeutic strategy for the replacement of aged and diseased human glia.

We aimed to determine survival probabilities to age 90 for various systolic blood pressure (SBP) levels among women aged ≥ 65 years with or without blood pressure (BP) medication. We analyzed blood pressure data from participants in the Women's Health Initiative (n = 16,570) who were aged 65 or older and without history of cardiovascular disease, diabetes, or cancer. Blood pressure was measured at baseline (1993-1998) and then annually through 2005. The outcome was defined as survival to age 90 with follow-up until 2020.

During a follow-up of 18 years, 9,723 (59%) of 16,570 women survived to age 90. The SBP associated with the highest probability of survival was about 120 mmHg regardless of age. Compared to an SBP between 110 and 130 mmHg, women with uncontrolled SBP had a lower survival probability across all age groups and with or without BP medication. A 65-year-old woman on BP medication with an interpolated SBP between 110 and 130 mmHg in 80% of the first 5 years of follow-up had a 31% absolute survival probability. For those with 20% time in range, the probability was 21%.

In conclusion, an SBP level below 130 mmHg was found to be associated with longevity among older women. The longer SBP was controlled at a level between 110 and 130 mmHg, the higher the survival probability to age 90. Preventing age-related rises in SBP and increasing the time with controlled BP levels constitute important measures for achieving longevity.