Fight Aging!

Hematopoietic cell populations of various types differentiated from hematopoietic stem cells reside in the bone marrow and are responsible for creating blood and immune cells. Hematopoietic stem cells become dysfunctional with advancing age, as is true of all stem cell populations. The proximate causes of this dysfunction are likely different for every type of stem cell, however. Of the stem cell populations that are well-researched, some remain fully functional in principle but become increasingly quiescent. Others suffer an accumulation of molecular damage that renders them dysfunctional.

In all cases, it is likely that aging of the stem cell niche is an important cause of stem cell dysfunction. The niche is a collection of specialized cells that support stem cells in their function. In search of a greater understanding of the age-related decline of hematopoiesis, research groups have devoted attention to mapping the bone marrow niche and its component cells. The goal is to identify specific age-related changes that might prove to be good points for intervention. This leads to intriguing work such as that outlined in today's research materials, in which the scientists involved identified specific signaling in mesenchymal cells of the hematopoietic niche that appears relevant to the aging of hematopoietic stem cells.

How old is your bone marrow?

As with any complex system, hematopoietic stem cells lose functionality as they age - and, in the process, contribute to the risk of serious diseases, including blood cancers. We know that the risk of developing aging-associated diseases is different among different individuals. Surprisingly, however, little is known about whether hematopoietic stem cells age differently between individuals. This is in part because these hematopoietic stem cells are so rare, researchers typically pool all of these stem cells together, studying them in aggregate.

Researchers recently studied hematopoietic stem cells at the single cell level in nine individual, genetically identical middle-aged mice - offering the first close look at how subtle changes in the bone marrow microenvironment ages hematopoietic stem cells across individual mice. Researchers found that despite the mice being all the same age, the hematopoietic stem cells in the bone marrow of these individual mice aged differently. But that's not all. The team could predict the function of the hematopoietic stem cells based on the activity of two growth factors that are also present in humans.

The two growth factors - Kitl and Igf1 - are produced by mesenchymal stromal cells (MSC) that surround the stem cells in the bone marrow microenvironment. By profiling the RNA transcriptome in these MSCs across individual mice, researchers found that the decline of these growth factors correlated with age-associated molecular programs in hematopoietic stem cells.

Variation in Mesenchymal KITL/SCF and IGF1 Expression at Middle Age Underlies Steady-State Hematopoietic Stem Cell Aging

Here, we generated individual single cell transcriptomic profiles of hematopoietic and non-hematopoietic cell types in five young adult and nine middle-aged C57BL/6J female mice, providing a web-accessible transcriptomic resource for the field. Among all assessed cell types, hematopoietic stem cells (HSCs) exhibited the greatest phenotypic variation in expansion among individual middle-aged mice. We computationally pooled samples to define modules representing the molecular signatures of middle-aged HSCs and interrogated which extrinsic regulatory cell types and factors would predict variance in these signatures between individual middle-aged mice.

Decline in signaling mediated by ADIPOQ, KITL and IGF1 from mesenchymal stromal cells (MSCs) was predicted to have the greatest transcriptional impact on middle-aged HSCs, as opposed to signaling mediated by endothelial cells or mature hematopoietic cell types. In individual middle-aged mice, lower expression of Kitl and Igf1 in MSCs highly correlated with reduced lymphoid lineage commitment of HSCs and increased signatures of differentiation-inactive HSCs. These signatures were independent of expression of aging-associated pro-inflammatory cytokines. In sum, we find that Kitl and Igf1 expression are co-regulated and variable between individual mice at middle age and expression of these factors is predictive of HSC activation and lymphoid commitment independently of inflammation.

There are many ways to construct a measure of biological age. Any form of complex data that varies over the course of aging will suffice. Machine learning can determine algorithmic combinations of measured values that correlate with age, and then one can assess the biological age of an individual by seeing where they fit into the established trend. Here, researchers advocate for the use of protein aggregate levels as the underlying data upon which to build a clock. Many different proteins can aggregate with advancing age, and tend to do so to a greater degree in later life, so this data could be used to build novel clocks with which to measure biological age.

As we age, the DNA and proteins that make up our bodies gradually undergo changes that cause our bodies to no longer work as well as before. This in turn makes us more prone to getting age-related diseases, such as cardiovascular disease, cancer, and Alzheimer's disease. One important change is that the proteins in our cells can sometimes become misfolded and clump together to form aggregates, so-called amyloids. Misfolding and aggregation can happen to any protein, but a specific group of proteins known as intrinsically disordered proteins (IDPs) are especially prone to forming amyloids. IDPs make up around 30 percent of the proteins in our cells and they are characterized by having no fixed structure. Instead, they are flexible and dynamic, flopping around like strands of cooked spaghetti.

While the molecular mechanisms are widely debated and an important aspect of basic research, scientists know that aggregates formed from IDPs tend to accumulate in many long-lived cells - such as neurons or muscle cells - as we age. Moreover, they can cause many age-related diseases, particularly neurodegenerative diseases such as Alzheimer's and Parkinson's disease. Thus, having many aggregates in a cell could be an indicator of how unhealthy the cell is or if a person is likely to develop an age-related disease soon. In a recently published article, researchers propose that IDP aggregation could be used as a biological "clock" to measure a person's health and age.

"In practice, we are still far away from a routine diagnostic test, and it is important that we improve our understanding of the fundamental mechanisms leading to IDP aggregation. However, we want to stimulate thinking and research in the direction of studying protein aggregates to measure biological ageing processes. We are optimistic that in the future we will be able to overcome the current challenges of reading a protein aggregation clock through more research on IDP dynamics and making further technological developments."

Link: https://press.uni-mainz.de/a-new-way-to-measure-ageing-and-disease-risk-with-the-protein-aggregation-clock/

Clocks to measure biological age can be constructed from any sufficiently large set of biological data that changes with age. The first such clocks used DNA methylation at a range of CpG sites on the genome. The primary challenge in the use of these clocks is that there is no well established link between specific mechanisms of aging and the clock data. For epigenetic clocks built on DNA methylation data, for example, it is not well understood how the methylation status of specific CpG sites on the genome is determined, so it is presently impossible to understand exactly why the clock gives the result that it does. An alternative approach is to construct clocks from clinical measures that are already well connected to specific mechanisms and conditions of aging. This will at least provide more insight into why a given individual is assessed with a higher or lower biological age.

Biological age (BA) is the most important risk factor determining individual risk of morbidity and mortality, with true BA of individuals generally different from chronological age (CA). Attempts to construct biological aging clocks, inferring BA from observable physical features (biomarkers), have a long history. BA clocks have been constructed based on different classes of biological features, including clinical parameters, DNA methylation (DNAm) and many types of omics data. Historically, BA is defined as the age at which the test subject's physiology (as determined by its position in feature space) would be approximately normal for the reference cohort. First-generation DNAm clocks follow this approach. Although such clocks have attained impressive accuracy in determining CA, they are not optimized to predict future morbidity and mortality.

Second-generation BA clocks aim to directly predict future mortality from biological parameters. These clocks define true BA as 'Gompertz age', or the age commensurate with an individual's future risk of dying from all intrinsic causes. Second-generation clocks share some similarities with traditional clinical risk markers, such as the atherosclerosis cardiovascular disease (ASCVD) score, but differ in that they predict all-cause mortality, better reflecting the high degree of interconnectivity between organ system and disease etiology. Successful aging is more than the absence of specific diseases. Unlike existing clinical risk markers, BA clocks can identify individuals likely to remain free from age-dependent dysfunction, morbidity, and mortality for years to come. BA clocks can, therefore, provide normative targets for clinical intervention and individual guidance to promote healthy aging.

Second-generation BA clocks require large-scale cohort data comprising data on biological features combined with long disease and mortality follow-up. For standard clinical chemistry and physiological features, datasets meeting these criteria are available, enabling construction of second-generation 'clinical clocks' (CCs), designed to predict future mortality and morbidity directly from clinical features and biomarkers. In settings where the relevant clinical features and blood markers are readily accessible, CCs have distinct advantages. The features on which CCs are built often have intrinsic well-established biological and pathophysiological meaning, making their findings comparatively easy to interpret and act upon clinically. The development and validation of more powerful CCs, as well as tools facilitating their clinical interpretation and application, should, therefore, be a priority.

Link: https://doi.org/10.1038/s43587-024-00646-8

Aging Biotech Info is a curated set of lists related to the aging-focused biotechnology field, maintained by one of the investors in the space and a coterie of helpful volunteers. The site started with companies and conferences, and has expanded from there. Maintaining lists in a rapidly moving field of research and commercial development is harder than it looks, and the effort is appreciated. The latest list to be added in a first pass form is an ambitious effort, as it aims to say something about the presently available therapies that are thought to slow or reverse aging, for some definition of "available", and some consensus on the evidence needed for a therapy to be thought to slow or reverse aging.

People tend to have opinions on this topic! If you want to start a debate among patient advocates for the treatment of aging, few approaches work as well as taking a position on which approaches to therapy are better or worse. At the same time, few people are hurrying to set up a roadmap for others to learn from. For other efforts to list and evaluate interventions, one might look at the Forever Healthy Foundation's Rejuvenation Now risk-benefit analyses, and the Lifespan.io Rejuvenation Roadmap. It takes a lot of work to assemble and keep up with this sort of mapping of the field, so if you appreciate what is being done here, consider volunteering a little of your time and knowledge to the organizers.

Announcing AgingBiotech.info/therapeutics, a table of available aging therapeutics

Here announcing agingbiotech.info/therapeutics (beta), a table of most available potential anti-aging therapeutics, including supplements, drugs, lifestyle interventions, etc. The goal isn't to judge or rank these therapies but to summarize other evaluations and link useful sources of information.

Important notes: I'm launching it not completely filled out on the assumption it's better to release the substantial info collected so far since many purported therapeutics are commonly discussed and used, but sometimes by people who haven't looked at much info. Many people experiment with the personal use of therapies despite the scientific understanding and evaluation of many being patchy. What data or analysis exists isn't easy to collect. There is no central place to find links to much of the relevant papers and data. This is meant to be one such collection.

The overall philosophy of Aging Biotech Info is that great things are on the way from aging biotech but not yet available. Some people naturally don't want to wait, but one should be cautious of over-interpreting available data for anti-aging therapies. This new table can aid deep dives. It is a jumping off point that is hopefully slightly better than just starting with a web search.

This is absolutely not a recommended "stack", nor a direct endorsement. My sense is that most molecules here don't yet come with enough evidence for most people to use them, especially at super-physiological levels, and the most important column is the who-needs-it column called "best diagnostics/biomarkers to determine individual need and to titrate dose", for which there are woefully inadequate answers for most things. I think that a lot of people overestimate how much good many supplement or drug molecules will do. Simultaneously my sense is that the lifestyle intervenations are woefully underestimated and underutilized, as well as being mostly safer.

I hope that this is useful to some people. Those who want to help fill in the missing details should reach out directly.

For those people who are not participating in the obesity epidemic or otherwise sabotaging their prospects for long-term health, remaining life expectancy at any given adult age is slowly increasing over time. Each generation could expect to live a few years longer than the prior generation. We live in an age of technological progress in the life sciences, and so the state of medicine advances to ever greater capabilities, even given the ball and chain of excessive regulatory costs. That said, we do have the choice to live better or live worse, and those choices do have an impact regardless of the technological environment we find ourselves in. This open access paper puts some numbers to the long-term consequences of better versus worse choices when it comes to weight, smoking, and their other usual approaches to self-sabotage.

In this nested case-control study, individuals aged 80 years or older were evaluated, including 1,454 centenarians and 3,768 individuals who died before reaching 100 years. Individuals with the highest healthy lifestyle score (constructed from smoking, exercise, and dietary diversity) had a significantly higher likelihood of becoming a centenarian, compared with those with the least healthy lifestyle behaviors. Previous studies have reported that lifestyle factors were associated with life expectancy and/or mortality, but most of them studied the middle-aged or older age groups (aged ≥60 years), and few focused on people aged 80 years or older.

A healthy lifestyle score for 100 (HLS-100, ranging from 0 to 6), including smoking, exercise, and dietary diversity, was constructed, with higher scores indicating potentially better health outcomes. he primary outcome was survivorship to becoming a centenarian by 2018 (the end of follow-up). Information on sociodemographic characteristics, lifestyle factors, and other covariates was collected.

During a median follow-up of 5 years, 373 of 1,486 individuals among the lowest HLS-100 (0-2) group and 276 of 851 individuals among the highest HLS-100 (5-6) group became centenarians. The adjusted odds ratio (AOR) comparing the highest vs the lowest HLS-100 groups was 1.61. An association was noted when we further treated centenarians with relatively healthy status as the outcome, as evaluated by self-reported chronic conditions, physical and cognitive function, and mental wellness (AOR, 1.54). Adhering to a healthy lifestyle appears to be important even at late ages, suggesting that constructing strategic plans to improve lifestyle behaviors among all older adults may play a key role in promoting healthy aging and longevity.

Link: https://doi.org/10.1001/jamanetworkopen.2024.17931

Microglia are innate immune cells of the central nervous system, analogous to the macrophages that serve the same role elsewhere in the body. Maladaptive inflammatory behavior on the part of microglia is a feature of many age-related conditions in the brain. Researchers here review what is known of the lasting consequences of this sort of microglial overreaction that occur following a stroke. Finding ways to dampen excessive microglial inflammation would likely prove useful in the treatment and prevention of many age-related conditions.

Post-stroke cognitive impairment (PSCI) is a clinical syndrome characterized by cognitive deficits that manifest following a stroke and persist for up to 6 months post-event. This condition is grave, severely compromising patient quality of life and longevity, while also imposing substantial economic burdens on societies worldwide. Despite significant advancements in identifying risk factors for PSCI, research into its underlying mechanisms and therapeutic interventions remains inadequate.

Recently, the role of microglia in PSCI has garnered increasing attention. Microglia, the brain's primary immune and pro-inflammatory cells, are critical to the central nervous system's (CNS) immune response. Evidence suggests that microglia-mediated neuronal damage and dysfunction play a pivotal role in the pathogenesis and progression of PSCI, involving neuropathological changes post-stroke and several signaling pathways implicated in cognitive deficits, such as TLR4, p25/CDK5, Nuclear factor kappa-B (NF-κB), and CX3CR1.

Moreover, existing studies underscore neuroinflammation as a pivotal mechanism in PSCI, with microglia playing a crucial role within this context. This review reveals that microglial activation can be triggered through multiple pathways, leading to the polarization of activated microglia into two distinct phenotypes: M1 and M2. These phenotypes exert divergent effects on PSCI, with M2 microglia serving a protective function, whereas M1 microglia contribute to detrimental outcomes. Identifying strategies to guide the polarization of microglia towards the M2 phenotype during PSCI progression represents a critical avenue for therapeutic intervention.

Link: https://doi.org/10.3389/fnagi.2024.1366710

Neurogenesis is the creation of new neurons from neural stem cell populations and their integration into existing neural networks in the brain, a process thought to be essential to memory, learning, and the limited recovery of the brain from injury. It is presently the consensus position in the research community that neurogenesis does takes place in the adult brain, not just during development, but this hasn't always been the case, and it remains a topic for some debate over the fine details. This is particularly the case because so much of the work relies on data obtained in mice and rats. Obtaining equivalent data from living human brains is challenging, and such data makes up very little of the supporting evidence for the present consensus.

Today's open access paper is interesting on two counts. Firstly, it is one of the few to put numbers to the age-related decline of neurogenesis in any part of the brain. Secondly, the researchers express some of their dissatisfaction with the present state of research into the question of adult neurogenesis, a position that is not uncommon in the scientific community. From their perspective, the small amount of neurogenesis in later life seems insufficient for it to be essential to cognitive functions such as memory. The numbers thus seem to indicate that a greater emphasis should be placed on changes in other processes that alter existing neural networks when it comes to understanding age-related cognitive decline.

Modelling adult neurogenesis in the aging rodent hippocampus: a midlife crisis

Adult hippocampal neurogenesis (AHN) has been a prolific topic of research and discussion for the last 30 years. The possibility of neuron renewal and the underlying promise of regeneration in the context of aging and neurological disease has been an important catalyst for the field that have attracted the attention of researchers, funding agencies, scientific journals, and the public. Due to the obvious limitations to perform studies on the human brain, functional inferences about adult neurogenesis have been collected almost exclusively in rodents, mostly in mice.

The functional relevance of new neurons relies on their distinct physiological properties during their maturation before they become indistinguishable from mature granule cells. Most functional studies have used very young animals with robust neurogenesis. However, this trait declines dramatically with age, questioning its functional relevance in aging animals, a caveat that has been mentioned repeatedly, but rarely analyzed quantitatively. In this meta-analysis, we use data from published studies to determine the critical functional window of new neurons and to model their numbers across age in both mice and rats. Our model shows that new neurons with distinct functional profile represent about 3% of the total granule cells in young adult 3-month-old rodents, and their number decline following a power function to reach less than 1% in middle aged animals and less than 0.5% in old mice and rats.

This acute decline of neurogenesis challenges the notion of a prominent functional role even in young adult animals, but particularly in middle aged and old animals, in which neurogenesis reach very low levels, well below 1% and the ratio of activated distinct functional neurons (here meaning new neurons 4-8-week-old exhibiting the differential physiology conferring them enhanced plasticity and excitability) drops to 3-5%. This functional controversy might be in part explained by experimental bias, as most functional studies have been performed in very young, sometimes adolescent rats and mice when they exhibit peak neurogenesis, disregarding the much lower levels of new neurons present in middle aged and old animals. For the same reason, extrapolation of those data to humans might not be very useful, as there might not be much interest in improving cognition of people in their 10s and 20s when they are in their cognitive prime, while it could be relevant to help people say beyond their 60s and 70s, when hippocampal function might take a hit due to aging or neurological disease.

We think our data provides a realistic framework to describe quantitatively adult neurogenesis in murine rodents, and based on these results, we find very difficult to reconcile - from a computational and from a commonsense perspective - that the low number of distinctly functional new neurons might have an essential role in the variety of functions in which they have been involved, a caveat that needs to be addressed in functional models of adult neurogenesis.

Researchers here provide evidence for retinal degeneration to be driven in part by maladaptive innate immune signaling running through the cGAS-STING pathway. This pathway is the target of a fair amount of research these days, as the research community is interested in finding novel ways to effectively interfere in the chronic inflammation that is characteristic of aging and many forms of degenerative disease. As always seems to be the case, the challenge is that unwanted, harmful inflammatory signaling uses the same mechanisms as the desirable, short-term inflammatory signaling that is necessary to the function of the immune system. A viable, useful way to distinguish between these two has yet to emerge.

Glaucoma is a kind of progressive optic neurodegeneration characterized by elevated intraocular pressure (IOP), severe eye pain, and irreversible vision loss that could lead to the progress of permanent blindness. Retinal ganglion cells (RGCs) are the neurons that convey visual information and their loss ultimately causes deficits in neuronal function, which is considered the main pathological hallmark of glaucoma. The loss of RGCs is triggered by multiple mechanisms, such as neurotrophic factor deprivation, axonal transport failure, activation of apoptotic signals, mitochondrial dysfunction, oxidative stress, and loss of synaptic connectivity, etc.

It is now confirmed that cellular injuries induced by aging or ischemia can cause unbalanced oxidative stress in mitochondria by producing uncontrolled levels of ROS, leading to severe cell death. DNA damage is involved in RGCs loss by mediating aging, oxidative stress, post-mitotic neurons, as well as glutamate excitotoxicity, and is considered the major form of neurological disorder. Therefore, strategies that halt and repair DNA damage are recognized to be beneficial for reducing RGCs loss in glaucoma.

It is believed that DNA damage is regulated by several mechanisms, such as protein modification and signaling pathway dysfunction. The cGAS-STING pathway is associated with DNA damage sensing, modulation of inflammatory responses, autoimmunity, and cellular senescence. Previous studies showed that inhibition of the cGAS-STING pathway exhibited potential alleviating effects on ischemia/reperfusion injury-induced retinal ganglion cell death. Moreover, diverse effects of the cGAS-STING signaling have been found in mediating ocular diseases including age-related macular degeneration, keratitis, diabetes mellitus, and uveitis. In the present study, we aimed to explore the potential mechanism underlying RGCs loss in glaucoma and the contribution of cGAS/STING signaling to the loss of RGCs in response to DNA stress.

A mouse model of glaucoma was established by injecting hypertonic saline into the limbal veins. In the hypertonic saline-injected mice, we found visual function was impaired followed by the increased expression of γH2AX, a DNA damage marker, and activation of cGAS-STING signaling. We found that DNA damage inducer cisplatin treatment incurred significant DNA damage, cell apoptosis, and inflammatory response. Mechanistically, cisplatin treatment triggered activation of the cGAS-STING signaling by disrupting mitochondrial function. Suppression of cGAS-STING ameliorated inflammation and protected visual function in glaucoma mice. Thus targeting cGAS-STING signaling represents a potential therapeutic strategy for glaucoma.

Link: https://doi.org/10.18632/aging.205900

Transposable elements, or transposons, are DNA sequences in the genome capable of hijacking transcriptional machinery to copy themselves into new locations, breaking other genes. They are thought to be largely the remnant of ancient viral infections, but are also potentially important contributors to evolutionary change. Transposons are effectively suppressed in youth, but this suppression breaks down with age, as the various epigenetic systems that manage packaging of nuclear DNA and access of transcriptional machinery to specific locations on the genome become dysregulated. One of the lines of research related to this is the search for regulators of transposon activity, trying to find ways to effectively turn off transposon activity in older people.

Transposons, genes that can relocate to different parts of the genome, are repressed earlier in life but get more active with age and are associated with age-related disease and decline. A new study highlights how transposons - commonly called "jumping genes" because of their ability to move to different parts of the genome - are associated with age-related disease and decline, as well as how additional genes governing transposon expression may one day be therapeutic targets for aging. Transposons make up approximately 45% percent of human DNA, and their activity is largely repressed in younger, healthy cells. However, with age, these genes are expressed more and become more mobile, correlating with various age-related declines in function

Researchers focused on long interspersed element 1 (LINE-1), a family of transposons that collectively make up about 17% of the human genome. Previous studies have shown that, like other transposons, LINE-1 also appears to be expressed more with age and in aging-related disease. The researchers worked with human cells in vitro to see how overexpression of the suspected regulatory genes affected the activity of LINE-1. Engineering cells to overexpress two of the genes, IL16 and STARD5, markedly increased overall LINE-1 expression. In addition, treating normal cells with a short-term exposure to IL16 protein also induced higher expression of LINE-1. "These are new validated regulators of transposable element activity, and they are potential targets for aging."

Regulating jumping genes is a new job description for both of these genes, but their potential connections to aging make sense. STARD5 is involved in moving cholesterol within cells and is upregulated in response to stress in the endoplasmic reticulum (ER) - an organelle involved in protein synthesis and lipid metabolism. "Aging is often accompanied by changes that can promote ER stress. Given its role, it's possible that STARD5 is involved in age-related alterations," Bravo said. "Interestingly, we observed that upregulating STARD5 led to an upregulation of IL16, suggesting that there may be a synergy between the two in activating transposons."

IL16 is mainly known for its role in regulating immune responses to infection, though they found that its blood levels increase with age. Connections between jumping gene activity and immune responses aren't far-fetched - evolutionary biology research has indicated that transposons are descendants of ancient viruses that took up residence in cells. In addition, chronic low-grade inflammation is one of the signs of biological aging, which could be tied to immune responses to transposon expression.

Link: https://gero.usc.edu/2024/06/13/study-regulators-of-jumping-genes-could-be-new-targets-for-aging-research-and-treatment/

Ice crystal formation is one of the big challenges in low-temperature tissue preservation. Ideally one wants vitrification rather than freezing. The former is the formation of a glass-like state in which even very fine-scale structure is preserved, such as axonal connections between neurons. The latter produces ice crystal formation that is disruptive to small-scale structures such as cells and their organelles. Existing cryoprotectants are good at their task of preventing ice crystal formation if they can be perfused through the whole tissue, which is unfortunately by no means a given in large tissue sections using existing techniques, at least if the tissue is to remain viable as a structure. Also unfortunately, these cryoprotectants are largely quite toxic.

These and related considerations are why there is a drive to produce better cryoprotectants. Mining the natural world for proteins that prevent ice crystal formation may open the door to molecules that can better spread through living tissues prior to harvest and cryopreservation, and some of these proteins are already better in some respects than the artificial cryoprotectants used in research. This isn't just a matter of better logistics for research samples. It isn't just a matter of finding ways to make the organ transplant industry more efficient, and allow donor organs to be stored indefinitely. It is also important to the field of cryonics, the low-temperature preservation of the brain and body at death, in order to offer those individuals a chance of restoration in a more technologically capable future.

At present, perfusing existing cryoprotectants into an entire body effectively immediately following clinical death is challenging. Parts of the brain and body may receive too little cryoprotectant and be vulnerable to ice-crystal formation. If a non-toxic cryoprotectant protein could be delivered systemically over a period of time prior to clinical death, this delivery issue could be solved: the patient would just have to be promptly cooled. This point of starting preparation well prior to clinical death is a strong theme across the board in cryonics. Time matters greatly when it comes to prevention of tissue loss in the brain after clinical death, and the worst thing that can happen is an unexpected, unprepared need for cryopreservation. Delay and cost are the almost least worst of the poor outcomes that can result.

Extended Temperature Range of the Ice-Binding Protein Activity

Cryopreservation is currently the main method for the long-term storage of cells and tissues. At extremely low temperatures, the diffusion is slow, and molecules do not have enough energy to pass energy barriers for chemical reactions. Therefore, biological activity practically ceases, and the cells and tissues can be preserved. However, ice growth during the cooling and warming stages poses a significant challenge. Intracellular freezing is usually considered to be lethal. Extracellular ice growth leads to water depletion from the solutions, resulting in an elevated solute concentration and diffusion of water out of the cells. This leads to osmotic stress due to heightened intracellular solute concentration, membrane injuries, and physical stress on shrinking cells. Ice recrystallization (IR), the process of enlargement of ice crystals at the expense of smaller crystals, is considered damaging and occurs during the freezing and thawing. The amount of ice and its growth pattern are contingent on the solutes and on the temperature profile through freezing, storage, and thawing.

The primary approach for mitigating ice growth damage in cryopreservation is through vitrification. Vitrification is the conversion of a liquid to an amorphous solid glass without undergoing crystallization. This process occurs through rapid cooling, effectively bypassing the ice growth and nucleation zones between the melting temperature (Tm) and the glass-transition temperature (Tg). The liquid water molecules do not have sufficient time to organize into a crystalline structure and rigidify into a glass state with exceptionally high viscosity. When the target is much larger than a single cell, it is impractical to obtain stable vitrification solely by fast cooling and heating. Vitrification of biological samples involves a combination of rapid cooling and heating rates, in addition to adding cryoprotective agents (CPAs). CPAs depress the melting temperature (Tm) and the homogeneous nucleation temperature (Th) while also elevating the Tg in a concentration-dependent manner. This results in a narrower temperature difference between Tm and Tg, effectively reducing the ice growth and nucleation phases and enabling vitrification at slower cooling rates.

One such approach to mitigate devitrification involves the introduction of various ice-active substances. Ice-binding proteins (IBPs), as suggested by their name, possess an inherent capability to bind to ice crystals and nuclei, aiding organisms in surviving freezing conditions. Through direct interaction with water molecules on the ice surface or at the ice-water interface, IBPs exert significant physical effects on the subsequent growth of the bound ice crystal. IBPs depress the freezing point of an ice crystal in a noncolligative manner by blocking the access of water molecules to the ice surface, resulting in a lower freezing point than the melting point within an IBP solution. This mode of ice growth inhibition markedly differs from the colligative effect of small molecule CPAs used in vitrification. Moreover, IBPs exhibit robust IR inhibition activities.

This study investigates the impact of two distinct IBP types on vitrified DMSO solutions at concentrations relevant to cryopreservation procedures. The IBPs used in our research are antifreeze proteins (AFPs), which are a subset of IBPs that particularly act to depress ice growth and recrystallization. We investigate the impact of two types of antifreeze proteins (AFPs): type III AFP from fish and a hyperactive AFP from an insect, the Tenebrio molitor AFP. We report that these AFPs depress devitrification at -80 °C. Furthermore, in cases where devitrification does occur, AFPs depress ice recrystallization during the warming stage. The data directly demonstrate that AFPs are active at temperatures below the regime of homogeneous nucleation. This research paves the way for exploring AFPs as potential enhancers of cryopreservation techniques, minimizing ice-growth-related damage, and promoting advancements in this vital field.

The grandmother hypothesis suggests that human longevity relative to other primates and large mammals evolved because grandmothers act to improve the reproductive fitness of the offspring of their daughters. This provides a selection pressure to increase the odds of survival into later life, and since cultural transmission doesn't require physical fitness per se, it allows for frail elders to evolve. The same sort of process appears to operate in killer whales. The grandmother effect might be considered a case of particularly extended maternal care, and researchers here discuss a model of evolutionary processes in which a link emerges between length of maternal care of offspring and species life span. This manifests not just over evolutionary time, but is evident in human and primate demographics, in which presence or absence of mother or grandmother produces a sizable difference in outcomes for the offspring.

Researchers found consistently that in species where offspring survival depends on the longer-term presence of the mother, the species tends to evolve longer lives and a slower life pace, which is characterized by how long an animal lives and how often it reproduces. "As we see these links between maternal survival and offspring fitness grow stronger, we see the evolution of animals having longer lives and reproducing less often - the same pattern we see in humans. And what's nice about this model is that it's general to mammals overall, because we know these links exist in other species outside of primates, like hyenas, whales, and elephants."

The researchers constructed a universal mathematical model that demonstrates the relationship between the maternal survival and fitness of offspring on the one hand, and on the other, pace of life. Two additional empirical models incorporate the types of data about maternal survival and offspring fitness collected by field ecologists. The hope is that these models can be further tested and utilized by field ecologists to predict how maternal care and survival impacts the evolution of a species' lifespan. "We hope we've made the model straightforward enough, that field ecologists can take their existing long-term demographic data that they've been collecting for decades and apply it to this model, and come up with this estimate of how much they expect mother's maternal care to have shaped the evolution of their study system."

The work builds off the Mother and Grandmother hypothesis, based on observations in 18th- and 19th-century human populations, that offspring are more likely to survive if their mothers and grandmothers are in their lives. The new models are both broader and more specific, incorporating more of the ways that a mother's presence or absence in her offspring's life impacts its fitness. The team makes predictions, based on research on baboons and other primates, about how offspring fare if a mother dies after weaning but before the offspring's sexual maturation, which researchers have found leads to short-term and long-term, even intergenerational, negative effects on primate offspring and grand-offspring.

Link: https://news.cornell.edu/stories/2024/06/mothers-care-central-factor-animal-human-longevity

It is now well known that former cancer patients exhibit an increased risk of age-related disease, including further cancers unrelated to the first cancer. As researchers note here, this appears to have a socioeconomic dimension in addition to the purely biological aspects of the problem. Considering those, cancer in later life is associated with a faster pace of aging, and the underlying mechanisms of aging drive the risk of all age-related diseases. But to a large degree, chemotherapy and radiotherapy are harmful treatments that have lasting negative side-effects. Even modern immunotherapies, while much better for the patient, produce harmful, lasting disruptions to immune function in a subset of patients that will have unpleasant consequences in the years ahead. In the case of chemotherapy and radiotherapy, the patient is left with a raised burden of senescent cells, producing signals that encourage chronic inflammation and disrupt tissue function. Researchers are investigating the use of senolytic drugs to prevent this outcome by clearing senescent cells; it is a promising line of work.

Since 1958, Sweden has registered all cancer patients in the National Cancer Register. Swedish researchers have now used this register to study all cancer survivors who had cancer as a child, adolescent, or adult to examine outcomes in later life. The study's data spans 63 years. From this data, approximately 65,000 cancer patients under the age of 25 were compared with a control group of 313,000 individuals (a ratio of 1:5), where age, sex and housing situation were matched with the patient group. From other registers, the researchers retrieved information on morbidity, mortality and demography.

The researchers found that the cancer survivors were about three times more likely to develop cancer later in life, 1.23 times more likely to have cardiovascular disease and had a 1.41 times higher risk of accidents, poisoning, and suicide. At present, the healthcare system usually follows up cancer survivors five years after the end of treatment. In other words, you are usually considered healthy if the cancer has not returned after five years, and no further follow-up is planned. But the current study, and also previous ones, show that this is probably not enough.

Link: https://liu.se/en/news-item/canceroverlevare-har-okad-risk-for-sjukdomar-livet-ut

Butyrate is produced by microbial species in the gut microbiome in response to dietary fiber intake. It can also be delivered as a supplement, although it has an unpleasant scent and taste. A broad range of research indicates that butyrate is a useful, beneficial metabolite. For example, it upregulates BDNF expression, which in turn upregulates neurogenesis. BDNF has other beneficial roles, such as in ensuring mitochondrial quality in skeletal muscle. Further, animal studies indicate that increased BDNF can raise dopamine levels and reduce the presence of inflammatory microglia in the brain, and even slow metabolic aging.

Unfortunately the gut microbiome changes with age, pro-inflammatory microbes increasing in number at the expense of populations that produce beneficial metabolites such as butyrate. Both levels of butyrate and expression of BDNF decline with age. Further, aging is characterized by a range of detrimental changes, such as reduced neurogenesis, that are influenced by butyrate and BDNF. Obviously, loss of butyrate production is just one factor among many accounting for reduced BDNF expression, and in turn reduced BDNF expression is only one contributing cause of issues such as loss of neurogenesis. Nonetheless, the situation can be improved to some degree by restoring a more youthful gut microbiome and its production of butyrate.

Butyrate attenuates sympathetic activation in rats with chronic heart failure by inhibiting microglial inflammation in the paraventricular nucleus

Sympathetic activation is a hallmark of heart failure and the underlying mechanism remains elusive. Butyrate is generated by gut microbiota and influences numerous physiological and pathological processes in the host. The present study aims to investigate whether the intestinal metabolite butyrate reduces sympathetic activation in rats with heart failure (HF) and the underlying mechanisms involved. Sprague-Dawley rats (220-250 g) are anaesthetized with isoflurane, and the left anterior descending artery is ligated to model HF. Then, the rats are treated with or without butyrate sodium (NaB, a donor of butyrate, 10 g/L in water) for 8 weeks. Blood pressure and renal sympathetic nerve activity (RSNA) are recorded to assess sympathetic outflow.

Cardiac function is improved (mean ejection fraction, 22.6%±4.8% vs 38.3%±5.3%), and sympathetic activation is decreased (RSNA, 36.3%±7.9% vs 23.9%±7.6%) in HF rats treated with NaB compared with untreated HF rats. The plasma and cerebrospinal fluid levels of norepinephrine are decreased in HF rats treated with NaB. The infusion of N-methyl-D-aspartic acid (NMDA) into the paraventricular nucleus (PVN) of the hypothalamus of HF model rats increases sympathetic nervous activity by upregulating the NMDA receptor. Microglia polarized to the M2 phenotype and inflammation are markedly attenuated in the PVN of HF model rats after NaB administration. In addition, HF model rats treated with NaB exhibit enhanced intestinal barrier function and increased levels of GPR109A, zona occludens-1, and occludin, but decreased levels of lipopolysaccharide-binding protein and zonulin.

In conclusion, butyrate attenuates sympathetic activation and improves cardiac function in rats with HF. The improvements in intestinal barrier function, reductions in microglia-mediated inflammation and decreases in NMDA receptor 1 expression in the PVN are all due to the protective effects of NaB.

The fly transcription factor xbp1 has been connected to improved cell maintenance resulting from calorie restriction and similar interventions. Researchers here dig into some of the biochemistry, finding that xbp1 upregulation produces different positive effects in different tissues, but overall acts to modestly slow aging and extend life span. This research is characteristic of the sort of exploration of biochemistry that results from studies of calorie restriction, as the changes produced in cell function are extensive. There is a great deal of ground to cover and only so many researchers. We might expect a full understanding of the response to calorie restriction to remain a work in progress even as we move into a world in which rejuvenation therapies of various sorts result from other lines of research and development.

Transcription factors (TFs) regulate gene expression and impact on a number of aging drivers, thus playing a crucial role in molding the longevity of an animal. Xbp1 is an evolutionary conserved TF that acts in the IRE1 branch of the endoplasmic reticulum unfolded protein response pathway (UPRER) and has a key role in maintaining cellular proteostasis.

Cellular ability to maintain the health of the proteome (proteostasis) declines with age, in part due to blunted activation and compromised capacity of the proteostasis-ensuring pathways, such as UPRER. Indeed, studies in worms have shown that Xbp1s overexpression solely in the intestine or pan-neuronally can increase lifespan. In both cases, Xbp1s stimulates the activation of UPRER in older animals. The lifespan extension is coupled with a metabolic shift and increased lysosomal activity in the intestine, which acts in concert with UPRER activation to maintain proteostasis. Indeed, Xbp1 is also required for the longevity and improved ER stress resistance of a daf2 mutant. Hence, Xbp1 with its canonical UPRER role contributes to longevity in worms.

Our recent work identified a pro-longevity effect of Xbp1 in Drosophila, where we found that Xbp1s overexpression in the gut and fat body can extend lifespan. In the current study we further characterize the role of Xbp1 in fly longevity. Surprisingly, Xbp1s induction triggered distinct gene expression programs in the two organs. Xbp1s's activity in the gut aligned with its canonical role in activating UPRER, and the activation of Xbp1s solely in the intestinal stem cells was sufficient to increase lifespan. In the fat body, Xbp1s regulated genes involved in metabolism and this activity was also sufficient to promote longevity.

Link: https://doi.org/10.1016/j.isci.2024.109962

Self evidently, differences in species life span are determined by genetic differences. It is intriguing, however, to see that it is possible to produce an epigenetic signatures of species life span in mammals. Epigenetic marks on and around the genome determine gene expression, the degree to which a given protein is produced from a given gene sequence. That an epigenetic signature of maximum life span can be determined in mammals indicates that differences in the expression of specific genes (most likely many, many specific genes) are an important component of species longevity, even in cases where the proteins are very similar in structure and function between species, and even given that these epigenetic differences must ultimately descend from differences in the genome.

By analyzing 15,000 samples from 348 mammalian species, we derive DNA methylation (DNAm) predictors of maximum life span (R = 0.89), gestation time (R = 0.96), and age at sexual maturity (R = 0.85). Our maximum life-span predictor indicates a potential innate longevity advantage for females over males in 17 mammalian species including humans.

The DNAm maximum life-span predictions are not affected by caloric restriction or partial reprogramming. Genetic disruptions in the somatotropic axis such as growth hormone receptors have an impact on DNAm maximum life span only in select tissues. Cancer mortality rates show no correlation with our epigenetic estimates of life-history traits.

The DNAm maximum life-span predictor does not detect variation in life span between individuals of the same species, such as between the breeds of dogs. Maximum life span is determined in part by an epigenetic signature that is an intrinsic species property and is distinct from the signatures that relate to individual mortality risk.

Link: https://doi.org/10.1126/sciadv.adm7273

Evidence obtained from animal and human studies in recent years suggests that the composition of the gut microbiome influences long-term health to a similar degree as choices relating to exercise and dietary choices. Certainly, the balance of populations making up the gut microbiome changes with age. Pro-inflammatory microbes grow in number at the expense of microbial populations responsible for the generation of beneficial metabolites, such as butyrate, which is known to upregulate neurogenesis. This process of gut microbiome aging begins quite early in adult life, perhaps as early as the 30s. These shifts may or may not be connected to shifts in the immune system and its ability to clear problematic microbes.

Fortunately several approaches to therapy have been demonstrated to produce a lasting rejuvenation of the gut microbiome, at least in animal models. Arguably the best of these is fecal microbiota transplantation using stool samples from a young donor. In animal studies, this approach as been shown to produce a lasting change in the balance of populations of the gut microbiome, improve health, and extend life span. This approach is used as a therapy in the treatment of C. difficile infection, but is not otherwise well developed. For those intent on trying this for themselves, it is possible to purchase screened stool samples from groups like Human Microbes. That screening for potentially problematic microbes in the donor sample is increasingly important as recipient age increases, as older people can be vulnerable to microbes that a younger person can tolerate.

The human gut microbiome and aging

The gastrointestinal microbiome is the collection of bacterial cells that reside within the human gastrointestinal tract representing more cells that are contained within the human body, and a metagenome (combined genome of these commensal organisms) that is far larger than the human genome. This community of organisms has been observed to change over the lifespan. Machine-learning-based analysis of published gut microbiome datasets could predict a subject's chronologic age within 5.9 years, although this study was conducted largely independent of any health information. A cross-sectional study across the lifespan (age 1 to over 100) in a Japanese population showed a characteristic microbiome within infants and young children prior to weaning, then a transition to a more diverse microbiome associated with introduction of solid foods. This diverse and dynamic microbiome develops until early adulthood and then becomes relatively stable when it begins to show a decline in diversity after peaking late in life (around 65) and becoming more pronounced in individuals older than 80 years.

Researchers have observed microbiome signatures that became more unique to the individual at extremes of age which may reflect the microbiome becoming tailored to the individual's diet and living environment that perhaps varies less at extremes of age. Intriguingly, very long-lived individuals (over 100 years old) have shown a distinct gut microbiome profile with greater diversity a high abundance of health-associated taxa such as Christensenellaceae and Akkermansia. Although the gut microbiome changes across the lifespan, there are features that have been associated with diseases that develop at different phases of life and contribute to the development of age-related disease later in life. Of particular interest are the microbiomes of "super-agers" who reach extremes of age in relatively good health and have the potential to offer insights into how the microbiome can affect longevity and resistance to age-related diseases.

Although age itself likely contributes to changes in the gastrointestinal microbiome, it is also greatly impacted by the environment in which an individual lives and ages. An exploration of data from metagenomic sequencing of microbiome samples across Europe, Africa, North and South America showed that there were distinct features of each geographic area throughout the lifespan. Much of the literature notes changes in taxa with age that tends to be conserved across different areas of the world. There are, however, notable differences depending on the region in which the study was undertaken. Studies of cohorts in Italy and Ireland have shown decreased abundances of Roseburia with aging, while studies cohorts in Korea and China have reported increases in this genus. Bacteroidetes are generally described as increasing with age, but the converse was observed among healthy older Indonesians. A study of healthy centenarians from India and comparing them with studies previously mentioned from Italy, China, and Japan found unique features in the Indian population such as lower Bacteroidetes, higher Enterobacteriaceae among the Indian cohort. Akkermansia, usually associated with healthy aging, was associated with frailty in a cohort of Chinese older adults.

These discrepancies highlight the extremely complex relationship between the gut microbiome and aging, which is affected not only by the myriad interactions between the host-specific organisms in the microbiome, but also the diet and environment in which the individual ages.

As researchers here note, there is ample evidence to suggest that lifestyle choices known to correlate with modestly longer life expectancy in epidemiological studies also correlate with lower measures of biological age. These include epigenetic clocks and combinations of physiological measures such as phenotypic age. None of this is terribly surprising. When it is clear that exercise improves traditional measures of health and life expectancy, only a poor measure of biological age would not also be improved.

Biological age is a concept that uses bio-physiological parameters to account for individual heterogeneity in the biological processes driving aging and aims to enhance the prediction of age-related clinical conditions compared to chronological age. Although engaging in healthy lifestyle behaviors has been linked to a lower mortality risk and a reduced incidence of chronic diseases, it remains unclear to what extent these health benefits result from slowing the pace of the biological aging process. This short review summarized how modifiable lifestyle factors - including diet, physical activity, smoking, alcohol consumption, and the aggregate of multiple healthy behaviors - were associated with established estimates of biological age based on clinical or cellular/molecular markers, including Klemera-Doubal Method biological age, homeostatic dysregulation, phenotypic age, DNA methylation age, and telomere length.

Individuals who engage in a healthy lifestyle may exhibit a slower pace of biological aging, as their DNA methylation profile and physiological biomarkers are in a healthier state that typically indicates lower risks of mortality and age-related diseases. However, most studies linking lifestyle factors and biological aging are cross-sectional designs, making it difficult to establish causation. Furthermore, it is worth noting that previous research investigating lifestyle factors and biological aging was commonly obtained from specific US cohorts, such as NHANES and the Sister study, probably due to the difficulty of having both biological age measures and comprehensive lifestyle data in other large cohorts. More evidence derived from diverse populations needs to be included.

Link: https://doi.org/10.14283/jarlife.2024.13

The interesting data in this open access preprint paper is a concrete example of the prevailing trend in human life expectancy. A slow, steady increase in life expectancy (both at birth and remaining life expectancy at middle age) has been underway for decades, driven in part by improvements in approaches to treating age-related disease. To a first approximation, these population-wide effects on the underlying processes of aging achieved over past decades have been unintentional side-effects of progress in medical science. Deliberate targeting of the mechanisms of aging is still a comparatively new idea, and too few people are making use of approaches that may have some benefit to noticeably affect the epidemiology of the entire population.

The World Health Organization (WHO) has proposed a framework in which healthy ageing is considered not from the perspective of disease but based on an individual's ability to be and do the things they value. This ability is understood to be determined by individual-level attributes - a person's "intrinsic capacity", as well as the environments they inhabit and the interaction between the individual and these environments. Since intrinsic capacity is framed as a continuum that can be considered across the second half of life, it can potentially be used to compare incremental changes among both relatively robust and severely disabled individuals.

We have previously examined intrinsic capacity in two large longitudinal studies of the English and Chinese populations: the English Longitudinal Study on Ageing (ELSA) and the China Health and Retirement Longitudinal Study (CHARLS) Both analyses identified an intrinsic capacity construct comprising subdomains of cognitive, locomotor, sensory and psychological capacity and a further subdomain labelled vitality, which may represent underlying age-related biological changes and energy balance. The aim of this paper is to conduct a longitudinal analysis of cohort trends in intrinsic capacity in these same studies to determine whether older adults in England and China are experiencing the same, better or worse capacity than people of similar ages in the past.

Our research suggests there have been significant improvements in functioning in more recent cohorts of older people in both England and China. Within ELSA, more recent cohorts entered older ages with higher levels of intrinsic capacity, and subsequent declines were less steep than for earlier cohorts. Improvements were seen in all subdomains. The observed improvements are substantial. To avoid undue extrapolation, we limited our assessment to direct comparisons of capacity in participants of different cohorts at the same age. Currently, the overlap between adjacent cohorts in the ELSA study is 6 years, and participants of non-adjacent cohorts cannot be directly compared. However, even with these limitations, we still found that a 68-year-old ELSA participant born in 1950 had higher intrinsic capacity than a 62-year-old born just 10 years earlier.

Improvement in cognition was even more substantial. When comparing earlier cohorts, additional improvements are observed, although the gains between these cohorts are not quite as large as between the 1940 and 1950 cohorts. Thus, while our models suggest that today's 70-year-olds have the equivalent functioning to substantially younger adults in previous generations (perhaps 70 really is the new 60), our direct assessments can only confirm that 68 is the new 62.

Link: https://doi.org/10.21203/rs.3.rs-4271576/v1

A sizable fraction of cell signaling is carried in extracellular vesicles, membrane-wrapped packages of molecules. In the course of investigating cell signaling, researchers have noted that some fraction of these vesicles are in fact mitochondria. Cells can readily ingest mitochondria, just as they do other vesicles, and put the mitochondria to work. Mitochondria are organelles descended from ancient symbiotic bacteria, primarily responsible for generating chemical energy store molecules to power cell processes, but also deeply integrated into a wide range of cellular mechanisms beyond this. Mitochondria have their own DNA, replicate like bacteria, and are cleared when damaged by the quality control mechanisms of mitophagy, a form of autophagy that delivers mitochondria to a lysosome where they are broken down. With aging, mitochondria become dysfunctional, and this dysfunction is thought to be important in aging.

The popular science article noted here reports on the discovery that cells in aged tissues can eject damaged mitochondria instead of recycling them. In this case the mitochondria are encapsulated into a vesicle rather than released as-is. The interesting question is what this might do to surrounding cells if they fail to direct these mitochondria to their lysosomes. To what degree can a dysfunctional cell cause harm by shipping out damaged mitochondria for other cells to ingest and react to? One thought is that while the general malaise in mitochondrial function in tissues throughout the body appears to stem from widespread changes in the expression of important nuclear genes, rare cases of severe damage to mitochondrial DNA can produce mitochondria that are both dysfunctional and capable of replicating more effectively than their functional peers, taking over the cell. Can that problem be exported from a dysfunctional cell to a functional cell, and how often does that occur?

The most interesting of strategies to address mitochondrial dysfunction with aging are (a) partial reprogramming, attempting to recreate the processes of early embryonic development that reset mitochondrial function, and (b) transplantation of large numbers of functional mitochondria harvested from cell cultures. The latter is more likely to become a viable, readily available therapy in the near future, as many clinics already work with harvested extracellular vesicles. In principle it should little matter whether and to what degree cells spread mitochondrial dysfunction given a cost-effective treatment that supplies new mitochondria to a sizable fraction of cells in a tissue.

Taking Out the Trash: An Alternative Cellular Disposal Pathway

Organelle health is vital to a cell's function. Consequently, cells have many mechanisms to repair or eliminate defective organelles. In a recent paper, researchers determined that cardiac myocytes and other cells use secretion to remove mitochondria from the cell when lysosomal degradation is inhibited. Mitochondria generate most of the cell's energy. However, when they become dysfunctional, damaged, or old, mitochondria can turn into pro-death organelles, which produce reactive oxygen species that damage the cell's proteins and DNA. This is a major problem for cardiac myocytes, which rely on the energy produced by mitochondria to contract. Additionally, the body cannot replace these particular cells because they do not divide.

Cells have various quality control mechanisms to detect and repair dysfunctional mitochondria, but when the organelles are too damaged, the cell degrades them using lysosomes. We wanted to determine what happens to the cell when the lysosomes are not functioning well or are overwhelmed, and if there was another pathway to temporarily deal with the damaged mitochondria. This information is of particular importance to patients with Danon's disease, who have mutations in a lysosomal protein that causes cardiomyopathy.

We discovered that fibroblasts and cardiac myocytes secrete mitochondria inside extracellular vesicles (EV) when their lysosomal function is compromised or overwhelmed. This encapsulation ensures that the mitochondria do not elicit a dangerous immune response once outside the cell because of their bacterial origin. The mitochondria-containing EV originate from within multivesicular bodies (MVB), which either deliver the cargo to the lysosomes for degradation or ship everything to the plasma membrane for secretion. We found that Rab7, a protein present on the MVB's outer membrane, is a regulator involved in dictating the fate of the vesicles. We believe that active Rab7 directs the EV toward the lysosomes, but in the absence of this protein or when it is inactive, the cell will traffic the EV to the plasma membrane.

Once cardiac myocytes release the mitochondria-containing EV, resident cardiac macrophages and other cells in the heart internalize the vesicles to degrade them through their lysosomes. The EV do not seem to enter circulation but stay within the heart. Ultimately, this is an alternative garbage disposal pathway used by cells to get rid of dysfunctional and damaged mitochondria when they cannot degrade the organelles in their own lysosomes.

Mitochondria are secreted in extracellular vesicles when lysosomal function is impaired

Mitochondrial quality control is critical for cardiac homeostasis as these organelles are responsible for generating most of the energy needed to sustain contraction. Dysfunctional mitochondria are normally degraded via intracellular degradation pathways that converge on the lysosome. Here, we identified an alternative mechanism to eliminate mitochondria when lysosomal function is compromised. We show that lysosomal inhibition leads to increased secretion of mitochondria in large extracellular vesicles (EVs). The EVs are produced in multivesicular bodies, and their release is independent of autophagy. Deletion of the small GTPase Rab7 in cells or adult mouse heart leads to increased secretion of EVs containing ubiquitinated cargos, including intact mitochondria. The secreted EVs are captured by macrophages without activating inflammation. Hearts from aged mice or Danon disease patients have increased levels of secreted EVs containing mitochondria indicating activation of vesicular release during cardiac pathophysiology. Overall, these findings establish that mitochondria are eliminated in large EVs through the endosomal pathway when lysosomal degradation is inhibited.

Researchers here evaluate the effects of a longer term dosing schedule of a few different senolytic drugs in rats, 5 days on and 14 days off repeated for 7 months. The dose of dasatinib and quercetin used is about half of that shown to be effective in clearance of senescent cells in mice and people, but those higher doses have typically not been used as frequently or for as long. That this fails to affect cognitive decline in female rats is a data point, to contrast with other studies in which senolytic therapies have slowed cognitive decline or produced benefits in animal models of neurodegenerative conditions. Determining dosage is a hard problem generally, and this is still a work in progress for first generation senolytic therapies such as the combination of dasatinib and quercetin. Near all such effort in the field is directed towards new senolytics under development by biotech companies.

There are sex differences in vulnerability and resilience to the stressors of aging and subsequent age-related cognitive decline. Cellular senescence occurs as a response to damaging or stress-inducing stimuli. The response includes a state of irreversible growth arrest, the development of a senescence-associated secretory phenotype, and the release of pro-inflammatory cytokines associated with aging and age-related diseases. Senolytics are compounds designed to eliminate senescent cells. Our recent work indicates that senolytic treatment preserves cognitive function in aging male F344 rats. The current study examined the effect of senolytic treatment on cognitive function in aging female rats.

Female F344 rats (12 months) were treated with dasatinib (1.2 mg/kg) + quercetin (12 mg/kg) or ABT-263 (12 mg/kg) or vehicle for 7 months. Examination of the estrus cycle indicated that females had undergone estropause during treatment. Senolytic treatment may have increased sex differences in behavioral stress responsivity, particularly for the initial training on the cued version of the water maze. However, pre-training on the cue task reduced stress responsivity for subsequent spatial training and all groups learned the spatial discrimination. In contrast to preserved memory observed in senolytic-treated males, all older females exhibited impaired episodic memory relative to young (6-month) females. We suggest that the senolytic treatment may not have been able to compensate for the loss of estradiol, which can act on aging mechanisms for anxiety and memory independent of cellular senescence.

Link: https://doi.org/10.3389/fnagi.2024.1384554

Decellularization involves stripping cells from donor tissue to leave behind the extracellular matrix and its chemical cues. That extracellular matrix can then be repopulated with patient-matched cells and transplanted, in principle minimizing many of the issues associated with tissue transplantation. The initial hype over decellularization has somewhat faded, but many groups continue to work with decellularized tissue in parallel with other approaches to tissue engineering. The production of thin patches of functional tissue to apply to organs such as the liver or heart has shown some promise in recent years, and here researchers demonstrate the ability to improve the function of damaged livers in rats via this strategy.

Liver fibrosis is primarily induced by liver inflammation, which triggers continuous secretion of the extracellular matrix (ECM) by hepatic stellate cells (HSCs). This secretion promotes liver repair, but eventually leads to fibrosis. The treatment of liver fibrosis is a complex process, and the optimal therapeutic strategy is to reverse the fibrotic progression. Conventional cell therapy has demonstrated promise in addressing fibrosis/cirrhosis. However, the direct infusion of hepatocytes faces challenges due to limited hepatocyte sources, poor cell viability, and the requirement for a large number of transplanted parenchymal functional hepatocytes.

Instead of stem cell therapy, liver tissue engineering presents another alternative therapeutic strategy. Tissue-engineering approaches for bioengineering of functional hepatic constructs shows potential to replicate liver physiological structures. However, to restore the normal hepatic architecture and functions, tissue engineering strategies for liver regeneration should position bioengineered hepatic constructs into the defect site of an injured liver instead of heterotopic implantation (subcutaneous or intraperitoneal accesses). Thus, cell sheet engineering technology holds promise because the transplanted cells might be better retained due to preserved contacts between the cells and the ECM.

We developed a hepatic patch by combining decellularized liver matrix (DLM) with the hepatocyte growth factor (HGF)/heparin-complex and evaluated its restorative efficacy. In vitro prophylactic results, the HGF/heparin-DLM patches effectively mitigated CCl4-induced hepatocyte toxicity and restored the cytotoxicity levels to the baseline levels by day 5. Furthermore, these patches restored albumin synthesis of injured hepatocytes to more than 70% of the normal levels within 5 days. In vivo, HGF/heparin-DLM patches attached to the liver and gut exhibited a significant decrease in collagen content (4.44 times and 2.77 times, respectively) and an increase in glycogen content (1.19 times and 1.12 times, respectively) compared to the fibrosis group after 1 week, separately. Thus the newly designed hepatic patch holds promise for regeneration therapy and preventive health care for liver tissue engineering.

Link: https://doi.org/10.1002/biot.202300570

Chronic inflammation is a feature of aging. Constant unresolved inflammatory signaling arises from a number of distinct causes, but leads to significant disruption of cell and tissue function, and contributes to the onset and progression of age-related disease. The list causes includes a growing population of lingering senescent cells, all secreting pro-inflammatory signal molecules that can be useful in the short term, but become harmful when sustained over the long term. The list also includes some of the consequences of mitochondrial dysfunction, wherein fragments of mitochondrial DNA are found in the cytosol or outside cells, where they can provoke the innate immune system due to a similarity to bacterial DNA.

In today's open access paper, researchers show a correlation between degree of chronic inflammation and later progression towards lack of physical capacity and frailty, as assessed by gait speed. The data captures a modest decline in physical function in people who are not earnestly sick. For context regarding the numbers given, the average gait speed for people in their 60s and 7ps is 124 cm/s, and thus high measures of inflammation markers in mid-life predicts an average ~8% decline of physical function over the next 20 years. Human epidemiological studies struggle to show correlation, but causation is largely well demonstrated in analogous animal studies. Chronic inflammation is an important problem in the biology of aging, and effective solutions are very much needed.

Associations of mid-to-late-life inflammation with late-life mobility and the influences of chronic comorbidities, race, and social determinants of health: The Atherosclerosis Risk in Communities Study

An estimated 15.4 million older Americans are unable to walk two to three city blocks. Poor physical function, such as slower walking speed, leads to poor quality of life, institutionalization, incident disability, high healthcare costs, and high mortality in community-dwelling older adults and is considered the "sixth vital sign" for older patients. The underlying mechanisms contributing to slowing gait speed and dismobility are poorly understood. One potential pathway is direct inflammatory effects on muscle and other tissues, leading to wasting and weakness, triggering pathways that contribute to muscle breakdown, fatty infiltration, and fibrosis which can lead to muscle weakness, inefficiency, and mobility disability.

High levels of interleukin-6, high sensitivity C-reactive protein (hsCRP), tumor necrosis factor alpha (TNFα), and TNFα soluble receptors are associated with slow walking speed and frailty primarily in older adults, supporting a role for inflammation on age-related mobility declines during late-life. However, whether chronically elevated levels of inflammation prior to older age, when interventions could be more effective, are associated with late-life mobility has not been well studied. Most studies only examined inflammation measured during older ages and did not consider duration of exposure from midlife, which would provide stronger evidence for causal mechanisms. Furthermore, relating inflammatory markers measured across the mid-to-late-life transition on late-life mobility could identify earlier intervention opportunities, yet studies of inflammation during this critical period are limited, particularly in diverse populations.

Among 4,758 community-dwelling participants in the Atherosclerosis Risk in Communities Study (ARIC), high-sensitivity C-reactive protein (hsCRP) was measured over 20+ years: in midlife at study visit 2 (V2: 1990-1992, 47-68 years); at visit 4 (1996-1998, 53-74 years); and with concurrent late-life 4-meter gait speed at visit 5 (2011-2013, 67-88 years, mean 75 years). We examined associations of late-life gait speed with midlife hsCRP (visit 2 continuous and clinically high ≥3 mg/L), with 20-year hsCRP history from midlife (visit 2 to visit 5 average continuous hsCRP and clinically high ≥3 mg/L) and with inflammation accumulation (visits and years with high hsCRP).

High midlife hsCRP was associated with slower late-life gait speed, even among those without chronic conditions in midlife: -4.6 cm/s. Importantly, sustained high hsCRP was associated with a 20-year slowing of -10.0 cm/s among those who never experienced obesity, diabetes, or hypertension over the 20-year period. Inflammation in midlife may contribute to clinically meaningful late-life slowing of gait speed, even among otherwise healthy-appearing adults. Regular monitoring and interventions for inflammation may be warranted from midlife.

BMP-7 is a myokine, involved in muscle growth and upregulated in response to exercise. It is also involved in the development of muscle tissue in early life. One of the reasons that researchers are interested in this gene and related mechanisms of muscle maintenance, growth, and regeneration is to be able to promote greater recovery in an injured heart. Heart muscle is one of the least regenerative tissues in the body, and this limits recovery from a heart attack and resilience to the harmful aged tissue environment. Activating pathways involved in development or exercise may be the road to therapies that can incrementally improve the present situation for older people with heart disease.

Zebrafish have a lifelong cardiac regenerative ability after damage, whereas mammals lose this capacity during early postnatal development. This study investigated whether the declining expression of growth factors during postnatal mammalian development contributes to the decrease of cardiomyocyte regenerative potential. Besides confirming the proliferative ability of neuregulin 1 (NRG1), interleukin (IL)1b, receptor activator of nuclear factor kappa-Β ligand (RANKL), insulin growth factor (IGF) 2, and IL6, we identified other potential pro-regenerative factors, with BMP7 exhibiting the most pronounced efficacy.

Bmp7 knockdown in neonatal mouse cardiomyocytes and loss-of-function in adult zebrafish during cardiac regeneration reduced cardiomyocyte proliferation, indicating that Bmp7 is crucial in the regenerative stages of mouse and zebrafish hearts. Conversely, bmp7 overexpression in regenerating zebrafish or administration at post-mitotic juvenile and adult mouse stages, in vitro and in vivo following myocardial infarction, enhanced cardiomyocyte cycling. Mechanistically, BMP7 stimulated proliferation through BMPR1A/ACVR1 and ACVR2A/BMPR2 receptors and downstream SMAD5, ERK, and AKT signaling. Overall, BMP7 administration is a promising strategy for heart regeneration.

Link: https://doi.org/10.1016/j.celrep.2024.114162

The development of cardiovascular disease outside the brain is thought to contribute to the aging of the brain. The brain is an energy-hungry tissue, and any reduction in blood flow, such as through atherosclerotic narrowing of the arteries and heart failure, will cause harm and functional decline over time. At the same time, and while every organ influences every other organ in some way, it is also the case that vascular aging and brain aging arise to some degree independently due to same underlying processes of aging that operate in every tissue. Mitochondrial dysfunction occurs in the brain just as much as it does in the vasculature, for example, and for reasons centered on the cell, not on the tissue - such as epigenetic changes that occur due to nuclear DNA double strand break repair, or stochastic mutation of mitochondrial DNA.

Aging is the greatest non-modifiable risk factor for most diseases, including cardiovascular diseases (CVD), which remain the leading cause of mortality worldwide. Robust evidence indicates that CVD are a strong determinant for reduced brain health and all-cause dementia with advancing age. CVD are also closely linked with peripheral and cerebral vascular dysfunction, common contributors to the development and progression of all types of dementia, that are largely driven by excessive levels of oxidative stress, e.g., reactive oxygen species (ROS). Emerging evidence suggests that several fundamental aging mechanisms (e.g., "hallmarks" of aging), including chronic low-grade inflammation, mitochondrial dysfunction, cellular senescence, and deregulated nutrient sensing contribute to excessive ROS production and are common to both peripheral and cerebral vascular dysfunction.

Therefore, targeting these mechanisms to reduce ROS-related oxidative stress and improve peripheral and/or cerebral vascular function may be a promising strategy to reduce dementia risk with aging. Investigating how certain lifestyle strategies (e.g., aerobic exercise and diet modulation) and/or select pharmacological agents (natural and synthetic) intersect with aging "hallmarks" to promote peripheral and/or cerebral vascular health represent a viable option for reducing dementia risk with aging. Therefore, the primary purpose of this review is to explore mechanistic links among peripheral vascular dysfunction, cerebral vascular dysfunction, and reduced brain health with aging. Such insight and assessments of non-invasive measures of peripheral and cerebral vascular health with aging might provide a new approach for assessing dementia risk in older adults.

Link: https://doi.org/10.18632/aging.205877

There are a great many hypotheses as to why there is a difference in life expectancy between sexes in many species, and even more when it comes to humans. Since the difference exists in other species, it seems reasonable to throw out most of the thinking that involves behavioral differences or lifestyle choice differences in humans: arguments that men are more prone to risky behavior, less conscientious in use of medical resources, and so forth. From an evolutionary perspective, one can model how reproductive strategies might affect the process of natural selection and its interaction with pace of aging, but even if the models turn out to be correct - and they are usually much debated - that doesn't say much about the specific biochemistry involved in determining life span differences between sexes.

Today's open access research materials present a compelling argument for germline cells to orchestrate processes that lengthen female life span and shorten male life span. Removing the germline acts to shorten female life span and extend male life span in the short-lived killifish species. This dovetails nicely with the existing evolutionary perspectives, and at least narrows down the area of study for those who want to chase down specific mechanisms. The challenge in this arena is rarely in identifying a mechanism that may contribute to the end result of interest, it is to prove that this mechanism is important relative to all of the others that may or may not be involved. Fortunately, modern genetic technologies make it possible, albeit still expensive when conducted in volume, to knock out cell functions one by one. Researchers might progress from here to ever more specific acts of sabotage in germline cell biochemistry, in search of the mechanisms that affect life span.

The gender gap in life expectancy: are eggs and sperm partly responsible?

Women live longer than men. This isn't unique to humans, either; we see this trend in a wide range of other animals. Biologists have theorized that the discrepancy in life expectancy between sexes might be partly related to reproduction, but how? Researchers have discovered for the first time that germ cells, the cells that develop into eggs in females and sperm in males, drive sex-dependent lifespan differences in vertebrate animals.

The researchers examined aging in the turquoise killifish, a small, fast-growing freshwater fish with a lifespan of only a few months. As in humans, female killifish live longer than males. However, when the researchers removed the germ cells from these fish, they found that males and females had similar lifespans. The team found that hormonal signaling was very different in females than in males. Female killifish without germ cells had significantly less estrogen signaling, which can shorten lifespan by increasing cardiovascular disease risk. The females also had significantly more growth factor signaling (insulin-like growth factor 1). This made the females grow larger while also suppressing signals within the body important for maintaining health and slowing aging. In contrast, male killifish without germ cells had improved muscle, skin, and bone health. Interestingly, these fish had increased amounts of a substance that activates vitamin D, as well as evidence of vitamin D signaling in their muscles and skin.

Sex-dependent regulation of vertebrate somatic growth and aging by germ cells

The function of germ cells in somatic growth and aging has been demonstrated in invertebrate models but remains unclear in vertebrates. We demonstrated sex-dependent somatic regulation by germ cells in the short-lived vertebrate model Nothobranchius furzeri. In females, germ cell removal shortened life span, decreased estrogen, and increased insulin-like growth factor 1 (IGF-1) signaling. In contrast, germ cell removal in males improved their health with increased vitamin D signaling. Body size increased in both sexes but was caused by different signaling pathways, i.e., IGF-1 and vitamin D in females and males, respectively. Thus, vertebrate germ cells regulate somatic growth and aging through different pathways of the endocrine system, depending on the sex, which may underlie the sexual difference in reproductive strategies.

Evidence suggests that the composition of the gut microbiome is as influential on long-term health as choices in diet and exercise. The relative proportions of microbial species shift with age, favoring harmful pro-inflammatory microbes over those that produce beneficial metabolites. It is reasonable to ask how much of the beneficial effects of fasting and calorie restriction are mediated via the gut microbiome, via slowing or reducing age-related changes in these microbial populations. With that in mind, researchers are beginning to assess how fasting and calorie restriction alter the behavior and balance of microbial populations making up the gut microbiome. The paper here is one example of this sort of study.

As a principal modulator of the gut microbiome (GM) and weight status, nutritional input holds great therapeutic promise for addressing a wide range of metabolic dysregulation. The GM must regulate its growth rate and diversity in response to nutrient availability and population density. Such maintenance is affected by caloric restriction (CR) coupled with periods of feeding and intermittent fasting (IF). The current study incorporates protein pacing (P), defined as four meals/day consumed evenly spaced every 4 hours, consisting of 25-50 g of protein/meal. Indeed, we have previously characterized a dietary approach of calorie-restricted IF-P combined and P alone.

In this current work, we compare the effects of two low-calorie dietary interventions matched for weekly energy intake and expenditure; continuous caloric restriction on a heart-healthy diet (CR) aligned with current United States (US) dietary recommendations versus our calorie-restricted IF-P diet. The current randomized controlled study describes distinct fecal microbial and plasma metabolomic signatures between combined IF-P (n = 21) versus a heart-healthy, calorie-restricted (CR, n = 20) diet matched for overall energy intake in free-living human participants (women = 27; men = 14) with overweight/obesity for 8 weeks.

Gut symptomatology improves and abundance of Christensenellaceae microbes and circulating cytokines and amino acid metabolites favoring fat oxidation increase with IF-P, whereas metabolites associated with a longevity-related metabolic pathway increase with CR. The plasma metabolome analysis revealed distinct metabolite signatures in IF-P and CR groups, with the convergence of multiple metabolic pathways. Differences indicate GM and metabolomic factors play a role in weight loss maintenance and body composition. This data may inform future GM-focused precision nutrition recommendations using larger sample sizes of longer duration.

Link: https://doi.org/10.1038/s41467-024-48355-5

GHRH knockout mice are one of the longest-lived lineages. It remains the case that disrupted growth hormone signaling extends life to a greater degree than any of the other interventions tested in mice. The equivalent Laron syndrome population in humans clearly doesn't experience the same sizable extension of life span, however. This should perhaps tell us that researchers must look elsewhere for approaches to the treatment of aging in long-lived mammals. The most well studied approaches to extend healthy life span in mice, meaning calorie restriction and disruption of growth hormone signaling, do not improve human life span to anywhere near the same degree.

Dysregulation of growth hormone (GH) signaling consistently leads to increased lifespan in laboratory rodents, yet the precise mechanisms driving this extension remain unclear. Understanding the molecular underpinnings of the beneficial effects associated with GH deficiency could unveil novel therapeutic targets for promoting healthy aging and longevity. In our pursuit of identifying metabolites implicated in aging, we conducted an unbiased lipidomic analysis of serum samples from growth hormone-releasing hormone knockout (GHRH-KO) female mice and their littermate controls.

Employing a targeted lipidomic approach, we specifically investigated ceramide levels in GHRH-KO mice, a well-established model of enhanced longevity. While younger GHRH-KO mice did not exhibit notable differences in serum lipids, older counterparts demonstrated significant reductions in over one-third of the evaluated lipids. In employing the same analysis in liver tissue, GHRH-KO mice showed pronounced downregulation of numerous ceramides and hexosylceramides, which have been shown to elicit many of the tissue defects that accompany aging (e.g., insulin resistance, oxidative stress, and cell death). Additionally, gene expression analysis in the liver tissue of adult GHRH-KO mice identified substantial decreases in several ceramide synthesis genes, indicating that these alterations are, at least in part, attributed to GHRH-KO-induced transcriptional changes.

These findings provide the first evidence of disrupted ceramide metabolism in a long-lived mammal. This study sheds light on the intricate connections between GH deficiency, ceramide levels, and the molecular mechanisms influencing lifespan extension.

Link: https://doi.org/10.1111/acel.14226

There is a certain class of supplement manufacturer that follows the hype rather than the science: hype enables the ability to take cheap substances, obfuscate and market, and charge a sizeable premium. I think that the most offensive thing about the publicly available materials for the Leap Years supplement for dogs (referred to as LY-D6/2 here) is that they do not tell customers exactly what is in it. It is claimed to be some kind of vitamin B3 derivative to upregulate NAD+ and some kind of plant extract senolytic (likely fisetin or quercetin), both categories that have received a lot of attention in recent years.

On the one hand, pharmacological NAD+ upregulation is likely less effective than exercise. On the other hand, some senolytics are interesting, but many are only slightly senolytic. Of the well-known plant extracts, fisetin is interesting, but still lacking any published data in a species other than mice, while quercetin may be a component of the senolytic combination of dasatinib and quercetin, but is not meaningfully senolytic on its own. Given that Leap Years don't tell us which they are using, or how large the dose is, there isn't much that can be said about the prospects of the supplement strategy in advance. This is straightforwardly bad behavior on the part of this organization.

The only good thing I can find to say about this group is that they at least published the results of a study in dogs in the only significant benefit occurred in an owner-reported measure of cognitive function. There was no benefit to physical activity and frailty. One can draw no conclusions about any of this that are useful to the broader field because, again, we have no idea what is in this supplement.

A randomized, controlled clinical trial demonstrates improved owner-assessed cognitive function in senior dogs receiving a senolytic and NAD+ precursor combination

Age-related decline in mobility and cognition are associated with cellular senescence and NAD+ depletion in dogs and people. A combination of a novel NAD+ precursor and senolytic, LY-D6/2, was examined in this randomized controlled trial. Seventy dogs with mild to moderate cognitive impairment were enrolled and allocated into placebo, low dose, or full dose groups. Primary outcomes were change in cognitive impairment measured with the owner-reported Canine Cognitive Dysfunction Rating (CCDR) scale and change in activity measured with physical activity monitors.

This randomized controlled blinded trial is one of the first of its kind, evaluating an anti-aging supplement that targets two hallmarks of aging in senior dogs. This clinical trial used a pragmatic approach that included dogs with mild to moderate cognitive impairment who met age, weight and relatively broad health criteria. Dogs were followed to a primary endpoint at 3 months and a secondary endpoint at 6 months.

Fifty-nine dogs completed evaluations at the 3-month primary endpoint, and 51 reached the 6-month secondary endpoint. There was a significant difference in CCDR score across treatment groups from baseline to the primary endpoint with the largest decrease in the full dose group. No difference was detected between groups using in house cognitive testing. There were no significant differences between groups in changes in measured activity. The proportion of dogs that improved in frailty and owner-reported activity levels and happiness was higher in the full dose group than other groups, however this difference was not significant. Adverse events occurred equally across groups.

Calorie restriction has a sizable effect on health and life span in the short-lived species used in scientific studies of aging, and produces sweeping changes in the regulation of cellular biochemistry. The combination of these two points has ensured that near all approaches discovered to slow aging to date operate on aspects of cellular biochemistry that are involved in the calorie restriction response. In the course of producing a body of data in numerous species including worms, flies, and mice, it has become clear that short-lived species are much more responsive to these interventions than is the case for long-lived species. There is an argument to be made that most of the research and development in the field of aging is looking in the wrong places for approaches that will work well in long-lived mammals such as our own species. That doesn't mean that the field as a whole is incapable of producing sizable gains in life span, however. It would be premature to draw that conclusion.

Well-documented anti-aging treatments across species of increasing complexity include drugs such as rapamycin, resveratrol, spermidine, chloroquine, and even medications historically employed for treating different diseases, like metformin, which is used in the management of type 2 diabetes. The decreasing magnitude of the positive effect with increasing species complexity in anti-aging treatments is obvious. Thus, we noted the positive effects of metformin decreased from 50% in S. cerevisiae to negligible (if any) effects in humans. Similarly, the effects of resveratrol decreased almost linearly from 70% in S. cerevisiae to 41% in Drosophila, to 30% in C. elegans, to 26% in rodents. The impact of rapamycin on lifespan across species decreased progressively, from 57% in S. cerevisiae to approximately 29% in Drosophila, further declining to 25% in C. elegans, and ultimately reaching 13% in rodents.

The limited translatability between species of increasing complexity can be explained by a number of factors. The effectiveness or significance of the targeted molecule from a pathway might differ in various metabolic scenarios. For example, the anti-aging mechanisms of resveratrol primarily involve ameliorating oxidative stress by scavenging reactive oxygen species (ROS). However, ROS play a more significant role in flying species like Drosophila than in mammals, which may possess additional mechanisms to counteract ROS. Indeed, recent research has revealed a more complex and beneficial role of ROS in regulating metabolism, development, and lifespan.

Second, the weight of targeted signaling pathways differs for a species' general metabolism. Therefore, single mutations that reduce insulin/IGF-1 signaling can significantly increase the lifespan of simple organisms such as C. elegans and D. melanogaster. However, the increased complexity of the pathway, attributed to additional regulators like insulin and growth hormone, has made it challenging to distinguish the roles of each key component in mammalian longevity.

Third, redundancy in pathways is a widespread phenomenon in species of increasing complexity, observed across all forms of life. It has developed as a safeguard against disturbances that might otherwise interfere with essential processes, such as mutations or shifts in the environment. Thus, blocking one pathway does not necessarily impede the cellular or organismal process.

Fourth, as we make progress into research on anti-aging therapies, the challenges posed by the increasing complexity of species remind us that, much like many aspects of biology and medicine, there exists a law of diminishing returns. While the initial interventions may yield significant and noticeable impacts, the subsequent benefits might be less pronounced with the addition of more layers of complexity and control.

Link: https://doi.org/10.1111/acel.14208

Is aging actively selected for by evolutionary processes, a program that provides some advantage to a species, or is aging the polar opposite, the consequence of a lack of selection pressure on late life health? The latter is the present mainstream view of aging, that aging arises because early reproduction is favored by evolution, and thus systems evolve that are initially effective but decline over time. Aging is a side-effect of these maladapted systems, a process called antagonistic pleiotropy.

The ideas put forward by the smaller part of the research community that sees aging as an evolved program are themselves evolving quite rapidly. It is interesting to dip a toe into that water every so often to see where matters stand. At present there is a fair amount of interest in ideas that fall under the heading of quasi-programmed aging, which do not clearly belong to either the traditional programmed aging viewpoints or the antagonistic pleiotropy viewpoints. The hyperfunction view of aging is one of these ideas, in which, to oversimplify, aging is seen as the consequence of developmental programs that continue to run past their useful span of time.

While ruling out programmed aging, evolutionary theory predicts a quasi-program for aging, a continuation of the developmental program that is not turned off, is constantly on, becoming hyper-functional and damaging, causing diseases of aging. Could it be switched off pharmacologically? This would require identification of a molecular target involved in cell senescence, organism aging and diseases of aging. Notably, cell senescence is associated with activation of the TOR (target of rapamycin) nutrient-sensing and mitogen-sensing pathway, which promotes cell growth, even though the cell cycle is blocked.

Is TOR involved in organism aging? In fact, in yeast (where the cell is the organism), caloric restriction, rapamycin, and mutations that inhibit TOR all slow down aging. In animals from worms to mammals caloric restrictions, life-extending agents, and numerous mutations that increase longevity all converge on the TOR pathway. And, in humans, cell hypertrophy, hyper-function and hyperplasia, typically associated with activation of TOR, contribute to diseases of aging. Theoretical and clinical considerations suggest that rapamycin may be effective against atherosclerosis, hypertension and hyper-coagulation (thus, preventing myocardial infarction and stroke), osteoporosis, cancer, autoimmune diseases and arthritis, obesity, diabetes, macular degeneration, Alzheimer's and Parkinson's diseases.

Finally, I discuss that extended life span will reveal new causes for aging (e.g. reactive oxygen species, 'wear and tear', Hayflick limit, stem cell exhaustion) that play a limited role now, when quasi-programmed senescence kills us first.

Link: https://doi.org/10.4161/cc.5.18.3288

The cryonics industry has remained non-profit and small for fifty years. Only a few hundred people have been cryopreserved on death, a tragedy that receives too little attention. A cryopreserved individual has, in principle, some unknown odds of a restored life at some point in a more technologically capable future. Higher odds than the other end of life alternatives, such as burial and cremation, of course. This is provided that the fine structure of the brain is sufficiently preserved, and there remains debate over the degree to which this can be achieved using the technologies and protocols of today. Cryonics organizations and researchers lack the resources needed to conduct the sort of research and development needed to firmly answer questions of this nature, and to effectively react to the answers by developing new approaches.

Expanding the cryonics industry has proven to be challenging, ever stuck in the earliest stages of bootstrapping small gains in reach and capabilities to obtain small increases in funding. The best of the present options for more rapid expansion involves a focus on achieving robust, reliable forms of reversible cryopreservation, initially of small tissues and then organs, as there is a strong demand for this capability. Small tissue preservation is need to improve research tools, while the ability to store organs indefinitely would dramatically improve the logistics and reduce the costs of the organ donor industry. Demand leads to funding and commercial development, and as the first applications of reversible cryopreservation spread into the market, this is expected to in turn change the perception of the feasibility of whole body cryopreservation.

All of that said, it is good to see progress on this front in the form of a well funded company. Laura Deming has been leading an effort to work on reversible cryopreservation for a few years now, and it seems that it is is now time to announce the progress achieved to date. Research into reversible cryopreservation has been at the point of making the leap to for-profit development for a decade or so, and hopefully this will encourage other groups to move more rapidly towards commercial applications of their approaches. The wheels turn slowly, but at least they are turning.

Cradle emerges with $48m to build reversible cryonics technology

Cryonics startup Cradle was unveiled this week, boasting $48 million in funding and a mission to develop and prove the feasibility of whole-body reversible cryopreservation. Co-founded by venture capitalist and longevity pioneer Laura Deming and chief scientist Hunter C Davis, the company is built on the belief that pausing and restarting biological functions on demand is a solvable problem. "We're building reversible cryo technologies. Think the hibernation pods you see in space movies for long-term travel - we want to build that."

Cradle's approach to cryopreservation focuses on pausing molecular motion through cooling, thus preventing tissue damage that typically occurs during freezing. This concept leverages technologies like those used in in vitro fertilization (IVF), where embryos can be stored at cryogenic temperatures for extended periods. By adapting and scaling these principles, Cradle seeks to achieve cryopreservation of larger biological systems, including human organs and potentially whole bodies. The company's web site states "We are optimistic that human whole-body reversible cryopreservation is solvable."

Cradle has identified three areas of medicine that it believes its technology can potentially benefit. First, by cryopreserving neural tissue, the company aims to improve the accessibility of human brain tissue samples for research, potentially accelerating drug development and neuroscience research. Second, Cradle believes that cryopreservation could extend the viability window for donor organs, allowing more time for testing and matching, thereby reducing rejection rates and improving transplant outcomes. And finally, the company suggests its technology could allow patients with terminal illnesses to pause their biological time, giving them the opportunity to survive until effective treatments become available.

Cradle said its first major milestone, achieved in February 2024, involved recovering electrical activity in a cryopreserved and rewarmed slice of rodent neural tissue. The company claims this breakthrough serves as a foundational proof of concept, paving the way for its more ambitious goals. Next steps for Cradle include demonstrating preserved synaptic function and long-term potentiation in cryopreserved neural tissue, and eventually, achieving functional preservation of whole organs and even entire organisms.

Lymph nodes are points of coordination for the immune system, where T cells of the adaptive immune system are presented with antibodies that match target molecules, in effect given instructions as to what to attack next. Calling a structure made of biomaterials and decorated with antibodies an "artificial lymph node" does get the point across, but this is a far cry from, say, a lymph node organoid that shares a similar structure and set of cell populations with a natural lymph node. Still, the artificial structure does serve this one purpose, to instruct T cells. Researchers here envisage implanting a lymph node substitute as a part of a T cell therapy for cancer, using appropriate antibodies to ensure that the T cells will aggressively attack cancerous cells.

Lymph nodes - tiny glands throughout the body, mainly in the neck, armpits and groin - are part of the immune systems of mammals, including mice and people. They number in the hundreds so that immune cells in one area of the body don't have to travel far to alert the immune system to impending danger. "They are a landing spot where T-cells, the immune system's fighting cells, lay dormant, waiting to be activated to fight infections or other abnormal cells. Because cancers can trick T-cells into staying dormant, the artificial lymph node was designed to inform and activate T-cells that are injected alongside the lymph node."

To create the artificial lymph node, the scientists used hyaluronic acid, a substance found naturally in the body's skin and joints. Because of its properties, hyaluronic acid is often used in biodegradable materials such as wound healing patches meant to be implanted or applied to the body. Among those properties, hyaluronic acid can connect with T-cells via a cell surface receptor. Researchers used hyaluronic acid as the scaffolding, or base, for their new lymph node, and added MHC (major histocompatibility complex) or HLA (human histocompatibility antigen) molecules, which rev up T-cells and other immune system components. Then, they also added molecules and antigens common to cancer cells to "teach" T-cells what to look for.

"By adding different antibodies to the artificial lymph node, we have the ability to control what the T-cells are being activated to search for. An advantage to this approach over other cell-based therapies such as CAR-T is fewer manufacturing steps. Current cell-based therapies require extracting T-cells from a patient, manipulating them outside of the body to recognize a particular type of cancer, and injecting them back into the patient. In our approach, we inject T-cells along with an artificial lymph node, and the T-cells get primed and educated by the artificial lymph node inside of the body. Then, the T-cells can travel anywhere to destroy cancer cells."

Link: https://www.hopkinsmedicine.org/news/newsroom/news-releases/2024/06/artificial-lymph-node-used-to-treat-cancer-in-mice

The mTOR protein forms complexes, of which mTORC1 is involved in nutrient sensing. Inhibiting mTORC1 mimics some of the effects of a low calorie diet, meaning cells will undertake greater maintenance and repair while also reducing activities that tend to produce molecular damage. The result of either low calorie intake or mTORC1 inhibition is a modestly slowed pace of aging, lesser degrees of dysfunction, lower chronic inflammation in later life, and so forth. Researchers here demonstrate that this can work in the other direction as well. They stimulate the activity of mTORC1 via RagC, producing the same downstream signaling that would occur with in response to a high calorie diet. This intervention reduces life span in mice via inflammatory mechanisms, one more piece of evidence pointing to the importance of inflammation in the processes of aging.

The mechanistic target of rapamycin (mTOR) complex 1 (mTORC1) controls cellular anabolism in response to growth factor signaling and to nutrient sufficiency signaled through the Rag GTPases. Inhibition of mTOR reproducibly extends longevity across eukaryotes. Here we report that mice that endogenously express active mutant variants of RagC exhibit multiple features of parenchymal damage that include senescence, expression of inflammatory molecules, increased myeloid inflammation with extensive features of inflammaging and a ~30% reduction in lifespan.

Through bone marrow transplantation experiments, we show that myeloid cells are abnormally activated by signals emanating from dysfunctional RagC-mutant parenchyma, causing neutrophil extravasation that inflicts additional inflammatory damage. Therapeutic suppression of myeloid inflammation in aged RagC-mutant mice attenuates parenchymal damage and extends survival. Together, our findings link mildly increased nutrient signaling to limited lifespan in mammals, and support a two-component process of parenchymal damage and myeloid inflammation that together precipitate a time-dependent organ deterioration that limits longevity.

Link: https://doi.org/10.1038/s43587-024-00635-x

Replication stress is the name given to disruptions to the process of DNA replication that takes place when a cell divides. The double stranded genome splits, unzipping into two single strands that are each provided with the complementary nucleotides in order to reform as two complete double-stranded copies. The rapidly moving point at which this unzipping takes place, where the two strands actually separate, is called the replication fork. It is a busy area of complex protein machinery, prone to failure and ongoing correction of failures. Unresolved failures lead to DNA damage, and DNA damage during this replication process can lead to cellular senescence.

Today's open access paper reviews what is known of the contribution of replication stress to the age-related burden of cellular senescence. Replication stress is a major culprit in at least one of the progeria conditions that give patients some of the appearance of accelerated aging, but to what degree is this the right place to look in order to measure the progression of normal aging? This is an open question, as replication stress is not so often measured versus markers of one of its outcomes, increased cellular senescence.

What other outcomes can replication stress produce in addition, however? Researchers here note an interesting connection to repair of double strand DNA breaks, that, as you may recall, has been implicated in driving the epigenetic changes that are characteristic of aging. If replication stress provokes greater double strand breaks and thus greater efforts to repair those breaks, it may well be a useful marker of aging.

Replication stress as a driver of cellular senescence and aging

Replication stress can be caused by an endogenous or environmental condition that disrupts the faithful copying of the genome. Replication stress is defined as stalling or slowing of replication fork progression which may lead to replication collapse and DNA damage. Stalled forks need to be protected and recovered to resume DNA synthesis and prevent genomic instability, a hallmark of aging.

A direct link between compromised stalled fork recovery and aging has been established by characterizing the molecular phenotypes of cells isolated from individuals with Werner Syndrome (WS), an autosomal recessive premature aging disease resulting from loss-of-function mutations in the WRN gene. Over the years, experimental evidence has demonstrated critical functions of the RECQ helicase WRN in stability and recovery of stalled replication forks under conditions of replication stress. Consistent with the roles of WRN in processing and stabilizing stalled forks, WS fibroblasts show reduced DNA replication capacity, fork asymmetry, heightened genomic instability, and premature replicative senescence. These phenotypes are likely attributed to failure to resolve complex replication intermediates resulting from stalled replication forks upon functional loss of WRN.

Cellular senescence driven by replication defects is considered a hallmark of aging. This prompts one to consider replicative stress as a potentially useful biomarker for aging. Although cell metabolism markers such as β-galactosidase staining have been a popular marker for senescent cells, markers of replication stress have not been as extensively studied. Rather, DNA damage emanating from replication stress or by other avenues (e.g., oxidative stress) has been postulated as a key biomarker for cellular senescence and even organismal aging. One of the most prominent DNA lesions associated with changes to the genome that is implicated in (and perhaps a driving force of) aging is the double strand break (DSB), one of the most lethal forms of DNA damage and a source of great genomic instability due to its recombinogenic nature.

Recently, the researchers developed an inducible DNA break mouse model that enabled them to investigate the importance of epigenetic changes induced by chromosome breaks for aging. Alterations in epigenetic landscape in regions surrounding the DSBs were associated with aging phenotypes at the cellular and organismal levels. However, whether the aging phenotypes associated with epigenetic changes are reversible at the organismal level remains to be seen. Nonetheless, the described model system will be useful for future work to study in vitro and in vivo aging. It remains to be determined if DSBs deriving from replication stress drive aging in replicative tissues by a mechanism that is different from the one described above, in which DSBs introduced frankly by the in vivo inducible restriction endonuclease system in both non-replicative and replicative tissues cause aging in a manner that is heavily dependent on epigenetic changes.

Although one could argue that DSBs represent only one of multiple DNA lesions to induce accelerated aging, the probability that they occur at the fork in replicative tissues in vivo is high. Replication fork stalling followed by blockage leads to single-stranded and ultimately DSBs, i.e., broken replication forks that cells must deal with using fork reconstruction pathways to preserve genomic stability. Typically, these repair mechanisms to heal DSBs at broken replication forks involve HR repair or the less faithful nonhomologous end-joining (NHEJ). Although stalled forks can be restarted by non-recombinogenic mechanisms, the transient single-stranded DNA that arises is susceptible to breakage. Thus, it is difficult to tease out if a structural feature of the stalled or arrested replication fork, the fork-associated DSB itself, or both represent a key signaling event in cellular senescence and aging. Either way, in proliferating cells of rapidly turning over tissues, replication stress is a driving force for age-associated signaling pathways associated with delayed fork progression.

Senolytic drugs selectively clear senescent cells from aged tissues. They are variably effective in different stages of cellular senescence, origins of cellular senescence, and tissue types, as senescent cells vary widely in the details of their biochemistry. We might expect a near future clinical marketplace to feature a dozen or more senolytic therapies, each of which is tailored to specific circumstances and age-related conditions. One of the interesting use cases is to destroy the senescent cancer cells that remain in the body after chemotherapy and other forms of cancer treatment. This will likely require somewhat different senolytics from those used to clear cells that become senescent in other contexts. As an example of this sort of research, scientists here explore the senolytic abilities of PI3K inhibitor drugs in cancer cells.

The targeted elimination of radiotherapy-induced or chemotherapy-induced senescent cells by so-called senolytic substances represents a promising approach to reduce tumor relapse as well as therapeutic side effects such as fibrosis. We screened an in-house library of 178 substances derived from marine sponges, endophytic fungi, and higher plants, and determined their senolytic activities towards DNA damage-induced senescent HCT116 colon carcinoma cells. The Pan-PI3K-inhibitor wortmannin and its clinical derivative, PX-866, were identified to act as senolytics. PX-866 potently induced apoptotic cell death in senescent HCT116, MCF-7 mammary carcinoma, and A549 lung carcinoma cells, independently of whether senescence was induced by ionizing radiation or by chemotherapeutics, but not in proliferating cells.

Other Pan-PI3K inhibitors, such as the FDA-approved drug BAY80-6946 (Copanlisib), also efficiently and specifically eliminated senescent cells. Interestingly, only the simultaneous inhibition of both PI3K class I alpha (with BYL-719 (Alpelisib)) and PI3K class delta (with CAL-101 (Idelalisib)) isoforms was sufficient to induce senolysis, whereas single application of these inhibitors had no effect. On the molecular level, inhibition of PI3Ks resulted in an increased proteasomal degradation of the CDK inhibitor p21WAF1/CIP1 in all tumor cell lines analyzed. This led to a timely induction of apoptosis in senescent tumor cells. Taken together, the senolytic properties of PI3K-inhibitors reveal a novel dimension of these promising compounds, which holds particular potential when employed alongside DNA damaging agents in combination tumor therapies.

Link: https://doi.org/10.1038/s41419-024-06755-x

A prion is a protein that can misfold in a way that encourages other molecules of the same protein to misfold in the same way. It can thus spread like a pathogen through cells and tissues, producing pathological changes in its wake. "Prion" is a term used inconsistently in the research community, as the very well researched amyloid-β and α-synuclein, drivers of neurodegenerative conditions, have prion-like properties but are rarely referred to as prions. So in one sense, yes, there are indeed prions in the aging brain, spreading and causing harm. Here, researchers look into the protein DDX5 in short-lived killifish, and report that it, too, can exhibit prion-like behavior and thus may be causing harm in the aging brain. As they note, the human version of this gene is very similar, similar enough that the observations may hold up in our species.

Prion-like properties have been proposed to drive the progression of several neurodegenerative pathologies by facilitating the transmission of protein aggregates from affected to unaffected areas of the brain. Long viewed as a rare biological oddity, prions have recently been discovered throughout evolution, from yeast to humans. Prions and prion-like self-assembly have been implicated in normal physiological functions, such as metabolism, cell fate determination, antiviral responses, and inflammation.

Here, we leverage the killifish as a powerful model to unbiasedly identify proteins that aggregate during normal brain aging. Using quantitative proteomics, we identify many proteins with an increased propensity to aggregate in the aging brain. One of these proteins, the RNA helicase DDX5, forms aggregate-like puncta in old brains of both killifish and mice and has prion-like seeding properties in cells. DDX5 rapidly undergoes phase separation in vitro, and these condensates mature into solid aggregates that are inactive and potentially infectious. The aggregation of key proteins during normal vertebrate brain aging could contribute to the age dependency of cognitive decline.

Link: https://doi.org/10.1016/j.celrep.2023.112787

The blood-brain barrier is a layer of specialized cells that only very selectively allow passage of molecules and cells to and from blood vessels that pass through the brain. The barrier separates the biochemistry of the brain from that of the rest of the body. Unfortunately, the blood-brain barrier becomes dysfunctional with age, allowing leakage of unwanted molecules and cells into the brain, where they can, for example, provoke chronic inflammatory behavior in innate immune cells and other supporting cell populations responsible for maintaining brain tissue. It is presently thought that blood-brain barrier dysfunction is important in the development of neurodegenerative conditions, and may be an early contributing cause, preceding many of the other biomarkers and pathological mechanisms.

In today's open access paper, researchers report on their use of MRI to produce regional maps of blood-brain barrier leakage in the brains of old and young volunteers. The researchers then compared these maps with PET imaging of amyloid-β and tau protein, both of which misfold and aggregate in old age, and particularly in the context of Alzheimer's disease, in search of correlations. The researchers found a tendency for blood-brain barrier dysfunction to follow the regional pattern of neurodegenerative pathology that is associated with Alzheimer's disease. This is another data point to add to the evidence for the importance of the blood-brain barrier in neurodegenerative conditions. More effort should be directed towards approaches that might reverse age-related blood-brain barrier dysfunction.

Associations between regional blood-brain barrier permeability, aging, and Alzheimer's disease biomarkers in cognitively normal older adults

Brain aging is accompanied by the aggregation of pathological proteins and the increasing prevalence of cerebrovascular disease. Recent research has shown that blood-brain barrier dysfunction is an important feature of both brain aging and Alzheimer's disease (AD). Blood-brain barrier permeability (BBBp) alteration in human aging and Alzheimer's disease (AD) has been documented through the detection of blood-derived proteins in the hippocampus (HC) and cortex of AD patients and increases in the cerebrospinal fluid (CSF) of the plasma albumin protein ratio (Qalb) in both aging and AD. More recent evidence of BBBp in humans comes from studies using the high spatial and temporal resolution imaging technique, dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI), which allows measurement of subtle BBB changes. A number of studies using DCE MRI have shown increased BBBp in both aging and AD with particular vulnerability of the hippocampus to this process. Major questions remain, however, regarding the overall spatial distribution of BBBp, whether abnormalities are limited to the medial temporal lobe (MTL) and most importantly, whether or how BBBp is related to the development of AD.

In this study, we investigated the relationship between BBBp and AD through two lines of evidence. First, we examined the full spatial distribution of BBBp which offers an ability to draw inferences about causal mechanisms and to help establish the role of BBBp in dementia. To do this, we compared BBB function in a group of cognitively normal older adults (OA) to young adults (YA) and mapped the whole brain distribution of BBBp. Second, we investigated whether BBBp in OA was associated with APOE4 genotype and regional Aβ and tau, measured using PET imaging.

Using DCE-MRI in cognitively normal OA and YA, we showed that increased BBBp in aging does not occur globally, but rather occurred predominately in the temporal lobe, with involvement of the parietal, and less involvement of occipital and frontal lobes. In these regions we also found that APOE4 carriers had greater BBBp than non-carriers. The regional BBBp we found strikingly reflects the pattern of brain vulnerability to AD pathology, particularly in regions that are affected early. Tau accumulation in normal aging begins in the medial temporal lobe and spreads to neighboring regions in the inferolateral temporal and medial parietal lobes in the presence of Aβ. The pattern of brain Aβ accumulation overlaps with the spatial location of tau best in later disease stages, covering regions in prefrontal, parietal, lateral temporal, and cingulate cortices.

In line with previous studies, we saw greater BBBp in the MTL, particularly regions which accumulate tau pathology and undergo atrophy in normal aging, but do not typically accumulate Aβ at early stages of AD. We also saw that in our sample the frontal lobe is relatively spared from increased BBBp, which is interesting because this brain region is associated with early Aβ accumulation but late tau accumulation. These differences suggest that increased BBBp follows a distribution pattern more like tau accumulation than Ab, with involvement of the MTL, temporal, parietal, and occipital lobes. The degree of BBBp alteration varied considerably in older individuals and increases were also seen in young adults, so it is difficult to say with certainty that these changes are pathological from these data alone. However, their associations with brain regions affected by AD and the suggestion of relationships with abnormal protein accumulation, raise concerns.

Researchers here report that the IRAK-M protein is protective of retinal cell health, but the amount of IRAK-M expressed in the retina declines with age. This may be due to the increased oxidative stress that is characteristic of aged tissues. Gene therapy to increase IRAK-M expression appears to slow the progression of damage and loss of function in the retina in mice, at least in the models tested. It remains to be seen as to whether this will hold up in the condition itself.

Progression of age-related macular degeneration (AMD) affects around 200-million people worldwide. Patients suffering from AMD often start with blurred vision or seeing a black dot in their central vision, which can ultimately expand to the point where there is no useful central vision. The exact cause of AMD is complex and thought to involve a combination of aging, genetics, environment, and lifestyle factors. Primarily affecting people over the age of 50, the risk of developing AMD significantly increases with age​ and makes tasks like reading and driving​ difficult.

Scientists believe that chronic inflammation, which is typical with aging, is associated with the reduction of a key immune regulatory protein called IRAK-M. This protein is crucial for protecting the retinal pigment epithelium (RPE), a layer of cells essential for maintaining a healthy retina. When RPE cells are damaged, it can result in serious eye conditions and vision loss.

In this study, researchers investigated the role of IRAK-M in AMD by examining genetic variations and their link to AMD risk. By studying IRAK-M levels in patient samples and mouse models of retinal degeneration, the team observed changes in retinal function in mice lacking the IRAK3 gene, which expresses the IRAK-M protein. They found that IRAK-M decreases with age, especially in the retinal pigment epithelium (RPE), and this decline is more pronounced in those with age-related macular degeneration (AMD).

The team then sought to explore whether increasing IRAK-M could protect retinal cells from degeneration in mouse models and whether it is a potential therapeutic target for macular degeneration. They show that increasing IRAK-M levels through RPE-specific gene delivery helps protect against the effects of aging and oxidative stress and reduces retinal degeneration. The researchers aim to help develop the therapies further through a new spin-out company called Cirrus Therapeutics.

Link: https://www.bristol.ac.uk/news/2024/june/amd-study.html

Amyloids are formed from a few varieties of protein that can misfold or otherwise become altered in ways that encourage other molecules of the same protein to also misfold or become altered in the same way. They spread and gather to form solid aggregates, disruptive to normal cell tissue function. Forms of amyloid relevant to the heart and vasculature include amyloid-β, transthyretin, and medin. Researchers here note that amyloid fibrils may act to encourage and accelerate unwanted calcification of tissue. They focus on the heart, but one might argue for the same processes to operate throughout the cardiovascular system.

Calcific aortic valve disease (CAVD) is the major heart valve disease that afflicts nearly 10 million patients globally with an annual mortality exceeding 100,000, and the numbers continue to rise. In CAVD, microcrystals of hydroxyapatite (a calcium phosphate mineral) deposit onto the heart valve leaflets and impair cardiac function. The disease has a dismal prognosis with most untreated patients dying two years after diagnosis. Currently, the only available treatment is surgical aortic valve replacement, which is not appropriate for all patients. While previous studies of the histology samples from explanted calcified aortic valves have found amyloid deposits in or near calcified areas, the causal relationship between amyloid deposition and calcification is unclear.

Researchers have now proposed a molecular mechanism that links amyloid deposition in the aortic valve with degenerative calcification. They also theorize that other risk factors for CAVD, such as high blood levels of lipoprotein, can contribute to calcification both directly and indirectly through the mechanisms that involve amyloid accumulation.

Harnessing the "resolution revolution" in cryogenic electron microscopy, groups of researchers around the world were able to determine hundreds of structures of patient-derived protein aggregates called amyloid fibrils. Such fibrils are associated with major human diseases including Alzheimer's and Parkinson's diseases, diabetes, and heart diseases such as atherosclerosis and calcific aortic valve disease. "We noticed that the unique geometry of amyloid fibrils, with their periodic arrays of acidic residues on the surface, provides a perfect match for the precursors of calcium phosphate crystals that deposit in the heart valve and impair its normal function."

Link: https://www.eurekalert.org/news-releases/1047231

Reprogramming occurs in the early embryo, a conversion of adult germ cells into embryonic stem cells mediated by expression of the Yamanaka factors - canonically Oct3/4, Sox2, Klf4, and c-Myc. This is accompanied by a reset of age-related changes in gene expression, and a clearing out of cell damage and dysfunction. This process cannot fix everything, but in conjunction with the ability to selectively sacrifice embryonic cells with too great a burden of molecular damage, it does effectively ensure that the embryo is young even though its parents are old.

Partial reprogramming involves a short period of exposure to one or more of the Yamanaka factors or other reprogramming agents that can indirectly induce expression in one or more of the Yamanaka factors. The goal is to provoke the rejuvenation of gene expression observed in embryonic development without causing a loss of cell state and function. Researchers continue to work towards the most optimal way to achieve this outcome, but a number of approaches are presently in preclinical development. Along the way, researchers are producing proof of concept demonstrations for novel applications of reprogramming technologies, such as the one noted in today's open access preprint.

A Single-Short Partial Reprogramming of the Endothelial Cells decreases Blood Pressure via attenuation of EndMT in Hypertensive Mice

Small artery remodeling and endothelial dysfunction are hallmarks of hypertension. Growing evidence supports a likely causal association between cardiovascular diseases and the presence of endothelial-to-mesenchymal transition (EndMT), a cellular transdifferentiation process in which endothelial cells (ECs) partially lose their identity and acquire additional mesenchymal phenotypes. EC reprogramming represents an innovative strategy in regenerative medicine to prevent deleterious effects induced by cardiovascular diseases.

Using a partial reprogramming of ECs, via overexpression of Oct-3/4, Sox-2, and Klf-4 (OSK) transcription factors, we aimed to bring ECs back to a youthful phenotype in hypertensive mice. OSK overexpression induced partial EC reprogramming in vitro, and these cells showed endothelial progenitor cell (EPC)-like features with lower migratory capability. OSK treatment of hypertensive BPH/2J mice normalized blood pressure and resistance arteries hypercontractility, via the attenuation of EndMT and elastin breaks. OSK-treated human ECs from hypertensive patients showed high eNOS activation and NO production, with low ROS formation. Single-cell RNA analysis showed that OSK alleviated EC senescence and EndMT, restoring their phenotypes in human ECs from hypertensive patients.

Overall, these data indicate that OSK treatment and EC reprogramming can decrease blood pressure and reverse hypertension-induced vascular damage.

In an interesting reversal of the usual goals in aged tissue, researchers here demonstrate an approach that reduces mitochondrial function in heart muscle to provoke replication of cardiomyocyte cells and consequent regeneration. Since this is achieved via downregulation of a single gene, it is a possible basis for future therapies aimed at improving function in the aged heart, or, the more usual focus in the research community, provoking greater regeneration following the injury and scarring of a heart attack.

Newborn mammalian cardiomyocytes quickly transition from a fetal to an adult phenotype that utilizes mitochondrial oxidative phosphorylation but loses mitotic capacity. We tested whether forced reversal of adult cardiomyocytes back to a fetal glycolytic phenotype would restore proliferative capacity. We deleted Uqcrfs1 (mitochondrial Rieske Iron-Sulfur protein, RISP) in hearts of adult mice. As RISP protein decreased, heart mitochondrial function declined, and glucose utilization increased. Simultaneously, they underwent hyperplastic remodeling during which cardiomyocyte number doubled without cellular hypertrophy. Cellular energy supply was preserved, AMPK activation was absent, and mTOR activation was evident.

In ischemic hearts with RISP deletion, new cardiomyocytes migrated into the infarcted region, suggesting the potential for therapeutic cardiac regeneration. RNA-seq revealed upregulation of genes associated with cardiac development and proliferation. Metabolomic analysis revealed a decrease in alpha-ketoglutarate (required for TET-mediated demethylation) and an increase in S-adenosylmethionine (required for methyltransferase activity). Analysis revealed an increase in methylated CpGs near gene transcriptional start sites. Genes that were both differentially expressed and differentially methylated were linked to upregulated cardiac developmental pathways.

We conclude that decreased mitochondrial function and increased glucose utilization can restore mitotic capacity in adult cardiomyocytes resulting in the generation of new heart cells, potentially through the modification of substrates that regulate epigenetic modification of genes required for proliferation.

Link: https://doi.org/10.1172/JCI165482

This popular science article notes the progress of a small molecule treatment that provokes growth of dendritic spines in neurons, helping to restore lost synaptic connections. The company plans to treat amyotrophic lateral sclerosis (ALS) patients, but it is an interesting question as to whether it is would be desirable to undergo this sort of boosted formation of synapses in the broader context of aging and dysfunction of neuromuscular junctions. Since the therapy has passed an initial test of safety in volunteers, we will no doubt find out in time.

Amyotrophic lateral sclerosis (ALS) affects nerve cells in the brain and spinal cord, called motor neurons, that control voluntary muscle movements like walking, talking, and breathing. As the neurons die and can't send messages to the muscles, loss of muscle control worsens over time and is eventually fatal. Spinogenix, a clinical-stage biopharmaceutical company, has developed SPG302, a unique once-a-day pill that regenerates the gaps, called synapses, between neurons to restore communication. Following promising results from clinical trials to evaluate the drug's safety, the FDA has approved the company's Investigational New Drug (IND) application, paving the way for further trials.

SPG302's early-stage clinical trials in Australia with healthy adults demonstrated that it's well-tolerated and produces therapeutic levels that match the results seen in preclinical animal models. Spinogenix started dosing ALS patients in April 2024 and has received significant interest from people wanting to enroll in the trial.

Link: https://newatlas.com/medical/als-regenerative-pill-clinical-trials/

To what degree is Alzheimer's disease driven by immune system aging and consequent dysfunction? The evidence is compelling for increased inflammatory behavior in microglia, innate immune cells of the brain, to be important in neurodegenerative conditions. The state of inflammation in the brain can be driven by inflammatory signaling from the body as well as by mechanisms local to the brain. For example, senescent cells in the aged body produce inflammatory signals that circulate to affect every tissue. It is the overall burden that matters, not just local excesses.

Many issues in the aged immune system arise in the bone marrow, due to changes in the production of immune cells, or damage to the systems of production. In today's open access paper, researchers show that transplanting bone marrow from young donors mice into aged Alzheimer's model mice, in order to restore a more youthful production of immune cells, acts to reduce pathology in the brain. Inflammation is reduced and circulating monocytes in the bloodstream outside the brain become more efficient at clearance of the amyloid-β associated with Alzheimer's disease and this mouse model. The burden of amyloid-β in the brain is also reduced.

While inflammation is important to Alzheimer's disease pathology, this data suggests that the effect noted here is associated with the dynamic equilibrium between amyloid-β in the brain versus the body. Other groups have demonstrated, in human trials even, that reducing amyloid-β outside the brain leads to a reduction within the brain, validating the peripheral sink hypothesis.

Rejuvenation of peripheral immune cells attenuates Alzheimer's disease-like pathologies and behavioral deficits in a mouse model

The aged immune system experiences a decline in the production of immune cells, a reduction in immune repertoire diversity, and an increase in dysfunctional immune cells. These changes are collectively referred to as immunosenescence, which not only plays a causal role in driving systemic aging, including brain aging, but also contributes to an increased susceptibility to age-related diseases such as Alzheimer's disease (AD). Therefore, rejuvenating aged immune cells represents a potential therapeutic strategy for AD.

Therefore, the objective of this study was to investigate the potential of immune rejuvenation as a therapeutic strategy for AD. To achieve this, the immune systems of aged APP/PS1 mice were rejuvenated through young bone marrow transplantation (BMT). Single-cell RNA sequencing revealed that young BMT restored the expression of aging- and AD-related genes in multiple cell types within blood immune cells.

The level of circulating senescence-associated secretory phenotype proteins was decreased following young BMT. Notably, young BMT resulted in a significant reduction in cerebral amyloid-β (Aβ) plaque burden, neuronal degeneration, neuroinflammation, and improvement of behavioral deficits in aged APP/PS1 mice. The ameliorated cerebral amyloidosis was associated with an enhanced Aβ clearance of peripheral monocytes. In conclusion, our study provides evidence that immune system rejuvenation represents a promising therapeutic approach for AD.

Over the past decade, researchers have put a great deal of effort into automating and otherwise reducing the costs of studies of aging in nematode worms. A properly equipped team can now screen thousands of compounds in a year in nematodes, while obtaining good data on life span and pace of decline with age via a range of metrics. Sadly, short-lived species such as nematodes have life spans that are far more plastic in response to interventions than is the case for longer-lived species such as our own. A 10-20% increase in nematode life span is likely irrelevant to humans; some interventions that probably do little in humans have increased nematode life span by 100% or more. It is worth bearing this in mind when reading papers such as the one noted here.

There is increasing interest in the concept of aging as a druggable target to prevent age-related diseases. However, developing new drugs to address human aging presents challenges in conducting clinical trials. In the absence of validated risk biomarkers, a large and initially healthy population would need to be treated over an extended period, making it difficult to conduct trials. Therefore, repurposing existing drugs with a good safety profile is a more practical short-term solution than developing new drugs.

Naltrexone is a prescription medication approved by the US Food and Drug Administration (FDA) in 1984 for the treatment of alcohol use disorder and opioid use disorder. It belongs to a class of drugs called opioid antagonists. In recent years, there have been several significant findings regarding a specific dosage of naltrexone called low-dose naltrexone (LDN). LDN has been shown to have immune-modulating properties that could reduce various oncogenic and inflammatory autoimmune processes and alleviate symptoms of certain mental ailments.

Here, we studied the potential benefits of low-dose naltrexone (LDN) in promoting healthy aging using Caenorhabditis elegans as a model organism. We found that LDN treatment extended both healthspan and lifespan in worms, while high-dose naltrexone did not produce the same effects. Further metabolomics analysis revealed that LDN treatment induced metabolic changes that led to increased activity of both amino acid and glucose metabolism, but the longevity effect was independent of the DAF-16/FOXO3 signaling.

We then tested various mutant strains and found that the lifespan extension induced by LDN treatment was dependent on the SKN-1/NRF2 transcription factor. We also observed that LDN treatment not only increased the expression of innate immune genes but also upregulated the oxidative stress response, in line with a role for SKN-1/NRF2 in LDN's lifespan promoting effects. Inhibiting the nuclear translocation of SKN-1 from the cytosol could attenuate the LDN-mediated innate immune gene expression and oxidative stress response. Overall, our study highlights the potential of LDN as a therapeutic agent for promoting healthy aging and identifies its mechanism of action.

Link: https://doi.org/10.1016/j.isci.2024.109949

Researchers here note some interesting findings when mapping age-related changes in the levels of lipid metabolites present in tissues in mice. This is a starting point on the road to finding novel aspects of aging that might be addressed. The researchers focus down on changes related to lipids produced in the gut microbiome. It is presently known that the gut microbiome is influential in health and pace of aging, and that the relative population sizes of microbial species undergo harmful changes with age. While some inroads have been made, a complete map of specific problematic changes has yet to be produced; here researchers have found another point of entry to that mapping process.

Lipids, often in the form of fats or oils, are essential molecules for storing energy in our bodies, among other things. In addition, lipids act as signaling molecules and as components of cell membranes. Metabolism - the breakdown of biomolecules such as lipids and sugars into their component parts - slows down as we age, which helps explain why it's easier to gain weight, and more difficult to lose it, as we get older. Although this has been known for over 50 years, how changes in lipid metabolism in particular affects lifespan and health remain unclear. Before this question can be fully answered, we need to know what the actual changes are, in great detail. Only then can scientists begin looking for links between aging lipid metabolism and human health. Toward this end, researchers used mice to develop an atlas of age-related changes in lipid metabolites.

By using a cutting-edge technique to take multiple snapshots of the mouse lipidome - all lipid metabolites present in a biological sample - the researchers found that bis (monoacylglycero) phosphate (BMP) type lipids increased with age in the kidneys, liver, lungs, muscles, spleen, and small intestine of the mice. These lipids play key roles in cholesterol transport and the breakdown of biomolecules within cellular recycling centers called lysosomes. Age-related lysosomal damage might result in cells making more BMPs, which could lead to further metabolic changes, such as increasing cholesterol derivatives in the kidney.

The researchers also investigated the impact of gut bacteria on the lipidome, discovering that while gut bacteria produced many structurally unique lipids, only sulfonolipids increased with age in the liver, kidney, and spleen. In fact, no other group of lipid metabolites from gut bacteria were even detected in these peripheral tissues. "As this kind of lipid is known to be involved in regulating immune responses, the next phase of our research will involve testing the gut bacteria-derived sulfonolipids to determine their structure and physiological functions."

Link: https://www.eurekalert.org/news-releases/1046823

The aging of the cardiovascular system contributes to the aging of the brain. As the authors of today's open access review paper note, the relationship isn't straightforward and is mediated by a range of mechanisms that are far less direct than the pressure damage caused by hypertension, or the consequences of a reduced blood supply to the brain. One thing to consider about this relationship is that some fraction of cardiovascular disease in the wealthier regions of the world appears to be self-inflicted. Hunter-gatherers such as the Tismane exhibit little cardiovascular disease. To the degree that the brain declines because the vasculature declines, these populations are likely to also exhibit a lower incidence of dementia.

To restate in a more applicable way, maintaining the level of trim physical fitness needed to run an antelope to exhaustion every so often, and keeping that up into later life, is both possible and beneficial. Those of us seduced into an unhealthy lifestyle of excess fat and little exercise by the modern reality of cheap calories and readily available engines of transport are paying the price, slowly over time, and have charted a course for a worse old age with a greater level of cognitive decline.

Cardiovascular Disease and Alzheimer's Disease: The Heart-Brain Axis

A plethora of shared pathophysiological processes link the cardiovascular and the cerebrovascular system forming the heart-brain axis. Abnormalities in the heart-brain axis are likely associated with the incidence of cardiovascular disease (CVD) and Alzheimer's disease (AD), two of the leading aging-related chronic diseases. The precise mechanisms and molecular processes that modulate the heart-brain axis remain elusive. However, there are several common CVD risk factors that are increasingly linked with AD dementia and AD-related dementia incidence.

The links between CVD and AD have been confirmed in observational cohorts as well as experimental data. Although the pathophysiologic mechanisms for AD have not been fully elucidated, studies link AD with CVD manifested by hypertension and intracranial and extracranial atherosclerosis and arteriosclerosis. Both AD and CVD are progressive diseases with decades-long incubation periods before clinical manifestation. Although aging is the greatest risk factor, AD and CVD also share several modifiable risk factors, such as smoking, lack of physical exercise, hyperlipidemia, and hypertension. Furthermore, recent studies have suggested that subclinical CVD in midlife may be associated with incidence of dementia, including AD dementia, in late life.

Atherosclerosis is the deposition of fibrofatty lesions in the arterial walls, and arteriosclerosis is the stiffening of the media of the arterial wall as a result of degeneration of connective tissue, particularly elastin. Although both atherosclerosis and arteriosclerosis commonly occur together, they are thought to have differing causes and classical risk factors. The pathogenesis of atherosclerosis is centralized to the collection of lipoproteins (mainly low-density lipoprotein particles in the subendothelial intima). The smaller and cholesterol enriched lipoprotein particles easily cross the arterial wall and undergo modification via oxidation, acetylation, and aggregation. These modifications allow an easier capture by macrophages and smooth muscle cells, which then form foam cells inducing an inflammatory cascade response.

How exactly does atherosclerosis or arteriosclerosis lead to AD or AD-related dementias independently of ischemic brain lesions or neurodegenerative pathology? Atherosclerosis could contribute to brain dysfunction and axonal damage by a subtle reduction in microvascular perfusion without causing overt ischemic lesions. Blood-flow-independent aspects of neurovascular function, such as blood-brain barrier permeability, neurotrophic support by endothelial cells or neuroimmune modulation, could also be involved. Clinical events in arteriosclerosis are postulated to be secondary to the systolic hypertension that results from aortic stiffening as well as other adverse hemodynamic effects.

Arteriosclerosis, marked by measures of pulse wave velocity (among others), is associated with cognitive impairment. The brain, which is both a high flow and low impedance organ, is susceptible to damage from increased pulse pressures. Increased pulse pressure is also associated with cerebrospinal fluid amyloid-β (Aβ) and tau levels. Hypertension, a primary factor in arteriosclerosis formation, is associated with in vivo measures of Aβ deposition and Aβ interacts with vascular risk factors to increase cortical thinning.

Researchers here note that specific species in the gut microbiome react to some forms of hyaluronic acid by increasing production of a metabolite that reduces inflammation in the body. This is likely one of many such discoveries waiting to be made, as researchers attempt to uncover specific mechanisms by which the gut microbiome can affect health. It remains the case that short-cuts exist for those who don't want to wait on a more complete understanding of these mechanisms. For example, resetting an aged gut microbiome to a more youthful configuration via fecal microbiota transplantation from a healthy young donor is one way to bypass a lack of specific knowledge as to what exactly has become less optimal in the aged gut microbiome.

In this study, the research team focused on investigating the effect of hyaluronic acid with various molecular weights. Utilizing a combination of multi-model and multi-omics technologies, the researchers established that hyaluronic acid with a specific molecular weight (300-400 kDa) can significantly mitigate inflammatory responses in mice. This effect is dependent on gut Bacteroides thetaiotaomicron and Bacteroides caccae, along with their crucial metabolite - myristic acid.

The research team found that hyaluronic acid stimulates Bacteroides to produce myristic acid, which in turn inhibits the NF-κB signaling pathway, thereby reducing cellular inflammation. This study identified the optimal molecular weight range of hyaluronic acid to improve host inflammation, elucidated the material basis and molecular mechanisms of gut effect strains, provided biomarkers for dietary polysaccharide strategies to alleviate host inflammation, and offered new strategies and insights for the efficient screening of microbiota-directed foods.

Link: https://www.eurekalert.org/news-releases/1045913

Non-healing wounds are a feature of aging and inflammatory metabolic diseases such as type 2 diabetes. To some meaningful degree these injuries are the result of dysfunction in the immune system, and thus strategies targeting the behavior of immune cells might prove to be useful, particularly if resolving excessive inflammatory signaling. The paper noted here focuses on the use of biomaterials, such as the scaffolding currently used in the development of cell therapies and tissue engineering approaches, to achieve this goal of immunomodulation.

Understanding the immune response in the context of chronic wound healing can inspire innovative strategies to enhance the efficacy of therapies by modulating immune cell behaviors. Thus, advances in this field require the convergence of multiple disciplines, including immunology, skin cell biology, biomaterial science, chemistry, and nanotechnology. Delving into the nuances of chronic wound healing from an immunology viewpoint reveals the complex interplay of the different immune cell types and their interactions between them and the extracellular matrix (ECM). By deciphering the dynamics of immune cell wound recruitment and leave and also the leucocyte polarization, we can devise strategies to optimize the healing process, minimizing inflammation and scarring, and also reducing the risk of infection.

Biomaterials, with their versatility, provide a platform for finely controlling immune cell behaviors. Thus, by carefully modulating their surface moieties, tuning their physical properties and combining them with bioactive agents or living entities, such as mesenchymal stem cells (MSCs), we can design therapies that can actively modulate the immune system. These modifications have been demonstrated to successfully facilitate different immune cells recruitment - polymorphonuclear neutrophils (PMNs), monocytes, macrophages, and lymphocytes - and activate and polarize macrophage and lymphocyte phenotypes.

Nonetheless, current research endeavors have primarily focused on understanding the behavior of macrophages, leaving a notable gap in the comprehension of the responses and interactions exhibited by mastocytes, lymphocytes, PMNs, and innate lymphoid cells (ILCs) in the context of varying biomaterial properties. In this regard, further investigation is needed to comprehensively understand the diverse immune responses elicited by biomaterial-based strategies, aiming to devise multifunctional therapeutic strategies for a precise modulation of distinct immune cell types.

Link: https://doi.org/10.1016/j.addr.2024.115342

SGLT2 inhibitors are a class of diabetes medication that falls within the broad present enthusiasm for pharmacological treatments that can reduce weight in obese individuals. In today's open access paper, researchers demonstrate that the SGLT2 inhibitor canagliflozin reduces the burden of senescent cells in obese mice fed a high fat diet. The researchers identify the mechanism as an increase in the efficiency with which immune cells clear senescent cells from tissues.

It is known that being overweight, specifically meaning a greater burden of metabolically active, inflammatory visceral fat tissue, increases the pace at which senescent cells accumulate. The consequent greater burden of senescent cells may contribute meaningfully to many of the negative consequences of visceral fat and excess weight. Given that cellular senescence is a hallmark of aging, it may be reasonable to say that being overweight accelerates aging.

However, it may well be the case that the senolytic effects of SGLT2 inhibitors will not occur to any great degree outside the context of obesity, a high fat diet, and their disruptions to normal metabolism. One would certainly want to see studies in aged mice of a normal weight before becoming too enthusiastic. While there is considerable interest in mining the panoply of diabetes drugs for compounds that might modestly slow aging, it remains to be seen as to whether benefits observed in overweight individuals with metabolic syndrome will also occur in individuals of normal weight and metabolism to any meaningful degree. One might suspect not, given the animal data.

SGLT2 inhibition eliminates senescent cells and alleviates pathological aging

It has been reported that accumulation of senescent cells in various tissues contributes to pathological aging and that elimination of senescent cells (senolysis) improves age-associated pathologies. Here, we demonstrate that inhibition of sodium-glucose co-transporter 2 (SGLT2) enhances clearance of senescent cells, thereby ameliorating age-associated phenotypic changes.

In a mouse model of dietary obesity, short-term treatment with the SGLT2 inhibitor canagliflozin reduced the senescence load in visceral adipose tissue and improved adipose tissue inflammation and metabolic dysfunction, but normalization of plasma glucose by insulin treatment had no effect on senescent cells. Canagliflozin extended the lifespan of mice with premature aging even when treatment was started in middle age.

Metabolomic analyses revealed that short-term treatment with canagliflozin upregulated 5-aminoimidazole-4-carboxamide-1-β-d-ribofuranoside (AICAR), a metabolite well known to activate AMP-activated protein kinase (AMPK), enhancing immune-mediated clearance of senescent cells by downregulating expression of programmed cell death-ligand 1 (PD-L1). These findings suggest that inhibition of SGLT2 has an indirect senolytic effect by enhancing endogenous immunosurveillance of senescent cells.

A number of lines of evidence point to decreased fluid drainage from the brain into the body with aging. This drainage occurs through pathways such as the cribriform plate behind the nose and the comparatively recently discovered glymphatic system. Both of these fluid pathways are known to become dysfunctional with age. It is thought that the reduced drainage has a negative impact on the brain by allowing metabolic waste products to build up, such as the various forms of disruptive protein aggregates associated with neurodegenerative conditions.

Physiological age-related alterations in the interstitial flow in the brain, which plays an important role in waste product removal, remain unclear. Using [15O]H2O positron emission tomography (PET), water dynamics were evaluated in 63 healthy adult participants aged between 20 and 80 years. Interstitial flow was assessed by influx ratio (IR) and drain rate (DR), using time-activity concentration data.

Participants were divided into four age groups with 15-year ranges, to evaluate age-related functional alterations. At least one of the indices declined significantly with age across all groups. A significant linear negative correlation between age and both indicators was found in the scatter plots; both indicators were predominantly lower after age 50 years. These results suggest interstitial flow decreases with age, especially after 50 years. These important findings can contribute to devising therapeutic interventions for neurological diseases characterized by abnormal accumulation of waste products, and suggest the need for taking measures to maintain interstitial flow starting around the age of 50 years.

Link: https://doi.org/10.1016/j.neurobiolaging.2024.05.006

At this point it seems an impossible task to write a review paper covering what is known of aging and avenues to treat aging as a medical condition. The only way forward is to do what the authors did here, which is to leave out nearly everything. Just focus on the high points, the areas of greatest study, to sketch an outline of a field in which, I would say, all of the truly transformative work is taking place in smaller programs, beneath the radar, less widely discussed, but poised to reshape the field of medicine.

The physiological characteristics of aging summarised in this article gradually accumulate over time and contribute to the aging process. Notably, antagonism of an organism's response to the characteristics of aging also plays a subtle role in the aging process. When the cumulative damage caused by primary and antagonistic markers is no longer compensated for by the complex markers of aging, it means that the rate of aging is accelerated. Furthermore, senescence also relies on the integration of cell-autonomous and non-cell-autonomous mechanisms, and mechanisms that promote senescence can be transmitted between different types of organs and cells.

In conclusion, aging is a gradual and complex process of decline in physiological function, and experiments in animal models have shown that certain interventions may not only extend lifespan, but also increase healthy longevity. However, in vitro models, tissue culture studies, and in vivo animal models, which are ultimately translated into human studies, are complex and diverse, and only a few models can be used to investigate these differences. There are also significant differences between physiological and pathological aging, and the scientific problem of slowing down aging and extending the healthy lifespan of humans involves a number of challenges, including inadequate regulation, barriers to clinical validation, failure to identify more biomarkers of human aging, and the unknown challenges of introducing new interventions to the market.

It is gratifying that years of basic research in the anti-aging field have laid the foundation for explosive biotechnology and industrial applications. Using modern biological techniques, including genetic manipulation or cell-based therapies with broad implementation prospects, to focus on the discovery of physiological mechanisms and interventions underlying the aging process will greatly advance anti-aging research, delay human aging to the maximum extent, maintain human physiological functions in later years, and mitigate the surge in age-related chronic diseases.

Link: https://doi.org/10.1186/s12964-024-01663-1

Many mechanisms are thought to contribute to the age-related decline of muscle mass and strength, but there are the usual debates over which are more important, which are the primary causes, and how they relate to one another. Little of our biochemistry is as fully understood as we might like it to be, and in some senses even the very well understood regions are only sketches of a yet to be fully mapped environment. One hypothesis places degeneration of neuromuscular junctions as an early cause, leading to the other observed issues. A neuromuscular junction is the synaptic connection between a motor neuron and muscle fiber, allowing the muscle to contract. The degree to which muscles are innervated in this way appears to go a long way towards determining how well they are maintained and function.

Unfortunately, and like all complex small scale structures in the body, neuromuscular junctions are subject to the damage and disarray of aging. The expression of necessary genes changes, the surrounding signaling environment changes, nearby cell behavior changes. All of this is disruptive, leading to loss of neuromuscular junctions and a reduced ability to function where they remain more or less intact. Like all aspects of aging, researchers have yet to build a complete understanding of how exactly the identified low-level processes of aging give rise to these high-level manifestations. They have also yet to produce a complete map of the important alterations in the expression of genes in aging neuromuscular junctions, and the consequences of those alterations - but more attention is given to that layer of degenerative aging, for better or worse.

Trio preserves motor synapses and prolongs motor ability during aging

Across species, motor ability diminishes as aging progresses, and this curtailment is one of the most debilitating aspects of human aging. Concomitant with the age-dependent decline of motor ability are degenerative alterations of motor synaptic structures. These changes include the subdivision or fragmentation of neuromuscular junction (NMJ) synaptic terminals into smaller units in addition to a reduction in the size or number of terminals. These structural alterations are associated with a decline of neurotransmitter release, which may undermine motor ability during aging.

We have shown previously that Drosophila neuromuscular synapses undergo structural synaptic bouton fragmentation during aging, co-incident with the decline of motor ability. Here, investigating mechanisms that could contribute to age-dependent synaptic structural degeneration, we find that levels of Trio, an evolutionarily conserved guanine nucleotide exchange factor (GEF), decline at NMJ synapses with age. We discover that increasing Trio levels during aging has a remarkable ability to conserve synaptic structures and prevent bouton fragmentation, maintaining the capacity of synapses to sustain high intensities of neurotransmitter release and enabling a postponement of the age-dependent decline of motor ability. Enhanced Trio expression can also prevent accelerated synaptic structural degeneration induced by loss of miniature neurotransmission.

Our results support a paradigm where the structural dissolution of motor synapses precedes and promotes motor behavioral diminishment and where intervening in this process can postpone the decline of motor function during aging.

The more that researchers correlate epigenetic clock results with mortality in the context of specific interventions and lifestyle choices, the more useful those epigenetic clocks become. At present the challenge in using clocks to assess the results of any novel therapy is that it is entirely unclear as to whether the results are accurate, useful, or actionable, since there is no established connection between the epigenetic marks measured and specific underlying processes of aging. Only when someone has calibrated a clock against the use of a therapy or intervention across a large study population does it become trustworthy for that therapy or intervention. At present it is fair to say that the more modern epigenetic clocks are trustworthy when it comes to the benefits of common lifestyle choices. One interesting outcome of the study noted here is that people with high genetic risk for age-related disease benefit more from a healthy lifestyle than those with low genetic risk.

Life's Essential 8 (LE8) is an enhanced metric for cardiovascular health. The interrelations among LE8, biomarkers of aging, and disease risks are unclear. LE8 score was calculated for 5,682 Framingham Heart Study participants. We implemented 4 DNA methylation-based epigenetic age biomarkers, with older epigenetic age hypothesized to represent faster biological aging, and examined whether these biomarkers mediated the associations between the LE8 score and cardiovascular disease (CVD), CVD-specific mortality, and all-cause mortality.

We found that a 1 standard deviation increase in the LE8 score was associated with a 35% lower risk of incident CVD, a 36% lower risk of CVD-specific mortality, and a 29% lower risk of all-cause mortality. These associations were partly mediated by epigenetic age biomarkers, particularly the GrimAge and the DunedinPACE scores. The potential mediation effects by epigenetic age biomarkers tended to be more profound in participants with higher genetic risk for older epigenetic age, compared with those with lower genetic risk. For example, in participants with higher GrimAge polygenic scores (greater than median), the mean proportion of mediation was 39%, 39%, and 78% for the association of the LE8 score with incident CVD, CVD-specific mortality, and all-cause mortality, respectively. No significant mediation was observed in participants with lower GrimAge polygenic score.

DNA methylation-based epigenetic age scores mediate the associations between the LE8 score and incident CVD, CVD-specific mortality, and all-cause mortality, particularly in individuals with higher genetic predisposition for older epigenetic age.

Link: https://doi.org/10.1161/JAHA.123.032743

The major therapies aimed at lowering lipid levels in the bloodstream all derive from the discovery of human mutants who exhibit low blood lipids and a lesser burden of atherosclerosis and cardiovascular mortality. The therapies aim at recapturing some of the effects of these mutations, which inevitably means that they confer smaller benefits than possessing the mutation over the full course of life. Over time these therapies have moved from small molecule drugs to the present approach of small interfering RNA to directly inhibit expression of specific genes. ANGPLT3 is the latest target, and here note the clinical trial performance of one of the ANGPLT3 inhibition therapies presently in development. It improves on statins in its effects on blood lipids, but the experience of PCKS9 inhibitors, also an improvement over statins, demonstrates that this approach of lowering circulating lipids can only slow the progression of atherosclerotic plaque, not reduce the size of existing plaques, no matter how much blood lipids are lowered.

A small interfering RNA (siRNA) investigational therapy that inhibits a gene involved in lipoprotein metabolism has been shown in a clinical trial to significantly reduce levels of different types of cholesterol and triglycerides in individuals with mixed hyperlipidemia, a condition in which fats build up in the blood. Researchers found the RNA interference (RNAi)-based therapy zodasiran to be a potentially promising option for substantially reducing a number of atherogenic lipoproteins while requiring less frequent dosing than conventional therapies.

Zodasiran (Arrowhead Pharmaceuticals) targets a specific gene expressed in hepatocytes known as angiopoietin-like protein 3 (ANGPTL3), which plays a role in regulating levels of low-density lipoprotein (LDL), non-HDL cholesterol (a measure of all the "bad" cholesterol in the blood including LDL), and triglycerides. Various research has identified these components as increasing risk of atherosclerotic cardiovascular disease.

In the phase 2b global trial (known as ARCHES-2) of 204 participants with mixed hyperlipidemia who received zodasiran (50, 100, and 200 mg) and background therapy of standard of care medications including statins, the researchers observed substantial reductions in all lipid level parameters monitored. These included lowering triglycerides by 54 to 74 percent compared to placebo, LDL cholesterol by up to 20 percent, non-HDL cholesterol by up to 36 percent, and remnant cholesterol by 73 to 82 percent. Remnant cholesterol measures the amount of "leftover" or remnant very-low-density lipoprotein (VLDL) particles. It is measured by adding up HDL and LDL and subtracting that sum from the individual's total cholesterol. Researchers suggested that based on prior genetic studies the magnitude of remnant cholesterol reduction evidenced by zodasiran in their study could translate into a 20 percent decrease in recurrent major cardiac events.

Link: https://www.eurekalert.org/news-releases/1046191

One of the interesting points made in today's open access review paper is that there is a lack of research into the early manifestations and prevention of frailty. According to the authors, it was only recently the case that the research community established that meaningful levels of pre-frailty exist in middle-age. Further, while it is well established that resistance exercise is the best intervention for the treatment of pre-frailty and frailty at this time, the data is far less comprehensive when looking only at the question of early prevention in middle-age than, say, the evidence for statin use in atherosclerosis or other widely used pharmacological therapies.

A number of the small molecule therapies under development in the longevity industry are targeting components of frailty, particularly sarcopenia, the loss of muscle mass and strength. Some of these may be exploiting one or more of the many mechanisms making up the beneficial response to exercise, and quite likely so if the small molecules arose from unbiased screening exercises. It remains to be seen as to whether the treatments will match the benefits produced by resistance exercise. Calorie restriction mimetics perform less capably than the practice of calorie restriction, and we should probably expect the same to be true for exercise mimetics versus exercise.

Effectiveness of interventions to prevent or reverse pre-frailty and frailty in middle-aged community dwelling adults: A systematic review

While this review identified multicomponent and resistance exercise as the most effective interventions for preventing or reversing pre-frailty/frailty in 40-65-year-olds, significant evidence gaps, limited methodologies, and risk of bias were present in the literature. Previous reviews have demonstrated the benefits of resistance training in preventing or reversing pre-frailty and frailty in older adults. However, we found only one study which independently evaluated resistance training for middle-aged adults. In most instances resistance training was incorporated into multicomponent exercise programs (MEPs) making it difficult to understand the effectiveness of these interventions beyond standalone resistance training. This trend may stem from World Health Organisation (WHO) recommendations favouring multicomponent exercise for older adults. However, it's unclear if these complex interventions add sufficient benefit over resistance training alone.

Low-intensity and dynamic exercises have been shown to be less effective for preventing or reversing pre-frailty than other forms of exercise, though they do improve balance, an early frailty predictor. While these exercises benefit older adults, especially in balance, resistance training also enhances balance and offers additional benefits such as increased bone density. Nonetheless, the practicality of integrating low-intensity exercises like walking into daily routines for balance improvement shouldn't be underestimated.

There was insufficient evidence to recommend flavonoid supplementation or metformin prescription for preventing or reversing pre-frailty/frailty in middle-aged individuals. These findings are not surprising as similarly, in older adults, evidence is sparse or emerging. Unlike these less supported interventions, nutritional approaches like protein and/or creatine supplementation have strong evidence for frailty prevention/reversal in older adults. Specifically, in older adults, protein supplementation in conjunction with resistance training exercise is more effective than either intervention alone. Yet, in none of these studies was protein supplementation or any nutritional intervention included in conjunction with exercise. Considering the established benefits in older adults, future research in this younger age group is indicated.

The small number of studies in this review underscores the emerging nature of evidence for interventions targeting frailty in middle-aged adults. Notably, the high levels of detectable pre-frailty in middle age is an only recently discovered phenomenon, highlighting a research gap in this age range. The infrequent use of terms like 'pre-frailty' and 'frailty' in 40-65-year-olds suggests missed opportunities for research. Although previous studies have focused on related concepts such as functional decline or sarcopenia in older adults, their relevance to this younger group remains underexplored.

Researchers recently found that inhibition of P2Y6R in microglia prevents these innate immune cells from excessively destroying synapses in the aging brain. The removal of synapses is just as important as their creation when it comes to the function of the brain, particularly memory. But with aging this removal process becomes too aggressive, for reasons yet to be fully understood. This short commentary offers a little more discussion on the topic. Work on P2Y6R inhibition remains at an early stage, some distance from compelling evidence for it to be a good basis for therapy. We shall see where it goes.

The brain shrinks with age, accompanied by a loss of synapses and memory. We outline here recent evidence in mice that this loss is due to microglial phagocytosis of the synapses, mediated by the microglial P2Y6 receptor (P2Y6R). Brain atrophy during aging appears to be partly due to brain cells, called microglia, eating bits of neurons and the connections between neurons, called synapses. Brain shrinkage and loss of synapses correlate with age-associated memory impairment.

There is evidence in mice that aging-induced loss of synapses and memory is due to the phagocytosis (i.e. eating) of synapses by microglia. Microglial phagocytosis is regulated by several factors, including the microglial P2Y6 receptor (P2Y6R) activated by extracellular UDP (uridine diphosphate). We recently reported that microglial phagocytosis of synapses during aging is mediated by P2Y6R. Inhibition or knockout of P2Y6R reduced microglial phagocytosis of synapses and synaptic loss in co-cultures of neurons and microglia. In vivo, microglial phagocytosis of synapses was increased in the brains of aged (17 months old) wild- type mice, compared to adult (4 months old) mice, but this increase was absent in P2Y6R knockout mice. P2Y6R knockout mice also had reduced aging-associated loss of synapses and memory.

What is inducing microglial phagocytosis of the brain in aging? We do not know for sure, but some factors that accumulate with age (such as amyloid-β aggregates, tau aggregates, or excess glutamate) stress neurons such that they expose so-called "eat-me" signals (such as UDP) that induce microglia to eat the neurons. Additionally, there is a general increase in inflammation within the brain with age that activates microglia and stimulates microglial phagocytosis, in part by the release of 'opsonins', such as complement factors C1q and C3, that bind to neurons and synapses, inducing microglia to phagocytose them. UDP activation of P2Y6R induces the engulfment phase of microglial phagocytosis, and expression of the receptor is increased by inflammation, while excitation of neurons and stress of other cells induces UDP release.

Link: https://doi.org/10.18632/aging.205887

Here find a study assessing whether or not high intensity exercise can have transient senolytic effects, at least based on using P16 as a marker of senescence. The effects seem to be transient, but the underlying biochemistry might be of interest for the production of more lasting senolytic therapies. As a caution, there is some thought that this marker can also represent non-senescent populations of macrophages. Given the role of these innate immune cells in the muscle tissue response to small-scale damage resulting from high intensity exercise, a part of the overall beneficial response, one might want to see other measures of the burden of cellular senescence in addition to P16.

Higher intensity exercise, despite causing more tissue damage, improved aging conditions. We previously observed decreased p16INK4a mRNA in human skeletal muscle after high-intensity interval exercise (HIIE), with no change following equivalent work in moderate-intensity continuous exercise. This raises the question of whether the observed senolytic effect of exercise is mediated by inflammation, an immune response induced by muscle damage.

In this study, inflammation was blocked using a multiple dose of ibuprofen (total dose: 1200 mg), a commonly consumed nonsteroidal anti-inflammatory drug (NSAID), in a placebo-controlled, counterbalanced crossover trial. Twelve men aged 20-26 consumed ibuprofen or placebo before and after HIIE at 120% maximum aerobic power. Multiple muscle biopsies were taken for tissue analysis before and after HIIE. p16INK4a+ cells were located surrounding myofibers in muscle tissues. The maximum decrease in p16INK4a mRNA levels within muscle tissues occurred at 3 hours post-exercise (-82%), gradually recovering over the next 3-24 hours. A concurrent reduction pattern in CD11b mRNA (-87%) was also found within the same time frame. Ibuprofen treatment attenuated the post-exercise reduction in both p16INK4a mRNA and CD11b mRNA.

The strong correlation between p16INK4a mRNA and CD11b mRNA in muscle tissues suggests a connection between the markers of tissue aging and pro-inflammatory myeloid differentiation. In conclusion, our results suggest that the senolytic effect of high-intensity exercise on human skeletal muscle is mediated by acute inflammation.

Link: https://doi.org/10.18632/aging.205827

Age-related hearing loss is commonplace. It occurs due to loss of sensory hair cells in the inner ear, or due to the loss of axons connecting these cells to the brain. Evidence conflicts on which of these is the important mechanism. A good number of research programs aimed at reversing hearing loss are focused on generating more sensory hair cells, such as by reprogramming supporting cells of the inner ear to force transdifferentiation to the sensory hair cell fate. To the degree that new hair cells will forge new connections to the brain and correctly integrate into sensory processing circuits, this should fix both problems. Ensuring that this integration takes place sounds a more challenging than generating new hair cells, however.

Hearing loss correlates with a number of other aspects of aging, such as frailty, Alzheimer's disease, cognitive decline, and microstructural change in the brain. For brain aging one can at least consider that similar underlying mechanisms of neural and axonal damage are at work. For frailty, it is somewhat harder to guess at the shared cause. Similarly, researchers here note that the raised blood pressure of hypertension correlates with hearing loss, and once again it is not obvious as to where one should start looking for causation and shared mechanisms. Vascular damage is one of the evident consequences of hypertension, but it isn't clear as to how that interacts with sensory hair cells specifically.

Relationship Between Hypertension and Hearing Loss: Analysis of the Related Factors

This was a single-center population-based observational study, and clinical, biological, and hospital data were collected from the inpatient ward. In the present study, 517 patients (1034 ears) with or without hypertension were included, and the proportion of patients with hearing loss, mean pure-tone average hearing threshold, low-frequency pure-tone average hearing threshold (LFPTA), medium-frequency pure-tone average hearing threshold (MFPTA) and high-frequency pure-tone average hearing threshold (HFPTA) were evaluated. Risk factors related to hearing loss and hearing threshold were also estimated at different frequencies.

In this study, the hypertensive group exhibited more pronounced subclinical target organ damage and hearing impairment than the nonhypertensive group. Compared with the nonhypertensive group, the hypertensive group showed elevated albumin-to-creatinine ratio (ACR) levels, increased left ventricular mass index (LVMI) values, higher bilateral cardiovascular ankle index (CAVI) measurements, decreased bilateral ankle-brachial index (ABI) values, and a higher proportion of carotid intima-media thickening/plaque. Furthermore, the hypertension group demonstrated a higher prevalence of hearing loss at the mean pure-tone average hearing threshold and at individual frequencies.

Among these indicators, ABI and CAVI serve as markers of atherosclerosis and arterial stiffness, respectively, while ACR and LVMI indicate damage to the microvascular target organ in hypertension. These indicators have a significant clinical predictive value for subclinical target organ damage in hypertension. Therefore, the simultaneous appearance of hearing loss with these indicators may also be associated with early vascular damage caused by hypertension, which is consistent with previous studies. Although the exact mechanism underlying the influence of hypertension on the hearing threshold remains unclear, this study discovered that injuries to the vascular system can potentially contribute to hearing loss.

Astrocytes react to the presence of extracellular amyloid-β aggregates in the aging brain by becoming more inflammatory and clustering around the aggregates of misfolded proteins. Researchers here show that this activity crowds out the microglia responsible for ingesting and breaking down these protein aggregates. The crowding can, however, be controlled to some degree by targeting plexin-B1, allowing microglia access to conduct greater clearance of amyloid-β. This is early stage research, so it remains to be seen as to whether it will actually offer a way to make forms of anti-amyloid therapies more effective, or can be the basis for such a therapy itself.

Researchers have made a significant breakthrough in Alzheimer's disease research by identifying a novel way to potentially slow down or even halt disease progression. The study, which focuses on the role of reactive astrocytes and the plexin-B1 protein in Alzheimer's pathophysiology, provides crucial insights into brain cell communication and opens the door to innovative treatment strategies.

This groundbreaking work is centered on the downregulation of the plexin-B1 protein to enhance the brain's ability to clear amyloid plaques, a hallmark of Alzheimer's disease. Reactive astrocytes, a type of brain cell that becomes activated in response to injury or disease, were found to play a crucial role in this process. They help control the spacing around amyloid plaques, affecting how other brain cells can access and clear these harmful deposits.

Link: https://www.eurekalert.org/news-releases/1045861

Drug sales efforts and research efforts merge at the boundary. Big, flashy, confirming trials of hot new drugs with already proven effects are more readily funded for all of the obvious reasons, primarily that the expected good results will help to sell more drugs. The hot new drugs of the past few years are GLP-1 receptor agonists, the first well-backed pharmaceutical answer to the widespread prevalence of obesity and its harmful consequences to health and longevity. The beneficial effects of losing excess weight (and specifically excess visceral fat tissue) are broad and sizable. Those who sell GLP-1 receptor agonists such as semaglutide are the first to lay these benefits at the feet of their drugs instead of loss of weight. As an example, the publicity materials noted here make no mention of weight loss whatsoever.

The FLOW (Evaluate Renal Function with Semaglutide Once Weekly) study is a double-blind, randomised, placebo-controlled international trial comprising 3,533 patients, with a median follow-up period of 3.4 years. The trial was designed to assess the efficacy and safety of semaglutide, a once-weekly subcutaneous glucagon-like peptide 1 (GLP-1) receptor agonist, in preventing major kidney outcomes, specifically kidney failure, substantial loss of kidney function, and death from kidney or cardiovascular causes, in individuals with type 2 diabetes and chronic kidney disease. Patients either received semaglutide 1.0 mg once weekly or placebo.

Participants who received semaglutide had a 24% risk reduction for the composite primary endpoint, including kidney outcomes and death due to cardiovascular and kidney causes, compared to those who received placebo. This reduction risk was consistent across both kidney-specific and cardiovascular death outcomes. Secondary endpoints also showed significant improvements with semaglutide. Specifically, the total estimated glomerular filtration rate (eGFR) slope was 1.16 ml/min/1.73m2/year slower, the risk of major cardiovascular events was decreased by 18%, and the risk of all-cause mortality was reduced by 20%. This evidence of efficacy, combined with fewer serious adverse events in the semaglutide group, offers hope to millions of patients globally who face the daunting prospect of chronic kidney disease and type 2 diabetes, and their related complications.

Link: https://www.eurekalert.org/news-releases/1045452