Fight Aging!

The Targeting Aging with Metformin (TAME) clinical trial has been a feature of the divide between regulators, researchers, and industry in the matter of treating aging as a medical condition for as about as long as the longevity industry has existed. Regulators such as the FDA do not consider aging to be a disease, and they only approve treatments for specific diseases, largely using the World Health Organization's International Classification of Diseases as the basis for what is and is not a disease. The TAME trial came into being as a way to convince the FDA to approve a treatment on the basis of endpoints that approximated aging, rather than a disease.

In that sense the heavy lifting has been accomplished: the FDA indeed agreed with the TAME trial design, and so in principle anyone else with deep pockets could now adopt the same approach if they wanted to stand behind a treatment for aging. The biotech industry and those who fund it are highly conservative, however. Companies working on therapies that can in principle slow or reverse aspects of aging have all chosen to pick one or more specific age-related diseases, and quietly plan for off-label use following approval, as it is unlikely that they could otherwise have convinced investors to back their clinical and regulatory development.

As today's popular science article notes, the TAME trial remains incompletely funded. This, I suspect is the case in large part because metformin is a poor choice of treatment. It was selected because it is so very widely used, for so long, and with such an abundance of safety data, that the FDA could not possibly object on those grounds. Hindsight is 20/20, but rapamycin would have been a much better choice. The evidence for metformin to slow aging is not great. The animal data is mixed, to say the least, and the human data from studies of type 2 diabetes patients has a great many issues. Rapamycin more clearly slows aging, the animal data is robust, and human evidence shows minimal to no side-effects at the dose for anti-aging use. Still, here we are: it remains unclear as to whether the TAME trial will be completed, or be overtaken by events. The evolution of regulation with regards to the treatment of aging will likely shift to a battle over widespread off-label use as the first longevity industry therapies are approved for specific disease.

A cheap drug may slow down aging. A study will determine if it works

Metformin was first used to treat diabetes in the 1950s in France. The FDA approved metformin for the treatment of type 2 diabetes in the U.S. in the 1990s. Since then, researchers have documented several surprises, including a reduced risk of cancer. As promising as this sounds, most of the evidence is observational, pointing only to an association between metformin and the reduced risk. The evidence stops short of proving cause and effect. Also, it's unknown if the benefits documented in people with diabetes will also reduce the risk of age-related diseases in healthy, older adults.

Back in 2015, a bunch of aging researchers began pushing for a clinical trial. "A bunch of us went to the FDA to ask them to approve a trial for metformin, and the agency was receptive. If you could help prevent multiple problems at the same time, like we think metformin may do, then that's almost the ultimate in preventative medicine." The aim is to enroll 3,000 people between the ages of 65 and 79 for a six-year trial. But it's been slow going to get it funded. "The main obstacle with funding this study is that metformin is a generic drug, so no pharmaceutical company is standing to make money."

Researchers have turned to philanthropists and foundations, and has some pledges. The National Institute on Aging, part of the National Institutes of Health, set aside about $5 million for the research, but that's not enough to pay for the study which is estimated to cost between $45 and $70 million. The frustration over the lack of funding is that if the trial points to protective effects, millions of people could benefit. Currently the FDA doesn't recognize aging as a disease to treat, but the researchers hope this would usher in a paradigm shift - from treating each age-related medical condition separately, to treating these conditions together, by targeting aging itself.

This open access review paper covers the high points of what is presently known of the contribution of senescent cells to neurodegenerative conditions. Somatic cells become senescent throughout life, largely as they reach the Hayflick limit to replication, but also due to damage or a toxic local environment. Senescent cells halt replication and begin to secrete pro-inflammatory signals to attract the immune system. In youth, senescent cells are rapidly cleared by programmed cell death or by immune cells. With age, the immune system becomes less efficient. As a consequence senescent cells begin to accumulate, and they help to generate a state of chronic inflammation and tissue dysfunction, contributing to the onset and progression of age-related disease.

Cellular senescence is a ubiquitous process and is a state of irreversible cell cycle arrest, induced by a variety of cellular stimuli such as DNA damage, telomere shortening/dysfunction, oncogenic activation and chromatin disruption. Cellular senescence limits the replicative lifespan of cells and contributes to aging and age-related diseases. Senescent cells resist apoptosis and secrete persistent pro-inflammatory signals that are fatal to neighboring cells.

Neurodegenerative disease are characterized by chronic, progressive and pathological changes in the brain, such as neuronal death, abnormal aggregation of proteins and inflammation. Recent evidences suggest that the pathological changes in the neurodegenerative disease begins much ahead of the actual appearance of the symptoms. Prolonged exposure to stress such as DNA damage may induce cellular senescence and contribute to the pathogenesis of the disease by altering metabolism and affecting gene expression.

Alzheimer's disease accumulates toxic protein aggregates in the brain, including amyloid-beta plaques and tau tangles. Recent studies have shown that cellular senescence plays a role in developing and accumulating these toxic protein aggregates. As evidenced by increased SA-β-gal expression, p53 expression, a mediator of cellular senescence, an increase in the release of senescence-associated secretory phenotype (SASP) components, DNA damage, telomere attrition or damage, and senescence-like morphological changes, increased senescence is found in various cell types of Alzheimer's disease brains, including astrocytes, microglia, and neurons. In 2018 researchers found that cellular senescence is associated with tau protein aggregation in the brain. The researchers combined genomic analysis with pharmacological interventions to induce senescence in neurons, which led to increased tau aggregation and neuronal dysfunction. Conversely, clearance of senescent cells reduced tau-dependent pathology.

Parkinson's disease (PD) is the most common movement disorder and the second most prevalent neurodegenerative disease after Alzheimer's disease. Pre-symptomatic midbrain inflammation plays a crucial role in the pathology of PD. Cellular senescence triggers a pro-inflammatory response, the SASP, so senescence and SASP together are a strong contributing factor in the pathophysiology of PD. The dopaminergic (DA) neurons in PD has been noted to express various senescence markers. Neuronal senescence has also been recognized to contribute to the "inflammaging" seen in PD. In a recent study, it was found that α-synuclein (α-syn) aggregates triggers stress induced premature senescence in PD models. α-syn preformed fibrils triggers cellular senescence in astrocytes and microglia and leads to their activation. Overactivation of microglia has been detected in PD patients. Microglia when activated produce inflammatory products which might contribute to the dopaminergic neuronal death in PD patients.

Link: https://doi.org/10.3389/fragi.2023.1292053

There is a bidirectional relationship between declining kidney function and raised blood pressure, two prominent features of aging. The kidney is responsible for managing blood volume (one contribution to blood pressure) by adjusting the amount of water in blood as the bloodstream is filtered, a process that depends on some combination of the sensing of soluble factors and pressure. These complex systems fail with age in ways that can lead to raised blood pressure. Raised blood pressure in turn can damage the kidney directly, but also indirectly disrupt the balance of blood pressure control systems elsewhere in the body, such as via the constriction and dilation of blood vessels, or heart rate, that interact with those of the kidney via signaling molecules. It is a complex set of feedback loops, well-balanced in youth, but prone to damage that can cause a spiral into ever high blood pressure with advancing age.

Cardiovascular diseases affect kidney function. The aim of this study was to investigate the possible associations between hemodynamic parameters and change in kidney function in individuals aged 75 years and older. Data on hemodynamics and blood and urine samples were collected at baseline and during one-year visits. Hemodynamics were split into two groups based on median values. Changes in the estimated glomerular filtration rate (eGFR) were investigated between low and high groups for each hemodynamic parameter using analysis of variance. Changes in the albumin-creatinine ratio (ACR) were examined as binary outcomes (large increase vs. stable) using logistic regression.

The study population consisted of 252 participants. Participants in the high central systolic blood pressure (cSBP) group had a greater decline in eGFR than participants in the low cSBP group (-6.3% vs. -2.7%). Participants in the high aortic pulse wave velocity (aPWV) group, indicative of greater arterial stiffness, had a greater decline in eGFR than those in the low aPWV group (-6.8% vs. -2.5%). Other hemodynamic parameters were not associated with eGFR changes.

In conclusion, we found that elevated central aortic stiffness is associated with a greater decline in kidney function in old age. Since aPWV and cSBP both appear to be predictors of eGFR decline, it might be of interest to identify older individuals with elevated aortic stiffness. In this specific population, intensive blood pressure reduction might be justified in order to slow down the process of vascular aging and prevent kidney function decline.

Link: https://doi.org/10.3390/jcm13051334

It is well known that metabolic dysfunction and cardiovascular disease correlate well with an accelerated onset and progression of neurodegenerative conditions. This is particularly evident when considering these conditions in the context of obesity. Age-related diseases are the late stage consequences of a progressive accumulation of cell and tissue damage, and so a lifestyle that accelerates those underlying damage processes will produce a greater incidence of all of the common age-related diseases. Suffering from one form of age-related disease thus implies greater odds of suffering other forms of age-related disease, as they all descend from the same roots.

As demonstrated in today's open access paper, it isn't just the end result of outright dementia that correlates with the presence of other forms of age-relate disease. Suffering from metabolic or cardiovascular disease clearly correlates with the earlier stages of brain aging as well, such as cognitive decline, measures of brain volume, and the presence of small white matter hyperintensities that result from ruptured capillaries in brain tissue. Some of these harms derive from the underlying forms of damage that cause age-related disease, others are downstream of vascular aging or the inflammation of metabolic disease, others are a mix.

Cardiometabolic disease, cognitive decline, and brain structure in middle and older age

Cardiometabolic diseases (CMDs), a cluster of related conditions including type 2 diabetes (T2D), heart disease (HD), and stroke, are well-established individual risk factors for cognitive/brain aging and dementia. Cardiometabolic multimorbidity - the coexistence of ≥ 2 CMDs in the same individual - has risen greatly with population aging and is estimated to affect up to 30% of older adults. Recent studies have described a dose-dependent increase in dementia risk with one, two, and three co-morbid CMDs. However, less is known about the combined influence of CMDs on the subtle cognitive decline and brain structural changes that can occur in the decades before dementia diagnosis.

Brain magnetic resonance imaging (MRI) studies have linked cardiometabolic multimorbidity and unfavorable cardiovascular risk profiles to lower volumes of subcortical structures and poorer white matter microstructural integrity in older age. Moreover, recent studies suggest that cardiovascular and metabolic risk factors could be associated with vascular lesions already in middle age. However, evidence is lacking on the relationship between cardiometabolic multimorbidity and brain structure at different stages of life.

In the present study, using longitudinal data from adults that were middle-aged, younger than 60 years, as well as individuals older than 60 years in the UK Biobank, we aimed to (1) assess the association between cardiometabolic multimorbidity and changes in global and domain-specific cognitive function and (2) identify the brain regions that are possibly associated with cardiometabolic multimorbidity in middle and older age. 46,562 dementia-free UK Biobank participants completed a cognitive test battery at baseline and a follow-up visit 9 years later, at which point 39,306 also underwent brain magnetic resonance imaging. CMDs were ascertained from medical records.

A higher number of CMDs was associated with significantly steeper global cognitive decline in the older but not middle aged cohort. Additionally, the presence of multiple CMDs was related to smaller total brain volume, gray matter volume, white matter volume, hippocampal volume, and larger white matter hyperintensity volume, even in middle age. Thus CMDs are associated with cognitive decline in older age and worse brain structural health beginning already in middle age.

There has long been a school of thought on Alzheimer's disease that consideres it a form of diabetes, in which dysregulated glucose metabolism features prominently. This dysregulation certainly occurs; the study noted here isn't the only one to show that the aging brain no longer manages glucose adequately. The question is whether this mechanism is important relative to all of the other processes thought to contribute to the pathology of Alzheimer's disease and other neurodegenerative conditions, and where it fits in a chain of cause and consequence. Finding ways to demonstrate the relative importance of different mechanisms remains the primary challenge in developing a sufficient understanding of aging and age-related disease to make rapid progress towards effective therapies.

Defective brain glucose utilization is a hallmark of Alzheimer's disease (AD) while Type II diabetes and elevated blood glucose escalate the risk for AD in later life. Isolating contributions of normal aging from coincident metabolic or brain diseases could lead to refined approaches to manage specific health risks and optimize treatments targeted to susceptible older individuals.

We evaluated metabolic, neuroendocrine, and neurobiological differences between young adult (6 months) and aged (24 months) male rats. Compared to young adults, blood glucose was significantly greater in aged rats at the start of the dark phase of the day but not during the light phase. When challenged with physical restraint, a potent stressor, aged rats effected no change in blood glucose whereas blood glucose increased in young adults. Tissues were evaluated for markers of oxidative phosphorylation (OXPHOS), neuronal glucose transport, and synapses.

Outright differences in protein levels between age groups were not evident, but circadian blood glucose was inversely related to OXPHOS proteins in hippocampal synaptosomes, independent of age. The neuronal glucose transporter, GLUT3, was positively associated with circadian blood glucose in young adults whereas aged rats tended to show the opposite trend. Our data demonstrate aging increases daily fluctuations in blood glucose and, at the level of individual differences, negatively associates with proteins related to synaptic OXPHOS. Our findings imply that glucose dyshomeostasis may exacerbate metabolic aspects of synaptic dysfunction that contribute to risk for age-related brain disorders.

Link: https://doi.org/10.1016/j.nbas.2024.100116

Because epigenetic clocks are produced from DNA methylation data via machine learning approaches, correlating patterns of change with chronological age, it remains unclear as to what exactly they measure. Which processes of aging produce the specific DNA methylation changes used in any given clock? As yet that question has no answer. Thus a discovery process continues, in which researchers uncover clock behaviors such as a dependency on aspects of the circadian rhythm. Determining exactly which aspects will be one small part of a much longer process of understanding the details of the relationship between DNA methylation and the rest of cellular biochemistry. For now it is a caveat for those using aging clocks, epigenetic or otherwise - either pick a clock demonstrated to lack this behavior, or be consistent in time of day when measuring.

Since their introduction, epigenetic clocks have been extensively used in aging, human disease, and rejuvenation studies. In this article, we report an intriguing pattern: epigenetic age predictions display a 24-hour periodicity. We tested a circadian blood sample collection using 17 epigenetic clocks addressing different aspects of aging. Thirteen clocks exhibited significant oscillations with the youngest and oldest age estimates around midnight and noon, respectively. In addition, daily oscillations were consistent with the changes of epigenetic age across different times of day observed in an independant populational dataset.

While these oscillations can in part be attributed to variations in white blood cell type composition, cell count correction methods might not fully resolve the issue. Furthermore, some epigenetic clocks exhibited 24-hour periodicity even in the purified fraction of neutrophils pointing at plausible contributions of intracellular epigenomic oscillations. Evidence for circadian variation in epigenetic clocks emphasizes the importance of the time-of-day for obtaining accurate estimates of epigenetic age.

Link: https://doi.org/10.1111/acel.14170

The hundreds of mitochondria found in every cell are in effect power plants, their primary task being to manufacture the chemical energy store molecule adenosine triphosphate (ATP), which is used to power cellular processes. Mitochondria become damaged like every cellular component, and are recycled frequently. With age, however, changes in expression of mitochondrial and other proteins lead to dysfunctional recycling and dysfunctional mitochondria. ATP production suffers, side-effects of ATP production such as the generation of free radical molecules grow to become problematic, and cell function is impacted. This happens throughout the body, and is thought to be an important contributing cause of degenerative aging.

At least two companies are working earnestly on developing mitochondrial transplantation therapies as a way to treat aging, Mitrix Bio and Cellvie Scientific. Cells will readily take up mitochondria from the surrounding environment. Studies in animals suggest that supplying fully functional mitochondria, harvested from cell cultures, to tissues in which mitochondria are dysfunction can fix the problem for long enough to be interesting as a basis for therapy. The primary challenges are (a) to understand whether mitochondrial haplotypes must match between donor and recipient, (b) cost-effective and reliable manufacture of large enough amounts of undamaged, function mitochondria, and (c) delivery to the harder-to-reach parts of the body. The companies are primarily engaged in the logistics of large-scale manufacture.

Today's open access paper is a compelling demonstration from researchers associated with Cellvie Scientific, demonstrating sizable gains in mitochondrial function, muscle function, and endurance in old mice resulting from direct injection of mitochondria into hindlimb muscles. The amount of mitochondria harvested and injected is reasonable from a manufacturing point of view if scaling up to human use. I expect these companies to initially target frailty, sarcopenia, and related conditions. I also expect the medical tourism community to begin to offer mitochondrial transplantation therapies on much the same timescale. Clinical businesses already have a great deal of experience in managing cell cultures and cell harvesting, and moving from there to harvesting mitochondria is an achievable goal. They have already achieved a similar shift in moving to the use of extracellular vesicles in therapy.

Mitochondrial Transplantation's Role in Rodent Skeletal Muscle Bioenergetics: Recharging the Engine of Aging

Cardiorespiratory fitness is a health indicator of all-cause mortality. One critical component of cardiorespiratory fitness is the function of mitochondria within the skeletal muscle which generates energy to perform exercise or activities of daily living. There is clear evidence that aging results in a reduction in mitochondrial function. Initially proposed as the mitochondrial theory of aging in the 1950s, age-related decreases in mitochondrial function have since been shown to play a major role in skeletal muscle decline. Not surprisingly, in regard to aging-related decline of skeletal muscle, mitochondrial oxidative capacity has been implicated in sarcopenia. Research suggests that the skeletal muscle of elderly individuals exhibits a rise in nonoperational mitochondria, an increase in mutated and deleted mitochondrial DNA with an associated decrease in mitochondrial density.

Non-exercise alternatives such as nutraceuticals or pharmacological agents to improve skeletal muscle bioenergetics act systemically and have resulted in moderate success. Nevertheless, these natural and pharmacological compounds have limitations, particularly in the duration of time (i.e., weeks or months) to induce beneficial molecular and cellular changes in skeletal muscle. Thus, the question arises: "Is there a faster, tissue targeted, and more effective approach to enhance skeletal muscle bioenergetics?"

Mitochondrial transplantation represents a novel therapy designed to enhance energy production of tissues impacted by defective mitochondria. This innovative approach involves transferring isolated mitochondria from either a donor to a host or from the host to itself. Initially used to attenuate the effects of ischemia-reperfusion injury in cardiac tissue transplanted mitochondria, which are rapidly purified and remain viable and capable of respiration, are directly injected into the target tissue. In skeletal muscle, mitochondrial transplantation has proven effective in enhancing hindlimb bioenergetics in various rodent models. Mitochondrial transplantation circumvents the limitations of both exercise and non-exercise interventions by directly delivering isolated mitochondria into the target tissue.

To date, no studies have used mitochondrial transplantation as an intervention to attenuate aging-induced skeletal muscle mitochondrial dysfunction. In this study 15 female mice (24 months old) were randomized into two groups (placebo or mitochondrial transplantation). Isolated mitochondria from a donor mouse of the same sex and age were transplanted into the hindlimb muscles of recipient mice. The results indicated significant increases (ranging between ~36% and ~65%) in basal cytochrome c oxidase and citrate synthase activity as well as ATP levels in mice receiving mitochondrial transplantation relative to the placebo. Moreover, there were significant increases (approximately two-fold) in protein expression of mitochondrial markers in both glycolytic and oxidative muscles. These enhancements in the muscle translated to significant improvements in exercise tolerance.

The practice of calorie restriction, intermittent fasting, and related strategies such the fasting mimicking diet are thought to produce benefits largely through increased or more efficient operation of the cellular maintenance process of autophagy. The various forms of autophagy work to remove damaged molecules and structures in the cell, and better cell function maintained over time throughout the body is expected to result in slowed aging. Certainly a great many of the approaches shown to slow aging in short-lived species are characterized by improved autophagy, and influence the same regulatory systems that are triggered by a low calorie intake and consequent hunger.

Autophagy is a prosurvival mechanism for the clearance of accumulated abnormal proteins, damaged organelles, and excessive lipids within mammalian cells. A growing body of data indicates that autophagy is reduced in aging cells. This reduction leads to various diseases, such as myocardial hypertrophy, infarction, and atherosclerosis. Recent studies in animal models of an aging heart showed that fasting-induced autophagy improved cardiac function and longevity. This improvement is related to autophagic clearance of damaged cellular components via either bulk or selective autophagy (such as mitophagy).

Short-term caloric restriction (CR) for 10 weeks in mice rejuvenated symptoms of the aging heart, such as significant improvement in diastolic function and regression of age-dependent cardiac hypertrophy. Moreover, CR reversed age-dependent cardiac proteome remodeling and mitigated oxidative damage and ubiquitination in these mice. In aged animals, hypertrophy, and fibrosis, as well as systolic and diastolic dysfunctions, improved after CR. The beneficial effects of CR observed in cardiomyocytes include enhanced mitochondrial fitness and reduced oxidative stress, apoptotic cell death, inflammation, and importantly, senescence.

In vasculature, CR helps improve endothelial cell function and attenuates collagen deposition, elastin remodeling, and oxidative stress; as a result, CR reduces arterial stiffness. Another study revealed improvements in numerous markers of cardiovascular health in humans after short-term periodic fasting, which is also a pro-autophagic dietary regimen.

In conclusion, fasting-induced autophagy is beneficial for ensuring cardiac function, preventing disease, and improving longevity. However, additional studies in vivo in animal models of cardiac aging are needed to determine the specific molecular mechanisms involved in normalizing autophagy by fasting. In addition, large-scale studies on humans are needed. Importantly, further in vitro research should be directed toward human cardiac tissues to better understand the molecular mechanisms of fasting-induced autophagy and its beneficial effects on longevity pathways and prevention of cardiovascular disease.

Link: https://doi.org/10.4330/wjc.v16.i3.109

Researchers here explore age-related changes that take place in the innate immune cells known as macrophages, as well as the precursor circulating cell type known as monocytes. Macrophages undertake a wide range of tasks, not just responsible for chasing down infectious pathogens, but also clearing molecular waste and cell debris, destroying problematic cells, and helping to coordinate regenerative processes following injury. Altered macrophage behavior is implicated in a range of age-related diseases, and this is also the case for changes that take place in the analogous cell population of microglia resident in the central nervous system. A better understanding of these alterations may lead to ways to restore a more youthful pattern of behavior in these cells.

Macrophages are central innate immune cells whose function declines with age. The molecular mechanisms underlying age-related changes remain poorly understood, particularly in human macrophages. We report a substantial reduction in phagocytosis, migration, and chemotaxis in human monocyte-derived macrophages (MDMs) from older (more than 50 years old) compared with younger (18-30 years old) donors, alongside downregulation of transcription factors MYC and USF1.

In MDMs from young donors, knockdown of MYC or USF1 decreases phagocytosis and chemotaxis and alters the expression of associated genes, alongside adhesion and extracellular matrix remodeling. A concordant dysregulation of MYC and USF1 target genes is also seen in MDMs from older donors. Furthermore, older age and loss of either MYC or USF1 in MDMs leads to an increased cell size, altered morphology, and reduced actin content. Together, these results define MYC and USF1 as key drivers of MDM age-related functional decline and identify downstream targets to improve macrophage function in aging.

Link: https://doi.org/10.1016/j.celrep.2024.114073

This messy popular science article is an essay length expression of futility on the part of a journalist who accepts that he is not equipped to understand the field of aging research and the longevity industry that has arisen in the past decade. One can talk to the talking heads, but they will all say something different. One can look for proof of efficacy for specific approaches, and find only contradictory data, or only compelling animal data, or only small effect sizes, and a lack of the sort of certainty that arises from large human trials. Those trials are still in the future for near every approach to the treatment of aging that might work.

Like most tours of the field written by journalists, the article lumps together terrible approaches, promising approaches, approaches with good supporting data, approaches with mixed to bad supporting data, and makes little attempt to distinguish between them. The journalist cannot distinguish between them, he doesn't have the several years of learning the science that would be needed to even start to have a useful opinion on approach A versus approach B. For the layman it is just a list, and those most willing to talk about the list are those with a vested interest in profiting from companies working on one item or another item, or are scientist with career prospects that require them to be overly cautious in their public pronouncements. Objectivity is hard to find.

The Wild Science of Growing Younger

There are a lot of hyperbolic and crazy-sounding theories and assertions in the vast movement to counteract the inexorable march from the quick to the dead. Xprize founder Dr. Peter Diamandis thinks we may one day upload our consciousness to the cloud. As such, the 62-year-old is doing everything he can to keep his body healthy in the meantime and maybe reach "longevity escape velocity" - continuing to extend his life long enough to take advantage of ever-more life-extending methods. His business partner - motivational speaker and entrepreneur Tony Robbins - says that stem cell injections he received in Panama (because it's illegal in the U.S.) not only repaired a torn rotator cuff but rejuvenated his entire body. Half-billionaire Bryan Johnson reportedly spends about two million dollars a year on testing, taking more than 100 drugs and supplements, and - for a time - infusing his teenage son's blood plasma. And they are not alone. Jeff Bezos, Yuri Milner, and other tech titans are reported to have together poured about $3 billion into Altos Labs, a startup promising to reprogram human cells to their youthful state.

Rejuvenation efforts also promise to brighten the twilight years by allowing people to live longer and be healthier and more vigorous. Picture 80-year-olds with the body of a 60-year-old. Proponents talk about not only extending lifespan but also what they call healthspan. "It's this biology of aging that makes us get Alzheimer's or cancer or heart disease or diabetes," says Dr. Nir Barzilai. "Aging is the mother of those diseases ... You deal with the mother, and you don't have those kids." After speaking with a dozen experts or advocates, reading four books, parsing over 30 research papers, and absorbing popular press coverage, I know two things about the possibility of slowing or reversing aging. First, anyone can do a few cheap, simple things (like exercise) to improve their longevity prospects. Second, several new tactics, technologies, and tools might someday work.

If you'd hoped for a conclusive destination at the end of this journey, I'm sorry. But in place of answers, we have a framework for evaluating the many questions that emerge. Science has a good sense of what healthy aging should look like. And objective research can begin to explore if any far-fetched ideas mimic that, without bad side effects. Some medications might slow down some aspects of aging. Or perhaps the side effects of these meds just substitute new health problems for the ones proponents aim to fix. You might wait for more info on that before you swallow. Can we inject foreign cells to repair our bodies or inject chemicals that reinvigorate our own cells? This seems to work in mice, worms, or petri dishes. But people without vested interests say we need much more evidence. That's going to take a long time. For so much of anti-aging or reverse-aging science, the old academic refrain applies: "further research is needed."

The evidence for transfusion of young plasma to produce benefits in old animals and human patients is mixed. Despite compelling demonstrations for the dilution of blood to produce benefits in older individuals, there remain many research groups who consider that the primary goal should be the identification of factors within young blood that can produce improvements to health. Inconveniently for those who argue for the primacy of dilution in producing the benefits of plasma transfusion, there are studies such as this one in which factors derived from young plasma do in fact improve health significantly in old mice.

Recent investigations into heterochronic parabiosis have unveiled robust rejuvenating effects of young blood on aged tissues. However, the specific rejuvenating mechanisms remain incompletely elucidated. Here we demonstrate that small extracellular vesicles (sEVs) from the plasma of young mice counteract pre-existing aging at molecular, mitochondrial, cellular and physiological levels. Intravenous injection of young sEVs into aged mice extends their lifespan, mitigates senescent phenotypes, and ameliorates age-associated functional declines in multiple tissues.

Quantitative proteomic analyses identified substantial alterations in the proteomes of aged tissues after young sEV treatment, and these changes are closely associated with metabolic processes. Mechanistic investigations reveal that young sEVs stimulate PGC-1α expression in vitro and in vivo through their microRNA cargoes, thereby improving mitochondrial functions and mitigating mitochondrial deficits in aged tissues. Overall, this study demonstrates that young sEVs reverse degenerative changes and age-related dysfunction, at least in part, by stimulating PGC-1α expression and enhancing mitochondrial energy metabolism.

Link: https://doi.org/10.1038/s43587-024-00612-4

You might compare the LEV Foundation's Rodent Aging Interventions Database with the DrugAge database, both emerging from the efforts of researchers who found themselves frequently reviewing the existing literature on age-slowing interventions in animal models. One of the things to bear in mind about the existing literature is that rodent studies that show an apparent modest slowing of aging frequently fail to replicate when later investors take a more rigorous approach, with larger numbers of mice. The history of the NIA Interventions Testing Program is largely a repeated demonstration of this point.

The Rodent Aging Interventions Database (RAID) project arose as a result of work conducted during late 2022 in preparation for the first study in LEV Foundation's Robust Mouse Rejuvenation (RMR) program: specifically, a comprehensive survey conducted by LEVF of publications documenting successful lifespan extension in strains of rodents (mice and rats) with normal baseline lifespans. That survey played an important role in informing the selection of interventions for the RMR program.

Recognising that this compilation of data may be of interest to other researchers in the field of longevity/aging research, we decided to make it publicly available. To enable convenient exploration of the results, we have also developed a visualization tool which depicts the increases in lifespan achieved in different studies as a single bar chart.

The dataset queried by this tool is intended to cover all published studies that meet the inclusion criteria: (a) in mice (Mus musculus) or rats (Rattus norvegicus), (b) a genetic background consistent with normal aging rates (e.g. no progeria, PolG mitochondrial DNA mutator, Alzheimer's models such as APP/PS1, etc.), and (c) the study reports an intervention with some statistically significant effect on average or maximum lifespan. It is our intention to update the dataset periodically, but some newer (or recently identified) publications may not yet be indexed.

Link: https://www.levf.org/projects/raid

A variety of approaches show some promise in improving the function of stem cells in aged tissues. Stem cell populations support their tissue by providing a supply of daughter somatic cells to replace losses. This supply diminishes over time as stem cells reduce their activity for reasons that descend from the known root causes of aging, but which are not fully understood in detail. To the degree that reduced stem cell function is a response to the aged environment rather than a consequence of damage inherent to these cells, then it is useful to find ways to force stem cells to be more active. Whether this is the case may differ for different cell types, but there is ample evidence for interventions that can at least modestly enhance stem cell activity.

Perhaps the most interesting of these interventions are partial reprogramming and CDC42 inhibition via CASIN. The latter is much more feasible than the former when considering the prospects for near-term human use, but both offer the prospect of one-time treatments that produce a lasting reversal of stem cell aging and consequent improvement in tissue function. It is most likely a long road ahead to the first partial reprogramming therapies, but CASIN only awaits initial human testing to establish that safety is similar to that observed in mice.

Rejuvenating aged stem cells: therapeutic strategies to extend health and lifespan

Aging is associated with a global decline in stem cell function. To date, several strategies have been proposed to rejuvenate aged stem cells: most of these result in functional improvement of the tissue where the stem cells reside, but the impact on the lifespan of the whole organism has been less clearly established. Here, we review some of the most recent work dealing with interventions that improve the regenerative capacity of aged somatic stem cells in mammals and that might have important translational possibilities.

The beneficial effect of exercise on health has been known for a long time. It has been shown that moderate intensity running for 30 minutes per day for 8 weeks increases the number of skeletal muscle stem cells in aged mice. The brain is another organ that is affected by exercise. Neurogenesis increases in mice transplanted with plasma from exercised aged mice. Some other aged stem cells also benefit from exercise, such as tendon stem cells.

Calorie restriction (CR) and fasting are two other strategies that have been largely studied for their rejuvenating capacities. Intestinal stem cells increase in number and replicate more after CR and fasting-mimicking diet (FMD), and their capacity to form organoids is improved after fasting. In the skeletal muscle, muscle stem cells seem to enter a deep quiescent state after fasting, which is not recovered by re-feeding. This slows muscle regeneration but improves the survival of these stem cells.

An exciting strategy that has been proposed for cell rejuvenation is reprogramming cells to a more undifferentiated state by inducing expression of the Yamanaka factors. A cyclic induction of OSKM was able to increase the numbers of muscle stem cells and hair follicle stem cells in adult mice with progeria and to improve regeneration of the skeletal muscle. Further studies will be needed to better understand the effect of reprogramming on stem cells and lifespan, and to define an optimal treatment strategy to achieve rejuvenation without the risk of cancer induction.

Cellular senescence is characterized by a stable cell-cycle arrest of dysfunctional cells which also present with a senescence-associated secretory phenotype (SASP). Clearance of senescent cells with senolytics was shown to exert promising results on hematopoietic stem cells and muscle stem cells. Senescent cells form an inflamed niche that mirrors the inflammation associated with aging by arresting stem cell proliferation and regenerative potential. In young and aged mice, the reduction of senescent cells or of the inflammation associated with senescent cells accelerates tissue regeneration.

Cell polarization, defined as the uneven distribution of RNAs, proteins, organelles, and cytoplasm, occurs in many forms and the most widely known is the apical-basal polarity of epithelial cells. The capacity of establishing cell polarity, associated with the activity or the expression of specific polarity proteins, appears to be linked to aging of asymmetrically dividing cells such as stem cells. In the context of somatic stem cell rejuvenation, targeting cell polarity represents a potential strategy to improve tissue and organ regeneration. For example, Cdc42 is involved in the establishment of cell polarity in many cell types and its activity level increases over time, driving loss of polarity and aging in stem cells. Cdc42 activity can be efficiently targeted by using a specific small molecule inhibitor named CASIN (Cdc42 activity-specific inhibitor). CASIN treatment has been shown to rejuvenate different somatic stem cell types.

In recent years, researchers have been putting more effect into analyses of the CALERIE 2 study of human calorie restriction. The study took place some years ago, but new results continue to be published. Here, researchers show that effects on telomere length and a related aging clock are inconclusive. Telomere length measured in the white blood cells of a blood sample is not a great measure of aging. It is highly variable between individuals, is influenced day to day changes in immune status, and it takes a fairly large study group for age-related trends to show up. It has rightfully been eclipsed by the development of aging clocks derived from omics data.

Caloric restriction (CR) modifies lifespan and aging biology in animal models. The Comprehensive Assessment of Long-Term Effects of Reducing Intake of Energy (CALERIE) 2 trial tested translation of these findings to humans. CALERIE randomized healthy, nonobese men and premenopausal women (age 21-50 years; BMI 22.0-27.9 kg/m2), to 25% CR or ad-libitum (AL) control (2:1) for 2 years. Prior analyses of CALERIE participants' blood chemistries, immunology, and epigenetic data suggest the 2-year CR intervention slowed biological aging. Here, we extend these analyses to test effects of CR on telomere length (TL) attrition.

TL was quantified in blood samples collected at baseline, 12-, and 24-months by quantitative PCR (absolute TL; aTL) and a published DNA-methylation algorithm, DNA methylation estimated telomere length (DNAmTL). Intent-to-treat analysis found no significant differences in TL attrition across the first year, although there were trends toward increased attrition in the CR group for both aTL and DNAmTL measurements. When accounting for adherence heterogeneity with an Effect-of-Treatment-on-the-Treated analysis, greater CR dose was associated with increased DNAmTL attrition during the baseline to 12-month weight-loss period. By contrast, both CR group status and increased CR were associated with reduced aTL attrition over the month 12 to month 24 weight maintenance period.

No differences were observed when considering TL change across the study duration from baseline to 24-months, leaving it unclear whether CR-related effects reflect long-term detriments to telomere fidelity, a hormesis-like adaptation to decreased energy availability, or measurement error and insufficient statistical power. Unraveling these trends will be a focus of future CALERIE analyses and trials.

Link: https://doi.org/10.1111/acel.14149

Researchers here report on the results of transfusion of young rat plasma into old rats, starting every other week in later life. The study is small, and is one more data point to add to a mixed set of results. Plasma transfusion from young individual to old individual doesn't look that impressive, all told, either in animals or in human patients. That doesn't appear to be discouraging the community of researchers and developers who continue to work on approaches to transfusion that they believe may move the needle. The example here is a straightforward approach to transfusion, the procedure conducted every other week, and is one of the studies in which the intervention appears to work well enough to be interesting.

There is converging evidence that young blood conveys cells, vesicles, and molecules able to revitalize function and restore organ integrity in old individuals. We assessed the effects of young plasma on the lifespan, epigenetic age, and healthspan of old female rats. Beginning at 25.6 months of age, a group of 9 rats (group T) was intraperitoneally injected with plasma from young rats until their natural death. A group of 8 control rats of the same age received no treatment (group C). Blood samples were collected every other week. Survival curves showed that from age 26 to 30 months, none of the group T animals died, whereas the survival curve of group C rats began to decline at age 26 months.

Blood DNA methylation (DNAm) age versus chronological age showed that DNAm age in young animals increased faster than chronological age, then slowed down, entering a plateau after 27 months. The DNAm age of the treated rats fell below the DNAm age of controls and, in numerical terms, remained consistently lower until natural death. When rats were grouped according to the similarities in their differential blood DNA methylation profile, samples from the treated and control rats clustered in separate groups. Analysis of promoter differential methylation in genes involved in systemic regulatory activities revealed specific gene ontology term enrichment related to the insulin-like factors pathways as well as to cytokines and chemokines associated with immune and homeostatic functions.

We conclude that young plasma therapy may constitute a natural, noninvasive intervention for epigenetic rejuvenation and health enhancement.

Link: https://doi.org/10.1093/gerona/glae071

The research community has come to see chronic inflammation and other age-related immune system dysfunctions as an important aspect of neurodegenerative conditions. Inflammation in the short term is necessary for defense against pathogens and regeneration following injury. Unresolved, constant inflammation is harmful to tissue structure and function, however, changing cell behavior for the worse. In brain tissue, the effects of inflammatory signaling on the behavior of innate immune cells called microglia appears particularly important. Neurogenerative conditions are characterized by activated microglia. These microglia are less able to perform maintenance activities, while also contributing to loss of synapses and other pathological changes in the brain.

The authors of today's open access review paper take a broad view of the impact of immune system aging on the brain, and its potential roles in the development of neurodegenerative conditions. All such conditions exhibit changes in cellular biochemistry that can be linked to changed immune activity. Further, an inflammatory state appears correlated with onset and progression of these conditions. There is ample evidence for immunomodulatory, anti-inflammatory approaches to be a sensible way forward in the treatment of neurodegeneration, but adjusting the immune system is not straightforward. The fine details of the inflammatory mechanisms involved in pathology matter when it comes to building a better therapy.

Immunological aspects of central neurodegeneration

The etiology of various neurodegenerative disorders (NDs) that mainly affect the central nervous system including (but not limited to) Alzheimer's disease, Parkinson's disease, and Huntington's disease has classically been attributed to neuronal defects that culminate with the loss of specific neuronal populations. However, accumulating evidence suggests that numerous immune effector cells and the products thereof (including cytokines and other soluble mediators) have a major impact on the pathogenesis and/or severity of these and other neurodegenerative syndromes. These observations not only add to our understanding of neurodegenerative conditions but also imply that (at least in some cases) therapeutic strategies targeting immune cells or their products may mediate clinically relevant neuroprotective effects. Here, we critically discuss immunological mechanisms of central neurodegeneration and propose potential strategies to correct neurodegeneration-associated immunological dysfunction with therapeutic purposes.

While most central NDs appear to originate from genetic or environmental alterations of cellular homeostasis in the brain parenchyma, it is now clear that such perturbations are accompanied by the activation of innate and (at least in some cases) adaptive immune effector mechanisms that contribute to disease pathogenesis. Multiple NDs are associated with mutations in genes encoding components of the innate or adaptive immune system, such as TREM2 or HLA-DRB1. Moreover, hitherto unrecognized connections are emerging between central ND susceptibility genes, such as SNCA, and core immunological functions, such as the development of normal innate and adaptive immune reactions to bacterial challenges. Finally, patients affected by numerous NDs including Alzheimer's disease, Parkinson's disease, Huntington's disease, Lewy body dementia, and frontotemporal dementia exhibit shifts in the circulating levels of pro-inflammatory cytokines or peripheral immune populations, further supporting a pathogenic role for altered immune responses in the central nervous system in the progression of NDs.

With a few exceptions including the robust implication of CD4+ in disease pathogenesis in mouse models of Lewy body dementia, most of the current links between immunological mechanisms and ND pathogenesis rely on observational and correlative rather than mechanistic experimental setups. While at least partially this reflects the limited number of rodent models that recapitulate the emergence and progression of NDs in humans, it will be important to harness currently available models to implement antibody-mediated depletion, pharmacological inhibition, or genetic deletion/downregulation experiments to mechanistically link altered immune functions to ND pathogenesis and potentially identify novel targets for therapeutic interventions. While additional work is required to elucidate the actual therapeutic potential of immunotherapy for patients with central NDs, both innate and immune dysfunctions have been documented in the progression of NDs. It will be important to obtain further mechanistic insights into the immunological aspects of human degeneration in existing and newly developed rodent ND models to develop disease-modifying treatment options for these patient populations.

Mitrix Bio is one of the companies developing the means to produce large amounts of mitochondria for transplantation. Cells will take up new mitochondria from the surrounding environment, and mitochondria can be harvested from cell cultures. Mitochondrial function declines with age, the result of (a) gene expression changes in the cell nucleus that alter mitochondrial dynamics and the quality control process of mitophagy, and (b) damage to mitochondrial DNA. Evidence from animal studies suggests that replacing mitochondria in aged tissues produces benefits to health and organ function that last for long enough to be interesting as a basis for therapy. From a regulatory perspective in the US, harvested mitochondria are in the same class of treatment as harvested stem cells, so it is somewhat easier to progress to initial human trials than is the case for new drugs. It will be interesting to see the results.

We are proud to announce "The 130-Year-Old-Lifespan Trials". Our volunteers - mostly in their 70s and 80s - aim to be the first people in history to break past the current "Lifespan Barrier" for the human species, which stands at 122. We aim to give them average lifespans of 130 with the health, strength, and appearance of 50. This trial will be conducted in our new division - Biotech Explorers. Because there will be very limited space to treat people in the early years, this treatment will be provided initially to current and former astronauts, and children with certain premature aging diseases.

We've known for the past year, from animal trials, that bioreactor-grown mitochondria transplantation had the potential to dramatically speed healing, fight infection, and extend lifespan. We could see in animal tests in the brain, muscles, immune system, and skin, that the effect was real. Other types of mitochondrial transplantation have already been safely used for in human patients for rare diseases. The 130-year-old lifespan treatment will be based on Bioreactor-Grown Mitochondrial Transplantation - a technique that our parent firm Mitrix Bio has been developing for several years. We are now making animals in the lab younger routinely.

Now the job in front of us, is to make the leap with careful, rigorous human trials targeting a 130-year-old lifespan. There is so much work to be done, but our team of top scientists from major universities and other research groups are ready to take on this challenge.

Link: https://www.linkedin.com/posts/activity-7181774280462938112-oLbY

Researchers here look at cellular dysfunction that may form the earliest stages of Alzheimer's disease, prior to the accumulation of misfolded amyloid-β and cognitive decline. In general, intervening early in the progression of a disease will always be easier, given the right target. The challenge lies in identifying and understanding the causative mechanisms, in an environment in which (a) there is little access to brain tissue in the earliest stages of Alzheimer's disease, and (b) the animal models are highly artificial, as mice do not normally develop anything resembling Alzheimer's disease, and thus may not accurately reflect important aspects of the human condition.

Amyloid precursor protein (APP) is found in the cell membranes of brain cells. The brain constantly produces new APP molecules while breaking down and removing old ones. This process involves enzymatic scissors, with gamma-secretase being the final one that generates the well-known and well-studied amyloid-β (Aβ) peptides in Alzheimer's disease (AD). For a long time, it was thought that blocking gamma-secretase would be the logical step to prevent the production of toxic Aβ fragments. However, this leads to the accumulation of their precursor, the APP-C-Terminal Fragments, or APP-CTFs. Now, researchers have discovered that these fragments are also toxic to neurons. They appear to accumulate between the endoplasmic reticulum (ER), the compartment that is crucial for lipid synthesis and calcium storage, and the lysosomes, the so-called 'waste bins' of neurons, which are critical for degrading the cell's waste products.

By doing so, APP-CTFs disrupt the delicate balance of calcium within lysosomes. This disruption triggers a cascade of events. The ER can no longer effectively refill lysosomes with calcium, leading to a buildup of cholesterol and a decline in their ability to break down cellular waste. This results in the collapse of the entire endolysosomal system, a crucial pathway for maintaining healthy neurons. The new study further supports that the APP-CTFs resulting from suppressing gamma-secretase might actually be the culprit behind endolysosomal dysfunction, as observed in the very early stages of AD.

This research significantly advances our comprehension of the potential causes of disease in the early stages of AD. A remarkable outcome of this study is that these early stages could be caused by another fragment of the same APP molecule rather than Aβ. This has significant implications for the current therapeutic approaches that aim to clear the AD brain from amyloid plaques, as they tend to ignore the toxic effects of other fragments. Other attempts focus on tau proteins or neuroinflammation, which are other hallmarks of AD progression that target later events. However, early intervention is likely the key to stopping or even preventing AD.

Link: https://press.vib.be/new-mechanism-uncovered-in-early-stages-of-alzheimers-disease

Like the accumulation of senescent cells, loss of stem cell function is a problematic feature of aging. Also like the accumulation of senescent cells, loss of stem cell function is likely downstream of a combination of forms of molecular damage and consequent changes in cell behavior and cell signaling that are presently incompletely understood in detail and harder to address. Senescent cells can be cleared more readily than prevented, and stem cells may be more readily coerced into activity or replaced entirely than is the case for prevention of their age-related functional decline.

Stemness is a property of stem cells. Tautologically it is what distinguishes stem cells from somatic cells, primarily meaning (a) continual self-renewal of the population and (b) the ability to differentiate into multiple other cell types. Stem cell activity declines with age, but that doesn't necessarily mean that stemness is in decline. In muscle stem cells, for example, there is evidence for aged muscle stem cells to perform just as well as young muscle stem cells once removed from the aged tissue environment, even given a presumably greater burden of many forms of age-related damage inherent to the cells themselves. One can argue that many types of stem cell are restrained by damage to their niches, or by changes in the aged signaling environment, not by any inherent damage that reduces the potential for stemness.

In today's open access paper, researchers generate a stemness score based on transcriptomic data, and see how it changes with age in many tissues in the human body. This may be a blurred measure of capacity for stemness coupled with the impact of the aged microenvironment in which cells find themselves. Another interesting addition to this data would be to take cell samples and put them in a youthful environment, then test again and see how their stemness score changes.

Evidence of a pan-tissue decline in stemness during human aging

Although the aging process is the leading cause of human mortality and morbidity, being associated with several diseases, scientists still debate its causes and mechanisms. Among the biological pathways associated with aging, we can highlight stem cell exhaustion, which argues that during normal aging, the decrease in the number or activity of these cells contributes to physiological dysfunction in aged tissues. This concept is supported by the observation that aging is associated with reduced tissue renewal and repair at advanced ages. Moreover, longevity manipulations in mice often affect growth and cell division, which has been hypothesized to relate to stem cells.

Despite their importance, in vivo detection and quantification of stem cells are challenging, which makes it difficult to study their association with aging, especially in humans. In this context, detecting stemness-associated expression signatures is a promising strategy for studying stem cell biology. Stemness refers to a distinctive attribute marked by a series of molecular processes that delineate the essential properties of stem cells, enabling the generation of daughter cells and self-renewal. While widely employed in oncology, the exploration of this concept in gerontology has been comparatively limited.

In this study, we applied a machine learning method to detect stemness signatures from transcriptome data of healthy human tissues. The methodology, developed by Malta et al., was trained on stem cell classes and their differentiated progenitors and went through rigorous validation steps including tests in several datasets from tumor and non-tumor samples. Although initially used to study oncogenic dedifferentiation, this approach has also been employed to study normal and pathological (non-tumorous) samples. Therefore, we first downloaded expression data of 17,382 samples, divided into 30 tissues aged between 20 and 79 years, from GTEx in transcripts per million (TPM). After that, we followed assigned a stemness score to all GTEx samples.

We found that ~60% of the studied tissues exhibit a significant negative correlation between the subject's age and stemness score. The only significant exception was the uterus, where we observed an increased stemness with age. Moreover, we observed that stemness is positively correlated with cell proliferation and negatively correlated with cellular senescence. Finally, we also observed a trend that hematopoietic stem cells derived from older individuals might have higher stemness scores. In conclusion, we assigned stemness scores to human samples and show evidence of a pan-tissue loss of stemness during human aging, which adds weight to the idea that stem cell deterioration may contribute to human aging.

Exercise is well known to correlate with reduced risk of cardiovascular disease in human epidemiological studies. In animal studies, it is possible to demonstrate that increased physical activity does in fact cause a lower incidence of cardiovascular disease. Here researchers argue that stress has a significant effect on cardiovascular outcomes, as demonstrated by the fact that patients with greater degrees of stress, such as those with major depressive disorder, exhibit a larger beneficial correlation of reduced cardiovascular disease with exercise. It is interesting to ask which mechanisms are causing this association; exercise produces sweeping beneficial effects on body and brain, so picking apart specific contributions to an observed correlation is challenging. Yes, exercise reduces the consequences of stress, but depression tends to lead to reduced activity, and those depressed patients who are exercising were probably better off than their peers to start with. And so forth. For every proposition, there is a counterargument.

To assess the mechanisms underlying the psychological and cardiovascular disease benefits of physical activity, researchers analyzed medical records and other information of 50,359 participants from the Mass General Brigham Biobank who completed a physical activity survey. A subset of 774 participants also underwent brain imaging tests and measurements of stress-related brain activity. Over a median follow-up of 10 years, 12.9% of participants developed cardiovascular disease. Participants who met physical activity recommendations had a 23% lower risk of developing cardiovascular disease compared with those not meeting these recommendations.

Individuals with higher levels of physical activity also tended to have lower stress-related brain activity. Notably, reductions in stress-associated brain activity were driven by gains in function in the prefrontal cortex, a part of the brain involved in executive function (i.e., decision making, impulse control) and is known to restrain stress centers of the brain. Analyses accounted for other lifestyle variables and risk factors for coronary disease.

Moreover, reductions in stress-related brain signaling partially accounted for physical activity's cardiovascular benefit. As an extension of this finding, the researchers found in a cohort of 50,359 participants that the cardiovascular benefit of exercise was substantially greater among participants who would be expected to have higher stress-related brain activity, such as those with pre-existing depression. "Physical activity was roughly twice as effective in lowering cardiovascular disease risk among those with depression. Effects on the brain's stress-related activity may explain this novel observation."

Link: https://www.eurekalert.org/news-releases/1040861

Researchers here discuss some of the results achieved in building the Human Skeletal Muscle Aging Atlas. Focusing on stem cells in muscle tissue, they find numerous changes in gene expression relating to inflammation and reduced activity. The chronic inflammation characteristic of aging, provoked by senescent cells and innate immune reactions to molecular damage, is known to be involved in many of the dysfunctions of aging. Loss of stem cell activity, and thus a reduced supply of daughter somatic cells to replace losses and repair damage, is one of those dysfunctions.

Skeletal muscle aging is a key contributor to age-related frailty and sarcopenia with substantial implications for global health. Here we profiled 90,902 single cells and 92,259 single nuclei from 17 donors to map the aging process in the adult human intercostal muscle, identifying cellular changes in each muscle compartment.

From our in-depth analysis, we identified aging mechanisms acting in parallel across different cell compartments. In the muscle stem cell (MuSC) compartment, we found downregulation of ribosome assembly resulting in decreased MuSC activation as well as upregulation of pro-inflammatory pathways, such as NF-κB, and increased expression of cytokines, such as CCL2. In the MF microenvironment, we found several cell types that expressed pro-inflammatory chemokines, such as CCL2, CCL3, and CCL4. These cytokines may mediate the recruitment of lymphoid cells into muscle and the pro-inflammatory environment of aged muscle. Moreover, our cross-species and cross-muscle integrated aging atlas highlights an overall downregulation in gene expression, an increase in inflammation and a decrease in pro-growth, repair, and innervation pathways. Pan-microenvironment upregulation of CCL2 with age was not recapitulated in mice, suggesting an interesting human-mouse distinction in orchestration of inflammation.

Our atlas also highlights an expansion of nuclei associated with the neuromuscular junction, which may reflect re-innervation, and outlines how the loss of fast-twitch myofibers is mitigated through regeneration and upregulation of fast-type markers in slow-twitch myofibers with age. Furthermore, we document the function of aging muscle microenvironment in immune cell attraction.

Link: https://doi.org/10.1038/s43587-024-00613-3

The Strategies for Engineered Negligible Senescence (SENS) is a view of aging as accumulated damage. Drawing from the extensive scientific literature on aging, the originators of SENS created an outline of the forms of cell and tissue damage that are fundamental causes of aging, in that they occur as a natural side-effect of the normal operation of our cellular biochemistry. So we might consider the loss of vital cells due to declining stem cell function, mutations to nuclear DNA and mitochondrial DNA, cross-linking of vital molecules in the extracellular matrix, accumulated metabolic waste in long-lived cells, generation of amyloids from misfolded proteins, and the accumulation of senescent cells, for example.

These forms of damage accumulate to cause other, downstream forms of damage and dysfunction that, collectively, give rise to degenerative aging and age-related mortality. Aging is a very complex in its details, but only because cellular biochemistry is very complex. Complex systems malfunction in response to damage in complex ways, but the root causes of aging, the forms of damage noted above, are much less complex and thus much easier to visualize, describe, and intervene in.

Because SENS specifies the forms of damage in some detail, it also describes what needs to be done in order to reverse the progression of aging: repair the damage. Removing damage that is disruptive to cell and tissue function allows cell and tissues to improve their function and restore a more youthful environment. That said, there are all too few examples in which an author picks a specific age-related disease and breaks down its pathology into SENS terms. Today's article does that for Parkinson's disease, and notes that multiple different forms of damage are significant in driving its progress, is the case for near all age-related conditions. Any one narrowly focused rejuvenation therapy that addresses only one form of damage will improve matters only somewhat. It won't solve the whole problem. The SENS view of medical development inevitably leads to the development and use of many different therapies in combination.

Repairing the Damage to Shake Off Parkinson's

While most aging people don't suffer clinically-diagnosable Parkinson's, it's unsettlingly common to be afflicted by what are called "mild parkinsonian signs" or "Parkinsonism:" about one in six people ages 65 to 74, nearly one-third of those 75 to 84, and over half of those 85 and older. In addition to having to live with less severe versions of many common symptoms of Parkinson's itself (see below), people with Parkinsonism are at roughly double the risk of death in any given year as people the same age without it. Scientists have made exciting progress against Alzheimer's disease recently, with two new AmyloSENS therapies having proven themselves in clinical trials and more benefits and insights continuing to roll in. So it's a good time to take stock of where we are with cellular and molecular aging damage-repair therapies that would prevent and reverse the second most common neurodegenerative aging disorder.

The most visible symptoms of Parkinson's, and the ones on whose basis people are diagnosed with the "disease," are what are called the "motor symptoms." These symptoms result from the progressive loss of - and damage to - a specific population of neurons located in an area of the brain called the substantia nigra pars compacta (SNc). There is enough built-in redundancy in the SNc that we continue losing these "dopaminergic" neurons for decades without any obvious problems. But once our supply of these neurons dwindles to beneath the "threshold of pathology," we can no longer make these fine adjustments to the movement-control signals, and the motor symptoms of Parkinson's subvert the movement of our faces, hands, and bodies. The rejuvenation biotechnology solution to this problem is to repair the damage by replacing the lost neurons. The good news is that scientists have been working on dopaminergic neuron transplantation for longer than any other kind of true cell replacement (RepleniSENS) therapy. BlueRock Therapeutics uses proprietary bioprocessing to create stable master cell banks of what they call "universal iPSCs," which they have found to be compatible with the immune system of any patient. BlueRock scientists then differentiate these cells into dopaminergic neurons for transplant into the brains of people with Parkinson's. They recently reported positive safety results from a Phase I trial.

Our brains accumulate aggregates comprised of the protein alpha-synuclein (AS) as we age, both inside and between our neurons. People suffering from diagnosed Parkinson's and closely-related neurological aging disorders bear especially high burdens of these aggregates. Fortunately, researchers are currently running clinical trials to test numerous AmyloSENS therapies to clear AS aggregates located outside of cells. Most of these trials are in Phase II. Unfortunately, no one has yet developed LysoSENS therapies to target AS aggregates inside the cell, and it's these intracellular AS aggregates that likely inflict the greatest harm. The main reason for this seemingly backward prioritization is that it's not obvious how you would target AS aggregates inside cells. Fortunately, there is a potential path forward. Several years ago, researchers reported on a novel way to smuggle antibodies into cells intact. If researchers could instead send in catalytic antibodies (catabodies) that would chop pathological aggregates into tiny pieces inside the cell. SENS Research Foundation scientists are working to develop this intracellular aggregate-targeting catabody approach right now.

As we age, a small percentage of long-lived cells that don't divide (such as neurons and muscle cells) get completely taken over by mitochondria that have suffered the loss of huge chunks of their DNA. And of all the cells in the body, the cell type that is most susceptible to this hostile takeover is the critical population of dopaminergic neurons whose loss is central to Parkinson's. It's not clear what the connection is between these DNA deletion-bearing mitochondria and the loss of dopaminergic neurons with age, but it seems safe to assume that even if they don't kill their host neurons, deletion-bearing mitochondria sweeping across the cell leads to an energetic brownout that makes any surviving neurons less effective. The MitoSENS lab at SENS Research Foundation is working to develop three different platform technologies (including the original MitoSENS strategy of allotopic expression) to prevent, replace, or bypass mitochondrial DNA mutations.

Astrocytes are a kind of cellular butler for brain neurons, serving them energy sources and keeping their environment orderly so they can do their job. But like many cell types, astrocytes can turn senescent with age in response to many kinds of stress and injury. Researchers have reported that the brains of people with Parkinson's have a higher burden of senescent astrocytes than do people the same age who are free of the disease. To see if senescent astrocytes were really driving Parkinson's-like degeneration in living mammals, the researchers conducted an experiment using mice in whom they could destroy senescent cells at will. Scientists had engineered these mice with ApoptoSENS "suicide genes" that would detonate in senescent cells anytime the scientists "pulled the trigger" by treating them with a drug that activates the genetic system. They treated one group of these Parkinson's-like mice with the drug that would activate the ApoptoSENS "suicide genes" in any senescent cells they might harbor, while leaving another group of Parkinson's mice untreated for comparison. The control Parkinson's mice suffered a massive loss of dopaminergic neurons, developed movement problems that stand in for the symptoms of Parkinson's, and lost much of their ability to generate new neurons elsewhere in the brain. But much of this damage and dysfunction was prevented when researchers gave Parkinson's mice an ApoptoSENS treatment.

Lipid metabolism is changed and disrupted with advancing age, as is the case for all complex mechanisms in the body. There are a great many different lipids present in the body; even the list of classes of lipid is a long one. Finding specific changes that relate to aging can be interesting, but the challenge lie in better understanding how those changes come about, and whether they causes significant harm to tissues. Many age-related changes in molecular biochemistry are far downstream of the important causes of aging and do not cause much further disruption in and of themselves.

In recent years, laboratory research has shown that we may be able to counteract age-related diseases by intervening in the fundamental processes that lead to ageing. Although science has increasingly mapped out how metabolism changes during aging, large parts remained uncharted. "We wanted to add a new chapter to the atlas. Lipids are an important part of our diet, and crucial for the functioning of our body cells. Specific lipids make up the membrane of cells, which ensures that the inside and outside remain separate."

In order to add this new chapter, the research team investigated how the composition of fats changes in mice. They looked at ten different tissues, including muscles, kidneys, liver and heart. It was noticed that one type of lipid, the bis(monoacylglycero)phosphates (or BMPs), were elevated in all tissues from the older animals. Suggesting an accumulation of these lipids during aging. They then investigated whether this also happens in humans. Although it was not possible to obtain as many different tissues, the accumulation of BMP was also visible in muscle biopsies of older people. Finally, they then completed more muscle biopsies from people before and after a healthy intervention that included one hour of exercise a day and saw the level of BMPs decreased in the active participants.

Link: https://www.eurekalert.org/news-releases/1040554

The causes of idiopathic pulmonary fibrosis remain somewhat unclear, which is often the case for conditions in which treatments struggle to achieve more than a slowed progression. There is evidence for cellular senescence to drive the progression of fibrosis, but most research remains focused on the molecular biochemistry of fibroblasts, the cells responsible for building the collagen deposits characteristic of fibrotic tissue.

The process by which lung injury either leads to healing or fibrosis relies in part on what happens to a cell called a fibroblast, which forms connective tissue. During injury or illness, fibroblasts are activated, becoming myofibroblasts that form scar tissue by secreting collagen. When the job is done, these fibroblasts must be deactivated, or de-differentiated, to go back to their quiet state or undergo programmed cell death and be cleared.

This is the major distinction between normal wound healing and fibrosis - the persistence of activated myofibroblasts. That deactivation is controlled by molecular brakes. The study examined one of these brakes, called MKP1 - which researchers found was expressed at lower levels in fibroblasts from patients with idiopathic pulmonary fibrosis. By genetically eliminating MKP1 in fibroblasts of mice after establishing lung injury, the researchers saw that fibrosis continued uncontrolled.

"Instead of at day 63, seeing that nice resolution, you still see fibrosis. We argued by contradiction: when you knock out this brake, fibrosis that would otherwise naturally disappear, persists and therefore MKP1 is necessary for spontaneous resolution of fibrosis. We demonstrated that neither of the FDA approved drugs for lung fibrosis, pirfenidone and nintedanib, are able to turn off myofibroblasts. That's totally in keeping with the fact that they do slow the progression, but they don't halt or reverse disease."

Link: https://www.michiganmedicine.org/health-lab/study-reveals-potential-reverse-lung-fibrosis-using-bodys-own-healing-technique

The consensus of the research community on senescent cells in old tissues is that (a) their presence causes harm, and (b) treatments based on the selective removal of such cells will be beneficial, reversing many aspects of aging and age-related disease. These cells secrete a pro-inflammatory mix of signal molecules that is disruptive to tissue structure and function when maintained over time. Cells become senescent constantly throughout life, only to be destroyed by programmed cell death or by the immune system. With advancing age, newly created senescent cells are cleared ever more slowly, however, and thus the burden of lingering senescent cells grows throughout the body.

As the authors of today's open access paper note, the presence of senescent endothelial cells in blood vessel walls is considered to be an important contributing cause of many of the age-related dysfunctions of the vasculature. One of the more consequential of these dysfunctions is the loss of capacity to grow new capillaries, leading to a decline in capillary density in tissues throughout the body. A more sparse capillary network reduces blood flow and delivery of oxygen and nutrients to cells, harming tissue function, particularly in energy-hungry tissues such as the brain and muscles. To the extent that senolytic therapies to clear senescent cells can reverse this particular aspect of aging, we should all be in favor of senolytic therapies.

Endothelial Senescence: From Macro- to Micro-Vasculature and Its Implications on Cardiovascular Health

Cellular senescence is originally defined as the irreversible loss of proliferative potential in somatic cells, which enter a viable and metabolically active state of permanent growth arrest that is distinct from quiescence and terminal differentiation. Accumulation of senescent cells contributes to age-related tissue degeneration by developing a complex senescence-associated secretory phenotype (SASP). By secreting a plethora of factors, including pro-inflammatory cytokines, chemokines, growth modulators, matrix metalloproteinases, and compromised extracellular vesicles which represent senescence-associated phenotype, senescent cells reprogram the surrounding microenvironment and cause tissue damage, thus promoting ageing and the development of age-associated diseases.

Intervention experiments have proven that senescent cell accumulation is an important driver of age-associated functional decline, multi-morbidity, and mortality, while systemic clearance of senescent cells delays ageing and extend lifespan. Therapeutically targeting cellular senescence, known as senotherapy, to eliminate senescent cells or induce senolysis, represents a rapidly growing and promising strategy for the prevention and/or treatment of ageing-related diseases. Targeting senescent cells can improve both health-span and life-span in mice.

Endothelial cells line at the most inner layer of blood vessels. They act to control hemostasis, arterial tone/reactivity, wound healing, tissue oxygen, and nutrient supply. With age, endothelial cells become senescent, characterized by reduced regeneration capacity, inflammation, and abnormal secretory profile. Endothelial senescence represents one of the earliest features of arterial ageing and contributes to many age-related diseases.

Compared to those in arteries and veins, endothelial cells of the microcirculation exhibit a greater extent of heterogeneity. Microcirculatory endothelial senescence leads to a declined capillary density, reduced angiogenic potentials, decreased blood flow, impaired barrier properties, and hypoperfusion in a tissue or organ-dependent manner. The heterogeneous phenotypes of microvascular endothelial cells in a particular vascular bed and across different tissues remain largely unknown. Accordingly, the mechanisms underlying macro- and micro-vascular endothelial senescence vary in different pathophysiological conditions, thus offering specific targets for therapeutic development of senolytic drugs.

The balance of microbial populations making up the gut microbiome is different from individual to individual, and changes with age in detrimental ways. Pro-inflammatory microbes, as well as those that create otherwise harmful metabolites, expand in number at the expense of microbial populations that produce beneficial metabolites. Evidence strongly suggests that both variations between individuals and age-related changes in the gut microbiome can contribute to age-related disease and mortality. Here, for example, a study in rabbits shows that specific differences in the gut microbiome correlate well with observed length of life.

Longevity and resilience are two fundamental traits for more sustainable livestock production. These traits are closely related, as resilient animals tend to have longer lifespans. An interesting criterion for increasing longevity in rabbits could be based on the information provided by its gut microbiome. The gut microbiome is essential for regulating health and plays crucial roles in the development of the immune system.

The aim of this research was to investigate if animals with different longevities have different microbial profiles. We sequenced the 16S rRNA gene from soft faeces from 95 does. First, we compared two maternal rabbit lines with different longevities; a standard longevity maternal line (A) and a maternal line (LP) that was founded based on longevity criteria: females with a minimum of 25 parities with an average prolificacy per parity of 9 or more. Second, we compared the gut microbiota of two groups of animals from line LP with different longevities: females that died/were culled with two parities or less (LLP) and females with more than 15 parities (HLP).

Differences in alpha diversity and beta diversity were observed between lines A and LP, and analysis showed a high prediction accuracy (more than 91%) of classification of animals to line A versus LP. Interestingly, some of the most important microbial taxa identified were common to both comparisons (Akkermansia, Christensenellaceae R-7, Uncultured Eubacteriaceae, among others) and have been reported to be related to resilience and longevity.

In summary, our results indicate that the first parity gut microbiome profile differs between the two rabbit maternal lines (A and LP) and, to a lesser extent, between animals of line LP with different longevities (LLP and HLP). Several genera were able to discriminate animals from the two lines and animals with different longevities, which shows that the gut microbiome could be used as a predictive factor for longevity, or as a selection criterion for these traits.

Link: https://doi.org/10.1186/s12711-024-00895-6

As some of you may know, I co-founded Repair Biotechnologies with Bill Cherman. The company is presently on the development of a gene therapy approach now demonstrated to rapidly reverse atherosclerosis in mice, the condition in which fatty plaques grow to narrow blood vessels and weaken blood vessel walls. One of the possible approaches to treating aging as a medical condition is to take the list of causes of human mortality, start at the top, and work down. Atherosclerosis is the single largest cause of death in our species, through the rupture of unstable atherosclerotic plaque leading to heart attack or stroke. The burden of established plaque correlates with mortality risk, but repeatable, sizable reversal of plaque in patients cannot be achieved by the current approaches to treatment that are focused on lifestyle factors and LDL-cholesterol level in the bloodstream.

To date, we have used our Cholesterol Degrading Platform (CDP) to demonstrate rapid and profound reversal of disease in mouse models of (a) metabolic dysfunction-associated steatohepatitis (MASH), a progression of fatty liver towards liver failure that is characterized by fibrosis and loss of liver function, (b) atherosclerosis, the buildup of fatty plaques in blood vessel walls, leading to cardiovascular disease and stroke, and (c) homozygous familial hypercholesterolemia (HoFH), an inherited condition involving loss-of-function mutations in low-density lipoprotein receptors (LDLR) that causes high blood cholesterol and greatly accelerated atherosclerosis.

These three conditions are characterized by being largely irreversible under the present standards of care. While slowing the progression of disease is sometimes possible, few patients have been shown to achieve any meaningful reversal of established liver fibrosis or arterial atherosclerotic plaque, and the methods used to treat those patients are not consistently effective in other patients.

In each case, 6 to 8 weeks of once-weekly injections of CDP therapy produced sizable improvements in blood chemistry, including reductions in alanine aminotransferase (ALT), a measure of liver cell death and stress, and in histological assessments of disease. In MASH model mice, a 52% reduction in liver fibrosis was observed versus untreated controls. In the ApoE-knockout mouse model of atherosclerosis, plaque lipids were reduced by 19% while plaque collagen increased by 23% versus controls, a dramatic stabilization of unstable plaques at risk of rupture. In the LDLR-knockout mouse model of HoFH, plaque cross-sectional area decreased by 17% and mouse treadmill performance improved by 60% versus controls, a considerable improvement in cardiovascular function.

To compare this with other present efforts, the drug, resmetirom (Madrigal Pharmaceuticals), recently approved by the FDA for the treatment of MASH, has no effect on fibrosis in mice over 8 weeks of treatment. In the MAESTRO human trial in patients with comparatively mild MASH, the treated groups saw only a 25% reduction in fibrosis compared to 14% in the placebo group after 52 weeks of treatment. In the case of atherosclerosis, large clinical trials have shown that long-term treatment with statins or other low-density lipoprotein (LDL)-lowering technologies such as PCSK9 inhibitors fails to produce a reduction in atherosclerotic plaque volume of more than a few percentage points. Our CDP therapy far outperforms these approaches to treatment.

Perhaps the most interesting outcome is that we have demonstrated that a localized excess of free cholesterol is indeed a major factor in many conditions, age-related and obesity-related. It had been theorized that this was the case for liver diseases such as MASH, but lacking a technology that selectively cleared only free cholesterol, this had to remain only a compelling theory. Armed with that selective clearance technology, our results have now convincingly demonstrated that free cholesterol toxicity is a major, important target for many conditions.

Link: https://www.lifespan.io/news/new-gene-therapy-reverses-atherosclerosis-in-mice/

Species that exhibit negligible senescence tend to be long-lived, but more interestingly appear to exhibit few to none of the functional declines of degenerative aging until very late in life, quite unlike the situation for most mammals, and particularly for humans. One can argue that the most useful species that exhibit negligible senescence are those with near relative species that age more normally. The closer the relative, the more likely it is that comparing the biochemistry of the two will lead to new knowledge regarding aging. So naked mole rats versus other, less long-lived mole rats, Brandt's bat versus other shorter-lived small bats, or as in today's open access paper, the red sea urchin versus short-lived urchin species.

Whether this work on the comparative biology of aging can cost-effectively produce a basis for useful therapies in human medicine remains an open question. Research into the biochemistry of naked mole rats, probably the closest negligibly senescent species to our own species, has yet to yield a way to build useful treatments for aspects of human aging. The one experiment conducted to date involving the transfer of naked mole-rat genes into mice didn't produce the hoped-for sizable gains. It may turn out to be slow, expensive, and challenging to work towards this sort of modification of our biochemistry, as compared with the more standard approaches to medical research

Genomic signatures of exceptional longevity and negligible aging in the long-lived red sea urchin

A tremendous variety of life history strategies have evolved across the animal kingdom, including some animals that achieve remarkably long lifespans (on the order of centuries) without the physiological decline that typically accompanies aging. This phenomenon, referred to as negligible senescence, is characterized by a lack of increased mortality rate or decreased fecundity as an organism ages, in combination with maintenance of physiological function and disease resistance. Animals with extraordinary longevity and negligible senescence rely on unique mechanisms to promote long-term maintenance of tissue homeostasis and physiological function while avoiding degenerative and neoplastic diseases. Understanding these mechanisms can reveal effective strategies to achieve longevity and healthy aging.

Comparative genomics between long-lived and short-lived species is a powerful approach to understand the evolution of longevity and enables unbiased discovery of genes and pathways that regulate lifespan. This approach has been used to identify molecular signatures related to longevity and has uncovered both shared and distinct strategies to modulate aging and disease resistance. Sea urchins represent a promising group of organisms to advance our understanding of lifespan determination and healthy aging. There are approximately 1,000 extant sea urchin species that exhibit a wide range of lifespans, including species with exceptional longevity and negligible senescence.

Life history data indicates that the red sea urchin, Mesocentrotus franciscanus, is one of the Earth's longest-living animals. It is reported to live more than 100 years and shows negligible senescence as defined by indeterminate growth, life-long reproduction, and no age-associated increase in mortality rate or increased incidence of disease, including no known cases of cancer. Negligible senescence has also been reported for other sea urchin species despite a wide range of lifespans. This includes the variegated sea urchin, Lytechinus variegatus, which is reported to live 3-4 years, the painted sea urchin, Lytechinus pictus, reported to live 5-7 years, and the purple sea urchin, Strongylocentrotus purpuratus, reported to live longer than 50 years.

Studies to date, conducted within the framework of known theories of aging, have demonstrated that both short-lived and long-lived sea urchin species lack many hallmarks of aging. Sea urchins maintain telomere length, antioxidant and proteasome enzyme activities, and regenerative capacity, and exhibit little accumulation of oxidative cellular damage with age. Gene expression studies using tissues of long-lived species indicate that key cellular pathways involved in protein homeostasis, tissue regeneration, and neurological function are maintained with age. Although genomes have been assembled for several sea urchin species, including S. purpuratus, L. variegatus, and L. pictus, to date no high-quality genome has become available for the long-lived red sea urchin M. franciscanus. Here we report a chromosome-level assembly for the red sea urchin genome. Targeted analysis of this genome and comparisons between long- and short-lived species sheds light on the molecular, cellular, and systemic mechanisms that promote longevity and negligible senescence.

A number of large epidemiological studies provide evidence for long-term exposure to greater levels of air pollution to accelerate the onset and progression of age-related disease. A few of these manage to control for the tendency for wealthier people to avoid living in areas with higher particulate air pollution, and the correlation with worse health remains. Mechanistically, it is thought that particulates provoke greater chronic inflammation via their interaction with lung and other tissues, and this in turn contributes to the cell and tissue dysfunction that leads to age-related disease.

The present study assessed cognitive test performance in English older adults in relation to long-term air pollution exposure at the residential address. The follow-up period of 15 years and the large number of repeated measurements make the present study unique in terms of design and data availability. Increasing exposure to NO2, PM10 and PM2.5 was consistently found to be associated with decreased memory and executive function test performance, whilst ozone showed the opposite effect. The results remained similar in the analysis including residents of London only, for whom exposure to NO2 and PM was higher. As an illustrative example, the decline in memory and executive function scores per interquartile range (IQR) increase in long-term NO2 exposure was found equivalent to ageing by about 1.5 and 4 years respectively.

In order to fully elucidate the potentially adverse cognitive effects of air pollution, further study into the underlying biological pathways and mechanisms through which air pollution may contribute to cognitive decline is required alongside the expanding epidemiological work. Translocation of inhaled particles from the lung to the brain via the bloodstream provides one possible pathway through which particulate matter may affect cognition, as well as inhalation through the nose and transportation to the olfactory bulb via olfactory nerves. Evidence for such pathways is currently limited and further experimental studies are required.

Link: https://doi.org/10.1186/s12940-024-01075-1

Many compounds are now known to have some positive influence on mitochondrial function. The biochemistry is complex and incompletely understood. Even in the well-studied cases, there are hypotheses regarding the mechanism of action, but little certainty. In general, improvement of the quality control mechanism of mitophagy appears to be a necessary factor in the improvement of mitochondrial function in old tissues, but that appears to happen as the result of many different types of intervention. Here, researchers note that a class of bacterial peptides originating from the gut microbiome appear to improve mitochondrial function in intestinal tissue. This may be the basis for yet another type of treatment or supplement to modestly improve mitochondrial function. Those developed to date struggle to improve on the effects of exercise, however.

Mitochondrial dysfunction critically contributes to many major human diseases. The impact of specific gut microbial metabolites on mitochondrial functions of animals and the underlying mechanisms remain to be uncovered. Here, we report a profound role of bacterial peptidoglycan muropeptides in promoting mitochondrial functions in multiple mammalian models. Muropeptide addition to human intestinal epithelial cells (IECs) leads to increased oxidative respiration and ATP production and decreased oxidative stress. Strikingly, muropeptide treatment recovers mitochondrial structure and functions and inhibits several pathological phenotypes of fibroblast cells derived from patients with mitochondrial disease.

In mice, muropeptides accumulate in mitochondria of IECs and promote small intestinal homeostasis and nutrient absorption by modulating energy metabolism. Muropeptides directly bind to ATP synthase, stabilize the complex, and promote its enzymatic activity in vitro, supporting the hypothesis that muropeptides promote mitochondria homeostasis at least in part by acting as ATP synthase agonists. This study reveals a potential treatment for human mitochondrial diseases.

Link: https://doi.org/10.1016/j.celrep.2024.114067

Taurine is a amino acid mainly found in fish and meat in the diet. It is not an essential amino acid, and can be synthesized in humans. Circulating taurine levels in the bloodstream decline with age by about 50% by middle age for reasons that have yet to be determined. Studies in aged mice and non-human primates have shown modestly improved function and slowed aging following taurine supplementation. Past human studies of taurine supplementation have produced entirely unimpressive outcomes, but given that they predated present aging clocks it may be that the researchers were evaluating the wrong metrics. Taurine may act on the pace of aging through a range of different mechanisms, and it remains unclear as to which of these are more or less important.

In the context of recent studies on taurine supplementation, today's open access paper seemed interesting. The authors report on correlations between taurine intake in the normal diet with a few measures of fitness and muscle strength in middle-aged individuals. Human studies of taurine supplementation require a dose in the range of 1.5-6.0 grams per day to remove the 50% loss in circulating taurine. This supplement dose is the human equivalent extrapolated from the effective doses in mice and non-human primates. Here, dietary intake of taurine in the study participants was estimated to be ~200 milligrams per day, which is actually higher than previously reported averages, particularly for vegetarians. Given that, one might argue that taurine levels in the diet are a proxy for the influence of some other better-studied aspect of dietary choices on long-term health, such as overall protein intake.

Association of taurine intake with changes in physical fitness among community-dwelling middle-aged and older Japanese adults: an 8-year longitudinal study

Taurine has diverse valuable biological functions, including antioxidant activity and regulation of osmotic pressure. Maintaining physical fitness from middle age is important for healthy life expectancy. Although taurine administration improves muscle endurance and strength, its role in maintenance remains unclear. We aimed to clarify the longitudinal taurine intake association with fitness changes.

Participants comprised men and women aged ≥40 years who participated in the third (2002-2004; Baseline) and seventh (2010-2012; Follow-up) waves of the National Institute for Longevity Sciences-Longitudinal Study of Aging (NILS-LSA) and completed a 3-day dietary weights recording survey at baseline. A table of taurine content was prepared for 751 foods (including five food groups: Seaweed; Fish and shellfish; Meat; Eggs; and Milk and dairy products) from the Standard Tables of Food Composition in Japan (1,878 foods) 2010. Four physical fitness items (knee extension muscle strength, sit-and-reach, one-leg standing with eyes closed, and maximum walking speed) were measured at baseline and follow-up. We analyzed the association of taurine intake with physical fitness change, employing a general linear model (GLM) and trend tests for baseline taurine intake and follow-up fitness change. Adjustments included baseline variables: sex, age, height, weight, educational level, self-rated health, smoking status, depressive symptoms, and clinical history.

The estimated average daily taurine intake was 207.5 ± 145.6 mg/day at the baseline. When examining the association with the four physical fitness parameters, higher taurine intake positively increased the change in knee extension muscle strength and reduced the decline in knee extension muscle strength in the subgroup analysis of participants aged ≥65 years. No relationship was found between taurine intake and the remaining three fitness factors.

Past evidence has suggested that the lowered body temperature characteristic of calorie restriction is important to the slowed aging that results in short-lived mammals. One might compare that to the strong evidence for upregulated autophagy to be the driving factor in slowed aging produced by the practice of calorie restriction. Researchers here conduct a similar study, inducing a reduction in metabolic rate, dietary intake, and body temperature in mice via activation of a specific brain region. As in past research, the resulting slowed aging was shown to be driven by that lowered body temperature rather than any of the other effects of this intervention.

Torpor and hibernation are extreme physiological adaptations of homeotherms associated with pro-longevity effects. Yet the underlying mechanisms of how torpor affects aging, and whether hypothermic and hypometabolic states can be induced to slow aging and increase health span, remain unknown. We demonstrate that the activity of a spatially defined neuronal population in the anterior and ventral portions of the medial and lateral preoptic area (avMLPA), which has previously been identified as a torpor-regulating brain region, is sufficient to induce a torpor like state (TLS) in mice.

Prolonged induction of TLS slows epigenetic aging across multiple tissues and improves health span. We isolate the effects of decreased metabolic rate, long-term caloric restriction, and decreased core body temperature (Tb) on blood epigenetic aging and find that the pro-longevity effect of torpor-like states is mediated by decreased Tb. Taken together, our findings provide novel mechanistic insight into the pro-longevity effects of torpor and hibernation and support the growing body of evidence that Tb is an important mediator of aging processes.

Link: https://doi.org/10.1101/2024.03.20.585828

Cells become senescent in response to damage, a toxic environment, the signaling of nearby senescent cells, or, most commonly, because they reach the Hayflick limit on replication. Senescent cells cease replication and begin to secrete pro-inflammatory signals, attracting the attention of the immune system. With advancing age he aged immune system becomes less able to clear senescent cells in a timely manner, leading to a growing, permanent presence of senescent cells in tissues. Some of these senescent cells are themselves immune cells. Given the importance of the immune system to tissue maintenance and regeneration, particularly tissue residence innate immune cells such as macrophages, it should be no surprise to find that senescence in these cells is viewed as contributing to degenerative aging.

Macrophage senescence, manifested by the special form of durable cell cycle arrest and chronic low-grade inflammation like senescence-associated secretory phenotype, has long been considered harmful. As the first-responder to the pathogens and damage in the immune response, macrophages play a vital role in the function of phagocytosis and polarization towards different situations to mediate the inflammation inside individuals. Senescent macrophages are usually featured with an unbalanced polarization state, compromised phagocytosis, impaired migration, and damaged autophagy. Due to the abnormal accumulation and the aberrant functions of senescent macrophages, aged people tend to be unhealthy or with acerbated diseases.

Senescent macrophages play various functions in different diseases or organs which indicates that treatments should be specialized for the distinctive characteristics of senescent macrophages. In the cognitive decline, senescent macrophages turn to behave abnormally in phagocytosis for the dampened scavenging of abnormal unfolded proteins in the central nervous system. The imbalanced polarization state in senescent macrophages also contributes to the development of malignant cancers. More senescent macrophages tend to the M2 phenotype promoting tumor cells proliferating and counteract against cytotoxic T lymphocytes.

Contrarily, in ovarian tissue, senescent macrophages turn to the M1 phenotype with a higher level of iNOS which causes ovarian aging. Secretions of senescent macrophages are also in close relationship with some organ disorders. Grancalcin produced by senescent macrophages would exacerbate skeletal aging for the impaired balance between osteogenesis and adipogenesis of bone marrow stroma cells. Additionally, metabolic disturbances like chaotic cholesterol levels in senescent macrophages cause age-related macular degeneration for their proangiogenic function.

Link: https://doi.org/10.1016/j.apsb.2024.01.008

In today's open access paper, researchers here look at some of the proximate causes of transposable element activation, the details of the epigenetic and transcriptional issues. It is well known that transposable element activity increases with age. These are sequences capable of self-replication in the genome, the remnants of ancient retroviral infections. Transposon activity is repressed in youth, the sequences hidden from transcription machinery within compact regions of the packaged genome, or hidden inside intron sequences that are normally excluded from transcription.

Aging produces a growing dysregulation of the epigenetic control of genomic structure and gene expression, allowing transposable elements to be exposed to transcription. Further, the process of splicing by which exons and introns are assembled into RNA molecules also becomes dysregulated, allowing occasional inclusion of introns that are normally excluded in youth. The resulting activation of transposable elements becomes a source of further damage and disarray. These sequences haphazardly insert copies of themselves into the genome, breaking existing genes. They can also potentially cause other harms via their gene products, such as via provoking forms of innate immune response to viral agents.

A concerted increase in readthrough and intron retention drives transposon expression during aging and senescence

Aging and senescence are characterized by pervasive transcriptional dysfunction, including increased expression of transposons and introns. Our aim was to elucidate mechanisms behind this increased expression. Most transposons are found within genes and introns, with a large minority being close to genes. This raises the possibility that transcriptional readthrough and intron retention are responsible for age-related changes in transposon expression rather than expression of autonomous transposons.

To test this, we compiled public RNA-seq datasets from aged human fibroblasts, replicative and drug-induced senescence in human cells, and RNA-seq from aging mice and senescent mouse cells. Indeed, our reanalysis revealed a correlation between transposons expression, intron retention, and transcriptional readthrough across samples and within samples. Both intron retention and readthrough increased with aging or cellular senescence and these transcriptional defects were more pronounced in human samples as compared to those of mice.

In support of a causal connection between readthrough and transposon expression, analysis of models showing induced transcriptional readthrough confirmed that they also show elevated transposon expression. Taken together, our data suggest that elevated transposon reads during aging seen in various RNA-seq dataset are concomitant with multiple transcriptional defects. Intron retention and transcriptional readthrough are the most likely explanation for the expression of transposable elements that lack a functional promoter.

Thymocytes generated in the bone marrow migrate to the thymus, near the heart, where they mature into T cells of the adaptive immune system. Unfortunately, the thymus atrophies with age. Most people have little active thymus tissue left by the time they are in their 50s. Absent a robust supply of new T cells, the adaptive immune system becomes ever more made up of malfunctioning, senescent, and other problematic cells, lacking the naive T cells needed to respond to new threats. Regeneration of the thymus is thus an important goal. There are some indications that the thymus is more plastic than thought, given that mild calorie restriction in humans produced some gains. Additionally, a growth hormone based therapy has shown some signs of improvement in small human trials. Here, researchers show that stem cell transplantation can produce thymic regrowth in old non-human primates, making this an option that should be evaluated in human patients.

A decrease in the number and activity of thymic epithelial cells (TECs) is an important factor in thymic degeneration. Mesenchymal stem cells (MSCs) treating thymic ageing is a promising strategy. Aged rhesus monkeys were treated with MSCs to establish a thymic senescence model, and hematoxylin-eosin (HE) staining, immunofluorescence staining, and ELISA were performed to observe the structure and function of the thymus. TEC aging model and MSCs co-culture system were established to detect DNA methylation modification and transcriptomic changes, correlation analysis between transcription factor methylation and mRNA expression, and q-PCR, immunofluorescence staining, and Western blot were used to identified key genes.

MSCs improved the structure and function of the thymus in elderly macaque monkeys; reduced the expression levels of β-Gal, P16, and P21; and increased the activity of aging TECs. There were 501 genes with increased methylation in the promoter region in the treated group compared with the untreated group, among which 23 genes were involved in the negative regulation of cell growth, proliferation, and apoptosis, while 591 genes had decreased methylation, among which 37 genes were associated with promoting cell growth and proliferation and inhibiting apoptosis. Furthermore, 66 genes showed a negative correlation between promoter methylation levels and gene transcription; specifically, PDE5A, DUOX2, LAMP1, and SVIL were downregulated with increased methylation, inhibiting growth and development, while POLR3G, PGF, CHTF18, KRT17, FOXJ1, NGF, DYRK3, LRP8, CDT1, PRELID1, F2R, KNTC1, and TRIM3 were upregulated with decreased methylation, promoting cell growth.

Link: https://doi.org/10.1016/j.reth.2024.03.008

There is a continuing debate over the degree to which Alzheimer's is driven by persistent infection in brain tissue, such as by varieties of herpesvirus. Amyloid-β is an antimicrobial peptide, a part of the innate immune response, and one could argue that persistently raised expression of amyloid-β will increase misfolding and generation of the aggregates that drive pathology in the early stages of Alzheimer's disease, at least under the amyloid cascade hypothesis. The data is not all convincing, however, which suggests that perhaps there are other factors involved - that multiple viruses interact in some people, for example, or a pathological interaction between viral infection and some other aspect of brain aging only occurs in some people. It remains to be seen as to where this line of research will lead, but even now it seems a good cost-benefit decision to be using antiviral drugs in later life.

Mounting data suggests that herpes simplex virus type 1 (HSV-1) is involved in the pathogenesis of Alzheimer's disease (AD), possibly instigating amyloid-beta (Aβ) accumulation decades before the onset of clinical symptoms. However, human in vivo evidence linking HSV-1 infection to AD pathology is lacking in normal aging. To shed light into this question, serum anti-HSV IgG levels were correlated with measures of Aβ deposits and blood markers of neurodegeneration in cognitively normal older adults. Additionally, we investigated whether associations between anti-HSV IgG and AD markers were more evident in APOE4 carriers.

We showed that increased anti-HSV IgG levels are associated with higher Aβ load in fronto-temporal regions of cognitively normal older adults. Remarkably, these cortical regions exhibited abnormal patterns of resting state-functional connectivity (rs-FC) only in those individuals showing the highest levels of anti-HSV IgG. We further found that positive relationships between anti-HSV IgG levels and Aβ load, particularly in the anterior cingulate cortex, are moderated by the APOE4 genotype, the strongest genetic risk factor for AD. Importantly, anti-HSV IgG levels were unrelated to either subclinical cognitive deficits or to blood markers of neurodegeneration.

These results suggest that HSV infection is selectively related to cortical Aβ deposition in normal aging, supporting the inclusion of cognitively normal older adults in prospective trials of antimicrobial therapy aimed at decreasing the AD risk in the aging population.

Link: https://doi.org/10.1186/s13195-024-01437-4

Dysfunction in hair follicles and loss of the capacity for hair growth is a perhaps surprisingly complex aspect of aging and disease. For all the the basic mechanisms of hair growth are well-investigated, the hair follicle is a complex structure, and hair growth involves the collaboration of many cell types, activities, and signaling that shifts over time as the follicle progresses through the stages of growth. It has proven to be hard to pin down any one specific mechanism as vital, and it may turn out to be the case that no one specific mechanism is the key to preventing loss of hair with advancing age and other circumstances.

Nonetheless, researchers continue to search for that one specific mechanism that may reverse age-related loss of hair follicle function and hair growth. In today's open access paper, researchers argue for innate immune involvement to be important, mediated by toll-like receptor 2 (TLR2). Level and activity of TLR2 both decline with age, while delivery of a suitable native ligand that interacts with TLR2 produces improved regeneration of hair follicles and hair regrowth following injury in mice. Whether this approach will also work to reverse hair thinning and hair follicle dysfunction in old, uninjured animals remains to be seen.

TLR2 regulates hair follicle cycle and regeneration via BMP signaling

Hair follicles (HFs) represent one of the best examples of mini-organs with the ability to regenerate throughout life, which, in turn, relies on the proliferation and differentiation of HF stem cells (HFSCs) within hair bulge. The cyclic renewal of HFs is orchestrated by the interplay between inhibitory and stimulatory signals. Despite the immune privileged status of HFs, they have a unique microbiome and immune system, including resident macrophages and other immune cells. Components of the HF immune system have been implicated in regulating the HF cycle and its regeneration. Given their exposure to pathogens, HFs are equipped with innate immune receptors, particularly Toll-like receptors (TLRs), which detect and respond to pathogens by stimulating the secretion of defensins.

TLRs play a key role in recognizing and responding to either pathogen-associated molecular patterns or damage-associated molecular patterns, mediating the cytokine response. However, the role of TLRs extends beyond this function, as they have been shown to directly promote tissue regeneration and homeostasis in multiple tissues, particularly in stem and progenitor cells.

Multiple reports connect altered HFs' immunity to hair loss, including a breakdown of immune privilege in alopecia areata. Likewise, androgen, which is tightly linked to TLR activation, was shown to influence the innate immunity of HFs in androgenic alopecia. The decline of innate immunity processes due to aging or conditions like obesity is widely recognized and these conditions are causatively associated with hair thinning and loss. Alopecia patients often have higher body weight index and weight compared to healthy individuals. Increased body weight index is linked to more significant hair loss severity in adults and a higher prevalence of hair disorders in children and adolescents. Mouse models support these findings, showing that activation of innate immunity through pathogen signals might lead to alopecia and that high-fat diets inducing obesity cause hair thinning through HFSC depletion.

Transcriptome analysis of aging hair follicles uncovered changes in immune pathways, including TLRs. Our findings demonstrate that the maintenance of hair follicle homeostasis and the regeneration capacity after damage depend on TLR2 in hair follicle stem cells (HFSCs). In healthy hair follicles, TLR2 is expressed in a hair cycle-dependent manner and governs HFSCs activation by countering inhibitory BMP signaling. Hair follicles in aging and obesity exhibit a decrease in both TLR2 and its endogenous ligand carboxyethylpyrrole (CEP), a metabolite of polyunsaturated fatty acids. Administration of CEP stimulates hair regeneration through a TLR2-dependent mechanism. These results establish a novel connection between TLR2-mediated innate immunity and HFSC activation, which is pivotal to hair follicle health and the prevention of hair loss and provide new avenues for therapeutic intervention.

A heart attack is triggered by rupture of an atherosclerotic plaque and downstream blockage of an important vessel feeding oxygenated blood to heart tissue. Much of the permanent harm resulting from a heart attack occurs when blood flow is restored to ischemic tissue, however. A cascade of maladaptive reactions, inflammation, and cell death occurs, leading to scarring and loss of function in the heart muscle. This damage to the heart can be reduced to some degree by anti-inflammatory signaling applied soon after the heart attack takes place, as researchers here demonstrate.

Despite major improvements using primary percutaneous intervention (PPCI) to treat patients with acute ST-elevation myocardial infarction (STEMI), progression to heart failure after infarction represents a major clinical problem. Despite state-of-the-art medical care, 22% of patients with STEMI treated with PPCI develop heart failure symptoms within 1 year. Detrimental progression is substantively determined by the original infarct size and time to reperfusion. An acute exuberant proinflammatory response can further enhance local cardiac injury. Over time, this can lead to adverse ventricular remodeling and gradual loss of cardiac function that can result in heart failure. For patients with STEMI, particularly those with large infarcts, additional intervention in the acute phase is needed to reduce ischemia-reperfusion injury and protect myocardial tissue, thereby reducing the risk of progression to heart failure.

Transforming growth factor (TGF)-β1 is a potent anti-inflammatory cytokine released in response to tissue injury. The aim of this study was to investigate the protective effects of TGF-β1 after myocardial infarction. In patients with STEMI, there was a significant correlation between higher circulating TGF-β1 levels at 24 hours after myocardial infarction and a reduction in infarct size after 3 months, suggesting a protective role of early increase in circulating TGF-β1. A mouse model of cardiac ischemia reperfusion was used to demonstrate multiple benefits of exogenous TGF-β1 delivered in the acute phase. It led to a significantly smaller infarct size (30% reduction), reduced inflammatory infiltrate (28% reduction), lower intracardiac expression of inflammatory cytokines IL-1β and CCL2 (more than a 50% reduction) at 24 hours, and reduced scar size at 4 weeks (21% reduction) after reperfusion.

Link: https://doi.org/10.1016/j.ajpath.2023.09.014

The question of whether there are long-lived molecules in long-lived neurons in the brain is an interesting one. Are there specific molecules in the brain that never get replaced across a lifetime, and thus might be vulnerable to damage in the form of modifications that disrupt function? This remains a somewhat hypothetical concern, in the sense that there is no direct demonstration that this is a significant source of dysfunction in late life. Researchers have found evidence for long-lived nuclear pore proteins, however, and here another group presents evidence for long-lived RNA molecules.

Most cells in the human body are regularly renewed, thereby retaining their vitality. However, there are exceptions: the heart, the pancreas, and the brain consist of cells that do not renew throughout the whole lifespan, and yet still have to remain in full working order. Now researchers were able to demonstrate for the first time that certain types of ribonucleic acid (RNA) that protect genetic material exist just as long as the neurons themselves.

"This is surprising, as unlike DNA, which as a rule never changes, most RNA molecules are extremely short-lived and are constantly being exchanged. We succeeded in marking the RNAs with fluorescent molecules and tracking their lifespan in mice brain cells. We were even able to identify the marked long-lived RNAs in two year old animals, and not just in their neurons, but also in somatic adult neural stem cells in the brain."

In addition, the researchers discovered that the long-lived RNAs, that they referred to as LL-RNA for short, tend to be located in the cells' nuclei, closely connected to chromatin, a complex of DNA and proteins that forms chromosomes. This indicates that LL-RNA play a key role in regulating chromatin. In order to confirm this hypothesis, the team reduced the concentration of LL-RNA in an in-vitro experiment with adult neural stem cell models, with the result that the integrity of the chromatin was strongly impaired.

Link: https://www.eurekalert.org/news-releases/1040098

As some of you know, Repair Biotechnologies is the company I co-founded with Bill Cherman back in 2018. We've been working on an approach to reverse atherosclerosis for much of that time, and matters have progressed through the stage of great data in mice to present preparations for a pre-IND meeting with the FDA. While excess cholesterol has long been understood to be important to the development of atherosclerosis, it turns out that circulating cholesterol bound to LDL particles is less important than the amount of localized excess cholesterol in the liver and blood vessel walls.

Any localized excess of cholesterol can overwhelm the ability of cells to reduce uptake or store cholesterol in either the cell membrane or in esterified droplets. The resulting free cholesterol inside cells is toxic. The gene therapies developed by the Repair Biotechnologies scientists put in place novel protein machinery that can selectively and safely break down this excess free cholesterol without harming the cholesterol necessary to cell function. This can, for example, protect macrophages from becoming foam cells when exposed to excessive cholesterol. It can also put a halt to dysfunction in liver cells affected by the excess cholesterol present in a fatty liver.

Repair Biotechnologies' gene therapy rapidly reverses atherosclerosis in mice

Gene therapy company Repair Biotechnologies has revealed promising preclinical results that demonstrate its technology rapidly reverses the progression of atherosclerosis in mouse models. The company says the development holds potential for treating both atherosclerosis and a rare genetic condition called familial hypercholesterolemia, in humans.

Atherosclerosis is a condition characterized by the buildup of plaque in arteries, eventually blocking blood flow, and contributing significantly to heart disease, stroke, and death. In experiments, scientists at Repair Biotechnologies treated atherosclerotic mouse models with the lipid nanoparticle (LNP)-messenger RNA (mRNA) therapy over a six-week period, with promising results.

Both groups of mice, one representing a general population model for atherosclerosis, and another modeling familial hypercholesterolemia, exhibited significant reductions in plaque buildup. Specifically, the atherosclerotic mice showed a 19% drop in plaque lipids and a 23% increase in plaque collagen, indicating stabilization of vulnerable plaque. The mice with familial hypercholesterolemia experienced a 17% reduction in plaque obstruction in the aortic root, alongside improved cardiovascular health demonstrated by increased treadmill capacity.

Based in Syracuse, New York, Repair Bio is developing LNP-mRNA therapies targeting a range of health conditions. Unlike traditional therapies that focus on reducing LDL-cholesterol levels in the bloodstream, the company's therapy targets intracellular free cholesterol, which is toxic to cells and contributes to the development of numerous conditions. Repair Bio's approach leverages its cholesterol degrading platform technology to safely break down excess free cholesterol within cells.

"Unfortunately statins and PCSK9 inhibitors that reduce LDL-cholesterol in the blood exhibit little ability to reduce the size of established atherosclerotic lesions," said Mourad Topors, CSO at Repair Bio. "Our studies in severely atherosclerotic mice demonstrate that LDL-cholesterol is the wrong target if the goal is the outright regression of plaque and dramatic reduction in risk of cardiovascular events. Instead, clearance of intracellular free cholesterol can potentially achieve these goals."

Researchers here describe a mechanism that reduces the ability of microglia to ingest and clear misfolded amyloid-β, the protein aggregates associated with Alzheimer's disease. Interestingly, this involves APOE, and thus might be affected by the different APOE variants connected to Alzheimer's disease risk. The researchers demonstrate that interfering in the interaction between APOE and the LILRB4 receptor present on microglia can restore microglia-mediated clearance of amyloid-β.

Toxic clumps of brain proteins are features of many neurodegenerative conditions, including Alzheimer's disease (AD), Parkinson's disease, amyotrophic lateral sclerosis, and Huntington's disease. Microglia surround plaques to create a barrier that controls the damaging protein's spread. They also can engulf and destroy the plaque proteins, but in Alzheimer's disease they usually do not. The source of their passivity could result from a protein called APOE that is a component of amyloid plaques. The APOE proteins in the plaque bind to a receptor - LILRB4 - on the microglia surrounding the plaques, inactivating them.

For reasons that are still unknown, the researchers found that, in mice and people with Alzheimer's disease, microglia that surround plaques produce and position LILRB4 on their cell surface, which inhibits their ability to control damaging plaque formation upon binding to APOE. Researchers treated mice that had amyloid beta plaques in the brain with a homemade antibody that blocked APOE from binding to LILRB4. The researchers found that activated microglia were able to engulf and clear the amyloid beta plaques.

After amyloid beta plaques form in the brain, another brain protein - tau - becomes tangled inside neurons. In this second stage of the disease, neurons die and cognitive symptoms arise. High levels of LILRB4 and APOE have been observed in AD patients in this later stage. It is possible that blocking the proteins from interacting and activating microglia could alter later stages of the disease. In future studies, the researchers will test the antibody in mice with tau tangles.

Link: https://medicine.wustl.edu/news/immunotherapy-for-alzheimers-disease-shows-promise-in-mouse-study/

Merging the non-profits SENS Research Foundation and Lifespan.io is one of those ideas that makes a lot of sense in hindsight. SENS Research Foundation is research focused and very much interested in expanding into patient advocacy, as it depends on philanthropic funding. Lifespan.io is a patient advocacy organization that is very much interested into expanding into helping to advance the science of aging and clinical trials for therapies of aging. They complement one another, and may well produce greater gains as one organization than as two.

Lifespan.io, renowned for its unwavering advocacy for longevity and responsible journalism, is joining hands with SENS Research Foundation, a trailblazer in longevity-focused research and a pioneer of the damage-repair approach to combating aging. Together, these organizations bring a formidable quarter-century of combined expertise to the table. Their collaborative efforts have propelled the field forward and been instrumental in garnering recognition for longevity research as a vital and transformative industry.

This merger represents a deliberate alignment of research and advocacy efforts, uniting them toward the immediate goal of expediting advancements in extending healthy human lifespan instead of waiting for the distant future. With an aim of bolstering the industry at large, they will offer a platform for information creation and dissemination to foster global impact. By pooling together resources, expertise, and networks, the newly formed entity is positioned to significantly influence the progress of rejuvenation biotechnologies while enhancing public awareness and involvement.

Upon completion of the regulatory process, the merger is slated to be finalized by the end of 2024. Lisa Fabiny-Kiser as Chief Executive Officer, and Stephanie Dainow as Chief Business Officer are poised to be Co-Founders of this new entity, joined by an equally representative Board of Directors. By leveraging their combined strengths and a redoubled focus on impactful and translatable research, the merged organization will serve a key sense-making and unifying role for the longevity industry, accelerating the development, translation, and equitable distribution of therapies to increase healthy human lifespan.

Link: https://www.sens.org/sens-research-foundation-and-lifespan-io-announce-intent-to-merge-forming-a-novel-longevity-entity/

Regulatory systems that detect low levels of the essential amino acid methionine are one of the more important triggers for the metabolic response to fasting and calorie restriction. Methionine is not manufactured in mammalian cells, can only be obtained from the diet, but is nonetheless essential for protein synthesis. Thus reducing only methionine levels in the diet can capture a sizable fraction of the benefits of calorie restriction.

While it is possible for a self-experimenter armed with time, a suitable database of methionine content by food type, and considerable willpower to practice significant levels of methionine restriction, it arguably requires a great deal more effort than simply restricting calories. Medical diets structured to have low methionine levels exist, but are expensive. Methionine restriction is thus not widely practiced as a dietary choice by anyone other than those forced into it by rare medical conditions.

In today's open access paper, researchers demonstrate that intermittent methionine restriction produces similar metabolic changes to continuous methionine restriction, while maintaining greater bone mineral density. This is interesting when considered in analogy to the past decade of work comparing the effects of intermittent fasting with calorie restriction. Some researchers theorize that the periods of refeeding between periods of restriction are beneficial, and that the optimal approach to nutrition is thus some arrangement of periodic fasting.

Intermittent Methionine Restriction Reduces Marrow Fat Accumulation and Preserves More Bone Mass than Continuous Methionine Restriction

Continuous methionine restriction (MR) is one of only a few dietary interventions known to dramatically extend mammalian healthspan. For example, continuously methionine-restricted rodents show less age-related pathology and are up to 45% longer-lived than controls. Intriguingly, MR is feasible for humans, and a number of studies have suggested that methionine-restricted individuals may receive similar healthspan benefits as rodents. However, long-term adherence to a continuously methionine-restricted diet is likely to be challenging (or even undesirable) for many individuals. To address this, we previously developed an intermittent version of MR (IMR) and demonstrated that it confers nearly identical metabolic health benefits to mice as the continuous intervention, despite having a relatively short interventional period (i.e., only three days per week). We also observed that female mice undergoing IMR show a more pronounced amelioration of diet-induced dysglycemia than continuously methionine-restricted counterparts, while male mice undergoing IMR retain more lean body mass as compared with continuously methionine-restricted controls. Prompted by such findings, we sought to determine other ways in which IMR might compare favorably with continuous MR.

While it is known that continuous MR has deleterious effects on bone in mice, including loss of both trabecular and cortical bone, we considered that mice undergoing IMR might retain more bone mass. Here, we report that, as compared with continuous MR, IMR results in a preservation of both trabecular and cortical bone, as well as a dramatic reduction in the accumulation of marrow fat. Consistent with such findings, mechanical testing revealed that the bones of intermittently methionine-restricted mice are significantly stronger than those of mice subjected to the continuous intervention. Finally, static histomorphometric analyses suggest that IMR likely results in more bone mass than that produced by continuous MR, primarily by increasing the number of osteoblasts. Together, our results demonstrate that the more practicable intermittent form of MR not only confers similar metabolic health benefits to the continuous intervention but does so without markedly deleterious effects on either the amount or strength of bone. These data provide further support for the use of IMR in humans.

While early senolytic therapies to clear senescent cells do well in mice, clearing a third to a half of the lingering senescent cells in some tissues and rapidly reversing many aspects of aging, to go much further than this will require a greater understanding of cellular senescence. Unfortunately, it is becoming clear that what we call senescence varies considerably from cell type to cell type, and there is much yet to be discovered regarding targets for therapy, ways to assess the burden of senescence, and more.

Despite significant advances in the characterization of senescent cells (SnCs), many questions about the biology of these cells remain open. Firstly, it is necessary to understand which markers are necessary and sufficient to define that a cell is in a "full" or "deep" senescent state. Similarly, the dynamics and adaptability of SnCs still need to be better understood, including how plastic those cells are for the expression of senescent cell anti-apoptotic pathways (SCAPs), the structure of intracellular compartments, or senescence-associated secretory phenotype (SASP) composition, the pathways governing these transitions, and how intense these phenotypic variations must be to influence the non-autonomous role played by SnCs. Understanding these aspects may also allow us to infer whether differences within SnCs of cell populations occur due to different states in different SnCs or the plasticity of individual SnCs. Finally, it is also imperative to comprehend the heterogeneity and the cause-and-effect between subcellular features and the outcome of SnCs. New evidence regarding the above questions can also contribute to understanding questions such as how long an SnC lives and whether death is the only possible outcome.

A better understanding of essential features of SnCs can also contribute to translational issues in which cellular senescence appears to be relevant. Questions like the role of SASP in acute responses and chronic conditions and the most relevant SASP molecules for pathophysiological responses may allow the mitigation of detrimental impacts or the increase of beneficial effects played by SnCs. It is also mandatory to uncover novel avenues for senotherapies, such as senolytics (for instance, by targeting the heterogeneity of this phenotype), senopreventives (by elucidating mechanisms allowing senescence entry), and senomorphics (by affecting the detrimental effects of SASP selectively). Nevertheless, several barriers need to be overcome to allow the clinical application of basic concepts in cellular senescence, such as the lack of specific therapies to reduce detrimental but not beneficial effects played by SnCs, the best time to affect senescence in pathophysiological responses, and how to assess the effectiveness of senotherapies.

In conclusion, although several clinical trials targeting SnCs are ongoing, various questions about the biology of SnCs remain open, resulting in a gap between molecular and cellular data. Concerning the need, initiatives such as SenNet aiming to create openly accessible atlases of SnCs should contribute enormously to the area. Advances in understanding the subcellular structure, the heterogeneity, and the dynamics of SnCs require the integration of molecular and cellular techniques with data analysis packages to evaluate high throughput evidence from microscopy and flow cytometry. It is also necessary to develop new equipment or protocols for long-term live cell tracking or high-resolution microscopy beyond new molecular reporters, allowing the chronic study of live cells. Combining evidence from these diverse sources can transform the field, enhancing our comprehension of how SnCs acts on human health and extending beyond the advancement of more effective and specific senotherapies.

Link: https://doi.org/10.1111/acel.14154

The aged immune system becomes consistently biased towards inflammation, existing in a state of constant low-grade unresolved inflammatory signaling. This changes cell behavior for the worse, and is disruptive to processes that require transient inflammation and participation of immune cells, such as regeneration following injury, or clearance of infectious pathogens. Here researchers discuss some of the details relating to the participation of the immune system in regeneration following bone injury. It is interesting to note the sizable differences between sexes, in addition to those introduced by aging.

Inflammation is thought to be dysregulated with age leading to impaired bone fracture healing. However, broad analyses of inflammatory processes during homeostatic bone aging and during repair are lacking. Here, we assessed changes in inflammatory cell and cytokine profiles in circulation and in bone tissue to identify age- and sex-dependent differences during homeostasis and repair. During homeostatic aging, male mice demonstrated accumulation of CD4+ helper T cells and CD8+ cytotoxic T cells within bone while both pro-inflammatory "M1" and anti-inflammatory "M2" macrophage numbers decreased. Female mice saw no age-associated changes in immune-cell population in homeostatic bone.

Concentrations of IL-1β, IL-9, IFNγ, and CCL3/MIP-1α increased with age in both male and female mice, whereas concentrations of IL-2, TNFα, TNFR1, IL-4, and IL-10 increased only in female mice - thus we termed these "age-accumulated" cytokines. There were no notable changes in immune cell populations nor cytokines within circulation during aging. Sex-dependent analysis demonstrated slight changes in immune cell and cytokine levels within bone and circulation, which were lost upon fracture injury. Fracture in young male mice caused a sharp decrease in number of M1 macrophages; however, this was not seen in aged male mice nor in female mice of any age.

Injury itself induced a decrease in the number of CD8+ T cells within the local tissue of aged male and of female mice but not of young mice. Cytokine analysis of fractured mice revealed that age-accumulated cytokines quickly dissipated after fracture injury, and did not re-accumulate in newly regenerated tissue. Conversely, CXCL1/KC-GRO, CXCL2/MIP-2, IL-6, and CCL2/MCP-1 acted as "fracture response" cytokines: increasing sharply after fracture, eventually returning to baseline. Collectively, we classify measured cytokines into three groups: (1) age-accumulated cytokines, (2) female-specific age-accumulated cytokines, and (3) fracture response cytokines. These inflammatory molecules represent potential points of intervention to improve fracture healing outcome.

Link: https://doi.org/10.1093/jbmrpl/ziae023

LyGenesis has been working towards liver organoid transplantation as a treatment for liver failure for some years now. Organs such as the liver, thymus, and a few others do not need to be in any specific place in the body to carry out many of their varied functions. Some of the vital work of the liver, for example, can be conducted in small organoids grown from liver cells transplanted into lymph nodes or other parts of the body that can act as stable bioreactors.

Even setting aside the possibility of growing functional liver organoids from patient cells or universal cell lines, it is worth noting that the old approach of harvesting donor livers could be used to create large numbers of organoids through the LyGenesis methology, and thereby help many more patients with liver disease than is presently possible through transplantation. In recent news, LyGenesis has now started a small clinical trial; we might hope that success for the company will spur the development of analogous approaches for other organs, such as the thymus.

'Mini liver' will grow in person's own lymph node in bold new trial

More than 50,000 people in the United States die each year with liver disease. In the end stage of the disease, scar tissue that has accumulated prevents the organ from filtering toxic substances in the blood, and can lead to infection or liver cancer. A liver transplant can help, but there is a shortage of organs: about 1,000 people in the United States die every year waiting for a transplant. Thousands more aren't eligible because they are too ill to undergo the procedure.

LyGenesis has been trialling an approach that could help people in this situation - and make use of donated livers that would otherwise go to waste because a person on the transplant waiting list with a compatible health profile hasn't materialized in time. The company's strategy delivers the donor cells through a tube in the throat, injecting them into a lymph node near the liver. Lymph nodes, which also filter waste in the body and are an important part of the immune system, are ideal for growing mini livers, because they receive a large supply of blood and there are hundreds of them throughout the body, so if a few are used to generate mini livers, plenty of others can continue to function as lymph nodes.

The treatment has so far worked in mice, dogs, and pigs. To test the therapy in pigs, researchers restricted blood flow to the animals' livers, causing the organs to fail, and injected donor cells into lymph nodes. Miniature livers formed within two months and had a cellular architecture resembling a healthy liver. Researchers even found cells that transport bile, a digestive fluid produced by the liver, in the mini livers of the pigs. In this case, they saw no build-up of bile acid, suggesting that the mini organs were processing the fluid.

The company aims to enroll 12 people into the phase II trial by mid-2025 and publish results the following year. The trial, which was approved by US regulators in 2020, will not only measure participant safety, survival time and quality of life post-treatment, but will also help to establish the ideal number of mini livers to stabilize someone's health. The clinicians running the trial will inject liver cells in up to five of a person's lymph nodes to determine whether the extra organs can boost the procedure's success rate. LyGenesis has ambitions beyond mini livers, too. The company is now testing similar approaches to grow kidney and pancreas cells in the lymph nodes of animals.

Researchers here report on an interesting in vitro demonstration, in which they show that hydrogen peroxide (H2O2) generated in mitochondria does not cause nuclear DNA damage. Oxidizing molecules generated as a byproduct of mitochondrial generation of the chemical energy store molecule adenosine triphosphate (ATP) are thought to be important in aging. Oxidative stress is a feature of aging and age-related changes to mitochondrial structure, dynamics, and function. Oxidative damage to nuclear DNA is also a feature of this cell-wide oxidative stress, and it is commonly thought that mitochondria are the source of this stress and thus this damage. But perhaps they are not.

Reactive Oxygen Species (ROS) derived from mitochondrial respiration are frequently cited as a major source of chromosomal DNA mutations that contribute to cancer development and aging. However, experimental evidence showing that ROS released by mitochondria can directly damage nuclear DNA is largely lacking. In this study, we investigated the effects of H2O2 released by mitochondria or produced at the nucleosomes using a titratable chemogenetic approach. This enabled us to precisely investigate to what extent DNA damage occurs downstream of near- and supraphysiological amounts of localized H2O2.

Nuclear H2O2 gives rise to DNA damage and mutations and a subsequent p53 dependent cell cycle arrest. Mitochondrial H2O2 release shows none of these effects, even at levels that are orders of magnitude higher than what mitochondria normally produce. We conclude that H2O2 released from mitochondria is unlikely to directly damage nuclear genomic DNA, limiting its contribution to oncogenic transformation and aging.

Link: https://doi.org/10.1038/s41467-024-47008-x

Variations in the relative proportions of microbial species making up the gut microbiome apparently contribute to variations in LDL-cholesterol in the bloodstream. Lower LDL-cholesterol sustained over a lifetime produces a slower development of atherosclerotic plaque, and lower risk of consequent cardiovascular disease. While it seems likely there is no one optimal gut microbiome, there are certainly specific improvements that can be achieved for most older individuals. Fortunately, producing lasting changes in the balance of microbial populations making up the gut microbiome is an achievable goal. Fecal microbiota transplantation works well, for example. This is a little explored but potentially quite useful area of medical development.

Researchers analyzed metabolites and microbial genomes from more than 1,400 participants in the Framingham Heart Study, a decades-long project focused on risk factors for cardiovascular disease. The team discovered that bacteria called Oscillibacter take up and metabolize cholesterol from their surroundings, and that people carrying higher levels of the microbe in their gut had lower levels of cholesterol. The results suggest that interventions that manipulate the microbiome in specific ways could one day help decrease cholesterol in people.

The researchers found that species in the Oscillibacter genus were surprisingly abundant in the gut, representing on average 1 in every 100 bacteria. The researchers then wanted to figure out the biochemical pathway the microbes use to break down cholesterol. To do this, they first needed to grow the organism in the lab. Fortunately, the lab has spent years collecting bacteria from stool samples to create a unique library that also included Oscillibacter.

After successfully growing the bacteria, the team used mass spectrometry to identify the most likely byproducts of cholesterol metabolism in the bacteria. This allowed them to determine the pathways the bacteria uses to lower cholesterol levels. They found that the bacteria converted cholesterol into intermediate products that can then be broken down by other bacteria and excreted from the body. Next, the team used machine-learning models to identify the candidate enzymes responsible for this biochemical conversion, and then detected those enzymes and cholesterol breakdown products specifically in certain Oscillibacter in the lab.

The team found another gut bacterial species, Eubacterium coprostanoligenes, that also contributes to decreased cholesterol levels. This species carries a gene that the scientists had previously shown is involved in cholesterol metabolism. In the new work, the team discovered that Eubacterium might have a synergistic effect with Oscillibacter on cholesterol levels, which suggests that new experiments that study combinations of bacterial species could help shed light on how different microbial communities interact to affect human health.

Link: https://www.broadinstitute.org/news/scientists-link-certain-gut-bacteria-lower-heart-disease-risk

The safest sort of investment into therapeutic development is one made in a part of a field that is well established, producing a small variant of an existing drug, using the well beaten path of small molecule development, targeting a mechanism that is very well understood, and that has extensive safety data associated with it. One could argue that mTOR inhibition is the canonical example of a low risk investment in the longevity field. Like most lower-risk exercises in medical development, the potential gain for patients is modest. mTOR inhibition can produce larger gains in mouse life span than exercise, but doesn't beat calorie restriction.

Still, higher odds of a return on investment tends to far outweigh the size of potential patient benefits in the eyes of conservative investors. This is one of the reasons why progress in medicine is so very incremental. It is perhaps surprising that that the longevity industry exhibits a relatively small investment in mTOR inhibitor development in comparison to, say, the billions directed towards reprogramming approaches, given that the development of partial reprogramming therapies can hardly be described as a low-risk program at the present time.

Hevolution is a Saudi Arabian fund that has for a while now been discussing a $1 billion investment into research and development of longevity-enhancing therapies. There has been some question over how and when the Hevolution leadership will start to deploy meaningful amounts of capital in the longevity industry. To date, they have focused on funding academic research, collectively to a sizable amount. It appears that the fund is now making its first inroads into funding companies, and, judging from the company selected, is taking the conservative, safe approach.

Hevolution Foundation Announces $20 million Impact Investment to Advance Promising Aging Therapies, Leading a $50 million Series A Extension in Aeovian Pharmaceuticals

Hevolution Foundation announced its first life science impact investment of $20 million to help Aeovian Pharmaceuticals advance its innovative platform of selective mTORC1 inhibitors which could lead to several promising therapies for disease of aging. This investment - the leading contribution in a $50 million Series A financing extension for Aeovian - has the potential to address major unmet medical needs including TSC refractory epilepsy, neurological diseases, and prevalent diseases of aging.

After careful evaluation of over 200 opportunities, Hevolution selected Aeovian based on the company's success in drug discovery, its expertise in development, the potential for commercialization, and its compelling platform for the discovery of selective mTORC1 inhibitors. Strategic collaborations focused on advancing the healthspan sector are integral to Hevolution's investment approach. As the lead investor, Hevolution is joined in this investment by Apollo Health Ventures, Sofinnova Investments, venBio, Evotec, and b2venture. Hevolution's Chief Investment Officer William Greene, M.D. will also join Aeovian's Board of Directors, bringing over 25 years of leadership experience as a founder, biotechnology executive, investor, and clinician.

This investment underscores Hevolution's commitment to increase the number of safe and effective treatments entering the market, compress the timeline of drug development, using the latest tools and technologies and increase accessibility to therapeutics that extend healthy lifespan. It follows Hevolution's launch of the Breakthrough Innovation Alliance at the Global Healthspan Summit in November 2023. To date, Hevolution has committed more than $250 million in scientific funding to catalyze the healthspan ecosystem.

Macrophages in the body and microglia in the brain are similar forms of innate immune cell, responsible for clearing metabolic waste, among other duties. A number of age-related conditions involve the growing incapacity of macrophages or microglia, their transition to inflammatory states, and inability to clear debris and waste as they should. Atherosclerosis, for example, is arguably a condition caused by macrophage dysfunction, in which macrophages fail to clear excess cholesterol from blood vessel walls. Neurodegenerative conditions such as Alzheimer's disease, on the other hand, are characterized by the presence of activated, senescent, and overly inflammatory microglia. Can these cells be made more resilient to the aged tissue environment, made less inflammatory, made better at the task of waste clearance? Perhaps, as the work here indicates.

Genetic and experimental evidence suggests that Alzheimer's disease (AD) risk alleles and genes may influence disease susceptibility by altering the transcriptional and cellular responses of macrophages, including microglia, to damage of lipid-rich tissues like the brain. Recently, single cell RNA sequencing studies identified similar transcriptional activation states in subpopulations of macrophages in aging and degenerating brains and in other diseased lipid-rich tissues. We collectively refer to these subpopulations of microglia and peripheral macrophages as disease-associated and lipid-associated cells, here DLAMs for brevity.

Using macrophage RNA-seq data from healthy and diseased human and mouse lipid-rich tissues, we reconstructed gene regulatory networks and identified 11 strong candidate transcriptional regulators of the DLAM response across species. Loss or reduction of two of these transcription factors, BHLHE40 and BHLHE41, in iPSC-derived microglia and human THP-1 macrophages as well as loss of Bhlhe40/41 in mouse microglia, resulted in increased expression of DLAM genes involved in cholesterol clearance and lysosomal processing, increased cholesterol efflux and storage, and increased lysosomal mass and degradative capacity. These findings provide targets for therapeutic modulation of macrophage/microglial function in AD and other disorders affecting lipid-rich tissues.

Link: https://doi.org/10.1038/s41467-024-46315-7

The glymphatic system is one of the pathways for drainage of cerebrospinal fluid from the brain to the body. This drainage is necessary to remove metabolic waste from the brain, and there is good evidence for reduced outflow of cerebrospinal fluid to lead to the development of neurodegenerative conditions. The work here adds to this body of evidence, showing that impaired flow of cerebrospinal fluid through the glymphatic system correlates with later severity of Alzheimer's disease.

The glymphatic system is an essential fluid-clearance system in the brain. The highly organized cerebrospinal fluid (CSF) transport system subserves the influx of CSF into the brain parenchyma along the arterial perivascular spaces and subsequent transfer to the brain interstitial space. Impaired brain clearance mechanisms may be an essential factor contributing to the deposition of pathological proteins in Alzheimer's disease (AD). The novel fluid transport system provides a promising target for the prevention or treatment of AD.

Recently, a measure of perivascular clearance activity in the human brain using diffusion MRI called diffusion tensor image analysis along the perivascular space (DTI-ALPS) has been proposed. The reliability of the ALPS index as a measure of glymphatic activity was supported in a recent study that found a significant correlation between the ALPS index and glymphatic clearance function. In the field of AD, previous studies have observed a decreased ALPS index in AD patients compared to controls. The ALPS index is also associated with cognitive performance in AD and is negatively associated with amyloid and tau deposition on positron emission tomography (PET) images.

In the present study, we used the ALPS index to investigate the cross-sectional and longitudinal associations between glymphatic activity and clinical and pathological features of AD, including diagnosis, cognitive scores, and CSF and neuroimaging biomarkers. Taking advantage of the large-scale and longitudinal measurements of the ALPS index and AD hallmarks in the Alzheimer's Disease Neuroimaging Initiative (ADNI) cohort, we further investigated the sequential relationship between glymphatic dysfunction, as measured by the ALPS index, and markers of AD pathology in the development of AD.

ALPS index was significantly lower in AD dementia than in mild cognitive impairment (MCI) or controls. Lower ALPS index was significantly associated with faster changes in amyloid positron emission tomography (PET) burden and AD signature region of interest volume, higher risk of amyloid-positive transition and clinical progression, and faster rates of amyloid- and neurodegeneration-related cognitive decline. Furthermore, the associations of the ALPS index with cognitive decline were fully mediated by amyloid PET and brain atrophy. Thus glymphatic failure may precede amyloid pathology, and predicts amyloid deposition, neurodegeneration, and clinical progression in AD.

Link: https://doi.org/10.1002/alz.13789

On the one hand, naked mole-rats are most likely long-lived because they live underground, and thus suffer much lower rates of predation than other similarly sized mammals. Lower rates of extrinsic mortality appear to be a necessary prerequisite for the evolution of a longer species life span. On the other hand, living in a low-oxygen environment appears to have spurred the evolution of broad range of adaptations to that environment that incidentally happen to extend species longevity. Today's open access paper covers one aspect of those adaptations, a resistance to ischemia that reduces the harms resulting from the loss of blood flow to important tissues that takes place during events such as a heart attack.

Interestingly, the researchers note differences in tolerance to hypoxia between naked mole-rats and similar species that correlate with a greater exposure to the low-oxygen underground environment. One can imagine interactions over evolutionary time between the characteristics of predation, instinct and willingness to remain underground, tolerance to hypoxia, and life span. Does all this discovery have relevance to human medicine? That remains an open question. Certainly there is considerable enthusiasm for understanding exactly how naked mole-rats are near immune to cancer, and building therapies based upon that understanding. It remains to be seen as to whether this is a practical goal, however.

Naked mole-rats have distinctive cardiometabolic and genetic adaptations to their underground low-oxygen lifestyles

While data on O2/CO2 levels in wild naked mole-rat (NMR) burrows is limited and has never been measured in a nest chamber full of animals, NMRs in captive colonies are able to tolerate hours of extreme hypoxia (5% O2 for up to 300 minutes), and can even survive up to 18 minutes of anoxia. NMRs often elect to spend more time in areas of their burrow system with extreme atmospheric conditions including the nest chamber, where they may spend up to 70% of their time. This is something not regularly seen in other social African mole-rat species.

This challenging hypoxic habitat creates strong selective pressures and has driven the evolution of unique adaptive traits in NMRs. Mammalian cells are not usually hypoxia-resistant, requiring uninterrupted O2 availability for survival. Fluctuations in O2 availability can lead to ischaemia/reperfusion injury and irreversible organ damage such as is observed following a heart attack. Given the absence of cardiovascular disease in NMRs, despite regular fluctuating exposure to hypoxia/anoxia and normoxia, NMR hearts appear to have evolved resistance to both reduced O2 availability and ischaemia/reperfusion (I/R) injury.

NMR metabolism has unusual features, such as the ability to switch from glucose to fructose-driven glycolysis in the brain during anoxia. However, the mechanisms that underpin the extraordinary physiological adaptation to limited O2 availability in the heart are unknown. To determine how these adaptations arise in NMR, we hypothesised that comparison to other African mole-rat genera would enable us to infer the changes in gene expression and metabolic signatures that contribute to the extreme hypoxia tolerance, resistance to cardiovascular injury, and longevity of NMRs.

To identify the mechanisms behind these exceptional traits, metabolomics, and RNAseq of cardiac tissue from naked mole-rats was compared to other African mole-rat genera (Cape, Cape dune, Common, Natal, Mahali, Highveld and Damaraland mole-rats) and evolutionarily divergent mammals (Hottentot golden mole and C57BL/6 mouse). We identify metabolic and genetic adaptations unique to naked mole-rats including elevated glycogen, thus enabling glycolytic ATP generation during cardiac ischemia. Elevated normoxic expression of HIF-1α is observed while downstream hypoxia responsive-genes are down-regulated, suggesting adaptation to low oxygen environments. Naked mole-rat hearts show reduced succinate levels during ischemia compared to C57BL/6 mouse and negligible tissue damage following ischemia-reperfusion injury. These evolutionary traits reflect adaptation to a unique hypoxic and eusocial lifestyle that collectively may contribute to their longevity and health span.

Researchers here demonstrate that the presence of phosphorylated α-synuclein in a skin biopsy is a good indicator of the presence of Parkinson's disease and other synucleinopathies. A skin biopsy is a more invasive procedure than most people want to undergo, but a greater ability to diagnose progressive diseases in their early stages will nonetheless tend to encourage the development of a greater ability to manage, treat, and avoid the later stages.

Affecting an estimated 2.5 million people in the United States, the synucleinopathies include Parkinson's disease (PD), dementia with Lewy bodies (DLB), multiple system atrophy (MSA), and pure autonomic failure (PAF). While the four progressive neurodegenerative diseases have varying prognoses and do not respond to the same therapies, they do share some overlapping clinical features such as tremors and cognitive changes. Additionally, all are characterized by the presence of an abnormal protein present in the nerve fibers in the skin called phosphorylated α-synuclein (P-SYN).

In this investigation, titled the Synuclein-One Study, researchers enrolled 428 people, ages 40-99 years, with a clinical diagnosis of one of the four synucleinopathies based on clinical criteria and confirmed by an expert panel or were healthy control subjects with no history of neurodegenerative disease. Participants underwent three 3-millimeter skin punch biopsies taken from the neck, the knee, and the ankle.

Among the participants with clinically confirmed PD, 93 percent demonstrated a positive skin biopsy for P-SYN. Participants with DLB and MSA tested 96 percent and 98 percent positive, respectively. One hundred percent of participants with PAF were positive for the abnormal protein. Among the controls, just over 3 percent tested positive for P-SYN - an error rate the authors suspect may indicate some of the healthy controls are at risk for a synucleinopathy. "Parkinson's disease and its subgroup of progressive neurodegenerative diseases show gradual progression, but alpha-synuclein is present in the skin even at the earliest stages."

Link: https://www.eurekalert.org/news-releases/1038327

Evidence suggests that the mammalian brain is operating at the very edge of its capacity, supplied with just enough oxygen and nutrients to barely get by. That exercise produces measurable short-term gains in cognitive function, while blood flow is increased, is one point in favor of this view. Another is provided here, in which researchers note that it is entirely normal to observe transient areas of hypoxia in the brain at rest, and that the occurrence of these regions is diminished by the increased blood flow of exercise. It is an open question as to what to do with this finding: we can imagine future technologies that greatly increase the capacity of the blood to carry oxygen around the body, but equally it is also the case that mild hypoxia is actually beneficial. A little stress provokes better cell maintenance.

Using a bioluminescent oxygen indicator, researchers discovered a spontaneous, spatially defined occurrence of "hypoxic pockets" in the mouse brain. Their technique offers a way to learn more about brain oxygen tension (pO2), a measure of oxygen delivery and demand in brain tissue that changes dynamically but is not well understood. The findings could have implications for how rest and exercise affect pO2 in the human brain, including the role of these activities in conditions such as dementia.

The researchers used a genetically encoded bioluminescent oxygen indicator in mouse cortical astrocytes to track pO2 changes. Under resting conditions, pO2 changed often and included transient but sharply defined events of hypoxia that lasted several seconds to minutes and were spatially confined. Further research confirmed that the hypoxic pockets were caused by circulation changes in the brain's capillaries. During exercise, the area covered by hypoxic pockets in the mouse brain decreased by 52% compared to the brain during rest.

"Our study predicts that physical inactivity has direct effects on tissue pO2 by favoring capillary occlusions and increasing the number of hypoxic pockets. Conversely, simply increasing sensory input or locomotion rapidly suppress the occurrence of hypoxic pockets perhaps explaining the linkage between sedentary lifestyle and an increased risk of dementia." As pO2 decreases with age, the researchers also note that their technique might someday be used to determine if hypoxic pockets expand or last longer with age.

Link: https://www.eurekalert.org/news-releases/1038912

RNA molecules are produced in the cell nucleus by transcription machinery that reads gene sequences from the genome. MicroRNAs are among the varieties of RNA molecule that are not translated by a ribosome to produce proteins. Instead they directly participate in cell functions, often by altering the expression of other genes. Many microRNAs appear to be important players in the regulation of specific cell behaviors and tissue functions, such as regeneration and maintenance of tissues.

In today's open access paper, the authors provide an overview of some of the microRNAs that have been identified as important or potentially interesting in the context of the aging of muscle tissue, particularly in the decline of maintenance and regeneration. In the broader context beyond muscle tissue, a few first therapies that target specific microRNAs are making their way towards the clinic, primarily to treat forms of cancer. A broader range of such therapies is a possibility for the years ahead, including those aimed at restored muscle function in later life.

The role of non-coding RNAs in muscle aging: regulatory mechanisms and therapeutic potential

Non-coding RNAs (ncRNAs) are a varied family of RNA that do not code for proteins but are crucial for many biological activities, including gene regulation, epigenetic modifications, and chromatin remodeling. This class of RNAs includes microRNAs (miRNAs), long non-coding RNAs (lncRNAs), circular RNAs (circRNAs), and others. Non-coding RNAs have emerged as critical players in the regulation of various cellular processes, including those governing muscle tissue. In the context of muscle aging, research has uncovered a wealth of information about the roles ncRNAs play in mediating muscle loss, muscle regeneration, and overall muscle maintenance. For instance, modulating these miRNAs, such as miR-29, miR-143, and miR-431, could potentially improve age-related muscle regeneration.

In 2016, miR-501-3p was identified as a muscle-specific miRNA enriched in activated myogenic progenitor cells during muscle regeneration. Subsequent research demonstrated that miR-501 knockout mice exhibited a significant reduction in the diameter of newly formed myofibers. This result is a result of miR-501 controlling the expression of the sarcomeric gene via the estrogen-related receptor gamma (Esrrg). Another noteworthy miRNA, miR-7a-1, has been identified as highly expressed in aged muscle and as a downstream factor of HuR and Msi2. This miRNA plays a role in inhibiting the translation of Cry2 and modulating Muscle Stem cell (MuSC) differentiation. These findings contribute to our understanding of how miRNAs are involved in muscle regeneration and the aging process.

Some miRNAs, known as senescence-associated miRNAs, are identified that differentially expressed during cellular senescence contribute to its establishment and maintenance. For instance, miR-24 has been found to be downregulated in ex vivo MuSCs and regenerating muscle during aging. miR-24 regulates the generation of mitochondrial ROS through Prxd6 and subsequently influences MuSCs viability, myogenic potential and senescence. Modulating miR-24 in aged mouse are preserve satellite cells viability and mitochondria function.

Sarcopenia, characterized by age-related muscle loss, is influenced by various factors, with increased expression of E3 ligases like MuRF1 and Atrogin-1 in aged muscles, highlighting their involvement in the ubiquitin-proteasome system. Recent research has identified specific miRNAs associated with sarcopenia that target or modulate these E3 ligases, underscoring their importance in maintaining muscle. Notably, miRNAs located within the Dlk1-Dio3 cluster have induced hypertrophic phenotypes in myotubes. Among these miRNAs, including miR-376c, miR-668, miR-1197, miR-495, miR-377, miR-379, and miR-431, they directly bind to the 3′UTR of Atrogin-1, leading to the suppression of Atrogin-1 in both human and mouse muscle cells. Furthermore, miR-376c has shown remarkable potential in ameliorating skeletal muscle atrophy and improving muscle function in old mice. These miRNAs consistently exhibit downregulation in aged human muscles.

Recent studies have reported on the regulation of mitochondrial homeostasis controlling muscle mass. It was shown that miR-181a is crucial in controlling the age-related alteration of mitochondrial dynamics in muscle via targeting p62 and Park2. In vivo restoration of miR-181a levels in the muscles of old mice inhibited the accumulation of p62, Park2, and DJ-1 while maintaining mitochondrial content. In the end, this enhanced the size and force of myofibers. Collectively, these results indicate that miR-181a functions as an effective mitochondrial dynamics regulator, both in vitro and in vivo.

It may turn out to be cost-effective to replace delivery of therapeutic monoclonal antibodies with delivery of messenger RNA (mRNA), encapsulated in a lipid nanoparticle or linked to a cell penetrating molecule of some sort in order to reach the desired tissues and be taken up into the cytoplasm. Researchers here consider this in the context of treating Alzheimer's disease, where the primary thrust of therapeutic development involves the use of antibodies targeting the various protein aggregates thought to contribute to disease progression.

Monoclonal antibodies have emerged as a leading therapeutic agent for the treatment of disease, including Alzheimer's disease. In the last year, two anti-amyloid monoclonal antibodies, lecanemab and aducanumab, have been approved in the USA for the treatment of Alzheimer's disease, whilst several tau-targeting monoclonal antibodies are currently in clinical trials. Such antibodies, however, are expensive and timely to produce and require frequent dosing regimens to ensure disease-modifying effects.

Synthetic in vitro-transcribed mRNA encoding antibodies for endogenous protein expression holds the potential to overcome many of the limitations associated with protein antibody production. Here, we have generated synthetic in vitro-transcribed mRNA encoding a tau specific antibody as a full-sized immunoglobulin and as a single-chain variable fragment. In vitro transfection of human neuroblastoma SH-SY5Y cells demonstrated the ability of the synthetic mRNA to be translated into a functional tau-specific antibody. Furthermore, we show that the translation of the tau-specific single-chain variable fragment as an intrabody results in the specific engagement of intracellular tau.

This work highlights the utility of mRNA for the delivery of antibody therapeutics, including intrabodies, for the targeting of tau in Alzheimer's disease and other tauopathies.

Link: https://doi.org/10.1093/braincomms/fcae100

Researchers here describe an interesting evolution of proteolysis targeting chimera (PROTAC) technology into a form that upregulates the dephosphorylation of tau protein. Tau becomes pathogenic in the aging brain when hyperphosphorylated, and thus reducing it back to its unphosphorylated form should provide benefits to patients in tauopathies such as Alzheimer's disease. The PROTAC style of approach, when applied to this situation, is to produce a molecule capable of binding to phosphorylated tau at one end and a phosphatase at the other. By encouraging phosphatase molecules into close proximity to phosphorylated tau, the pace at which dephosphylation occurs is greatly upregulated.

Abnormal hyperphosphorylation and accumulation of tau protein play a pivotal role in neurodegeneration in Alzheimer's disease (AD) and many other tauopathies. Selective elimination of hyperphosphorylated tau is promising for the therapy of these diseases. Following the development of proteolysis targeting chimeras (PROTACs) for selectively strengthening degradation of protein of interest (POI), a variety of new chimeras, like autophagy-targeting chimeras (AUTACs), autophagosome-tethering compounds (ATTEC), lysosome-targeting chimeras (LYTACs), antibody-based PROTACs (AbTACs) or proteolysis-targeting antibodies (PROTABs), have been developed. Taking advantage of these technologies, we and others have developed several chimeras for selectively facilitating tau removal in AD and other tauopathies.

Notwithstanding, the general removal of tau protein might be somewhat arbitrary since tau per se plays multifaceted physiological roles in maintaining cell structure and functions. It is the pathological hyperphosphorylation of tau that initiates the formation of neurofibrillary tangles and neurodegeneration in tauopathies. Therefore, specific downregulation of tau phosphorylation might be more refined for the therapy of these diseases. However, direct use of either tau kinase inhibitors or phosphatase activators should take unacceptable toxic side effects, because each of these enzymes concurrently modulates numerous signaling pathways aside from tau.

To achieve better selectivity and inspired by the design of PROTAC-like chimeras, we have conceptualized a strategy, named dephosphorylation-targeting chimeras (DEPTACs), for specific suppression of tau hyperphosphorylation. Our DEPTAC consists of the following motifs: (1) a "warhead" specifically recognizing and binding tau (named tau binder, TB), (2) an "anchor" for recruiting phosphatase (named phosphatase recruiter, PPR), (3) an inter-motifs linker, (4) a cell membrane-penetrating sequence, if necessary. Here, we reported the generation and screening principle of DEPTACs and the further verification of their therapeutic effectiveness in cell and animal models of tauopathy.

Link: https://doi.org/10.1016/j.scib.2024.01.019

Onset, progression, and resolution of inflammation are all driven by the interaction of many different complex signaling processes. The immune system as a whole is highly complex, an array of many different interacting populations of specialized cells. Nonetheless, there are a few individual circulating signal proteins that, to some degree at least, tend to reflect overall inflammatory status. Not reliably, but enough to produce correlations in patient populations of any reasonable size.

Today's open access paper is a survey of the literature on inflammatory cytokines IL-6, TNF, and IL-1β, pulling reported measures and patient comorbidities from many different published studies. As one might expect, there is a correlation between raised levels of inflammatory cytokines and the presence of age-related disease. Chronic inflammation is a feature of aging, and it is known to accelerate the progression of all of the common age-related conditions. The correlation isn't large or strong, however, indicating the point made above: individual cytokines are not great measures of the state of the immune system, and what they do in fact reflect varies widely from individual to individual. The state of chronic, unresolved inflammation is too complex to be measured so simply.

Level of IL-6, TNF, and IL-1β and age-related diseases: a systematic review and meta-analysis

Aging facilitates a pro-inflammatory state by disrupting the peripheral immune system, which leads to excessive innate immune activity with the release of pro-inflammatory cytokines and a decrease in anti-inflammatory cytokines. Different pro-inflammatory cytokines, such as interleukins: IL-1β, IL-6, IL-12, IL-18, interferon (IFN-γ), and tumor necrosis factor (TNF), as well as anti-inflammatory ones, such as IL-4, IL-10, IL-13, and IL-19 which are secreted from immune cells, interact with body cells to mediate the immune responses and thus elicit its most optimum outcome.

Elevated levels of interleukin-6 and TNF, as well as IL-1β, are associated with diseases, disability, and mortality in older adults. Interleukin-6, also known as 'the cytokine for gerontologists', plays a key role in the acute phase response in metabolic control and in the pathogenesis of many chronic diseases. IL-6 is produced mainly by the monocytes and macrophages. It produces a pleiotropic effect, and although in healthy and younger people its level is usually relatively low, in the elderly its elevated levels may correlate with increased mortality. IL-1β is produced in large quantities during infections and other stressful events. High glucose concentration was reported to stimulate the production of IL-1β by pancreatic β cells, which implies the role of this cytokine also in type 2 diabetes. TNF is a pro-inflammatory mediator that can produce beneficial effects when activated locally in the tissues but it can be highly harmful when released systemically. It is one of the most important cytokines, produced by several types of cells: monocytes, T-cells, macrophages, fibroblast, adipocytes, and smooth muscle cells. In elderly people and centenarians, it has been shown that the level of TNF rises, which significantly increases mortality.

The assessment of chronic inflammation, including the level of pro-inflammatory cytokines in elderly people with comorbidities, may be the key to more effective treatment. Our hypothesis was that independent measurements of cytokines such as IL-6, TNF and IL-1β were significantly associated with the development of age-related diseases. Therefore, the aim of this study was to independently evaluate three cytokines: IL-6, TNF and IL-1β in elderly people with comorbidities compared to disease-free controls.

The electronic bibliographic PubMed database was systematically searched to select all the relevant studies published up to July 2023. The total number of the subjects involved in the meta-analysis included patients with diseases (n = 8,154) and controls (n = 33,967). The overall concentration of IL-6 was found to be higher in patients with diseases compared to controls and the difference was statistically significant. The heterogeneity was considerable. The potential diagnostic usefulness of IL-6 was confirmed by odds ratio (OR) analysis, with OR = 1.03. The concentration of both TNF and IL-1β was elevated in the control group compared to patients. For TNF, however, the difference was statistically insignificant.

The hematopoietic cell populations of the bone marrow are responsible for producing red blood cells and immune cells. With advancing age, the production of immune cells shifts to bias myeloid cells of the innate immune system versus lymphocyte cells of the adaptive immune system. This is thought to be an important aspect of immune aging. Researchers here attempt to reverse this myeloid bias in immune cell production by selectively destroying some of the myeloid-focused hematopoietic cells, an interesting idea. The results are positive and intriguing.

During aging, the number of hematopoietic stem cells (HSCs) that make balanced proportions of lymphocytes and myeloid cells decline, while those that are myeloid-biased increase their numbers. This favors the production of myeloid cells. Early in human history, when people rarely left their birthplace and lived shorter lives, this gradual change probably had no consequences (it may even have been favorable) because people were likely to encounter all their surrounding pathogens by young adulthood and be protected by their memory lymphocytes. But now it's distinctly disadvantageous.

The researchers wondered if they could tilt the balance back toward a younger immune system by depleting myeloid-leaning HSCs and allowing the more balanced HSCs to replace them. Their hunch was correct. Mice between 18 and 24 months old (doddering in the mouse world) that were treated with an antibody targeting the myeloid-leaning HSCs for destruction had more of the balanced HSCs - and more new, naïve B lymphocytes and naïve T lymphocytes - than their untreated peers even several weeks later.

"These new, naïve lymphocytes provide better immune coverage for novel infections like those humans increasingly encounter as our world becomes more global. Without this renewal, these new infectious agents would not be recognized by the existing pool of memory lymphocytes. Not only did we see a shift toward cells involved in adaptive immunity, but we also observed a dampening in the levels of inflammatory proteins in the treated animals. We were surprised that a single course of treatment had such a long-lasting effect. The difference between the treated and untreated animals remained dramatic even two months later."

When the treated animals were vaccinated eight weeks later against a virus they hadn't encountered before, their immune systems responded more vigorously than was the case for the untreated animals, and they were significantly better able to resist infection by that virus. Finally, the researchers showed that mouse and human myeloid-biased HSCs are similar enough that it may one day be possible to use a similar technique to revitalize aging human immune systems, perhaps making a person less vulnerable to novel infections and improving their response to vaccination.

Link: https://www.eurekalert.org/news-releases/1038681

Researchers here review a variety of species and conclude that defense against predation is the most important determinant of species longevity. Long-lived species tend to have shells, or fly, or live underground. Evolution will not favor longevity until other factors reduce extrinsic mortality at the hands of predators. After that, proximate biochemical causes of longevity can come into play in what looks to be a wide variety of ways.

Various environmental morphological and behavioral factors can determine the longevity of representatives of various taxa. Long-lived species develop systems aimed at increasing organism stability, defense, and, ultimately, lifespan. Long-lived species to a different extent manifest the factors favoring longevity, such as body size, slow metabolism, activity of body's repair and antioxidant defense systems, resistance to toxic substances and tumorigenesis, and presence of neotenic features.

In continuation of our studies of mammals, we investigated the characteristics that distinguish long-lived ectotherms (crocodiles and turtles) and compared them with those of other ectotherms (squamates and amphibians) and endotherms (birds and mammals). We also discussed mathematical indicators used to assess the predisposition to longevity in different species, including standard indicators (mortality rate, maximum lifespan, coefficient of variation of lifespan) and their derivatives. Evolutionary patterns of aging are further explained by the protective phenotypes and life history strategies.

We assessed the relationship between the lifespan and various studied factors, such as body size and temperature, encephalization, protection of occupied ecological niches, presence of protective structures (for example, shells and osteoderms), and environmental temperature, and the influence of these factors on the variation of the lifespan as a statistical parameter. Our studies did not confirm the hypothesis on the metabolism level and temperature as the most decisive factors of longevity. It was found that animals protected by shells (e.g., turtles with their exceptional longevity) live longer than species that have poison or lack such protective adaptations. The improvement of defense against external threats in long-lived ectotherms is consistent with the characteristics of long-lived endotherms (for example, naked mole-rats that live in underground tunnels, or bats and birds, whose ability to fly is one of the best defense mechanisms).

Link: https://doi.org/10.1134/S0006297924020111

The mortality characteristics resulting from type 2 diabetes look very much like an accelerated form of normal aging, as noted in today's open access paper reporting on a large epidemiological study. This mortality characteristic is so much like aging that at times in the past researchers have used animal models of type 2 diabetes as stand-ins for aging, in order to conduct studies more rapidly. Type 2 diabetes is a metabolic disease, a condition that usually arises from excess fat tissue, and is characterized by chronic inflammation, excessive blood sugar, high levels of circulating advanced glycation end-products, and other disruptive influences resulting from too much fat in the body, a state of hyperlipidemia.

In some senses being overweight is a form of accelerated aging: it results in a greater burden of senescent cells, for example. Mammals have evolved the capacity to become fat, but not to operate well over the long term while being fat. Perhaps the most important thing to note about type 2 diabetes is that it is reversible even in its late stages; type 2 diabetes is in a sense actively maintained by the presence of excess fat tissue. Sustained low calorie diets and weight loss have been shown to profoundly reverse type 2 diabetes in human clinical trials.

Mortality of type 2 diabetes in Germany: additional insights from Gompertz models

The Gompertz law of mortality proclaims that human mortality rates in middle to old ages grow log-linearly with age and this law has been confirmed at multiple instances. We investigated if diabetes mortality in Germany also obeys the Gompertz law and how this information helps to communicate diabetes mortality more intuitively.

We analyzed all statutory health-insured persons in Germany in 2013 that were aged 30 years or older. Deaths in 2014 were recorded and given in 5-year age groups. The study population consisted of 47,365,120 individuals, 6,541,181 of them with diabetes. In 2014, 763,228 deaths were recorded, among them 288,515 with diabetes. We fitted weighted linear regression models (separately for females and males and for people with and without diabetes) and additionally computed the probability that a person with diabetes dies before a person of the same age and sex without diabetes, and the "diabetes age", that is, the additional years of mortality risk added to an individual's chronological age due to diabetes-related excess mortality.

We found that diabetes mortality for females and males aged 30 years or older in Germany in 2014 followed the Gompertz law of mortality. The survival information of the population with diabetes during a large part of the lifespan can thus be reduced to the two parameters of the Gompertz distribution. In addition, the Gompertz distribution gives better fits than two competing, mechanistically also plausible distributions for the age at death. The probability that a female/male with diabetes dies before a female/male without diabetes (and the same age) is 61.9%/63.3%.

A range of conditions produce chronic pain in muscle and skeletal tissue. While conditions such as osteoathritis are comparatively well understood, the etiology of chronic muscular pain disorders such as myofascial pain syndrome is poorly understood and treatment options are consequently limited. Here, researchers analyze available epidemiological data on knee osteoarthritis, and show that it suggests an inflammatory link between chronic pain and an accelerated pace of degenerative brain aging.

Individuals suffering from chronic musculoskeletal pain (CMP) may face a higher high risk of brain aging. CMP is a leading cause of disability, affecting more than 40% of the world's population and impacting patients' cognitive function. Although the exact mechanism is not fully understood, thus hampering prevention and treatment efforts, research indicates that inflammatory markers associated with brain aging are higher in CMP patients, suggesting a link between brain aging and CMP.

Using structural MRI data from over 9,000 individuals, researchers developed a brain age model to compare brain age to chronological age. They found that individuals with knee osteoarthritis, who were identified from both the UK Biobank and additional replication datasets from the local community, experienced more rapid brain aging than healthy individuals. In addition, brain regions responsible for human cognitive function, such as the hippocampus, were found to be associated with such accelerated brain aging.

Moreover, the researchers delved into the genetic landscape and identified the gene SLC39A8 as a shared link between knee osteoarthritis and accelerated brain aging. This gene, which is particularly expressed in microglial cells and astrocytes, underscores the potential role of inflammation and neurodevelopment in the observed phenomena.

Link: https://www.eurekalert.org/news-releases/1039040

Access to human brain tissue for medical research is more limited than most people realize is the case, and, for obvious reasons, far too little of the available tissue data covers the early stages of disease. This limitation is one of the factors slowing the pace of research into age-related neurodegenerative conditions. Here, for example, researchers make use of an unusual resource to show that the prevalence of Lewy body disease may be greater than presently thought, with pathology beginning in the 50s, even if there are no outright symptoms of disease at that stage.

Lewy body disease is the second most common brain degenerative disease after Alzheimer's disease. Lewy bodies, deposits of alpha-synuclein protein, are found in the brainstem, limbic system, and cerebral cortex. Similar tissue changes are also seen in patients clinically diagnosed with Parkinson's disease. Lewy body disease can be difficult to recognise at the beginning of the disease, as it progresses slowly. Symptoms often include movement disturbances, memory problems, and psychiatric symptoms.

In their recent study, researchers investigated for the first time the occurrence of Lewy body disease markers in young and middle-aged subjects who were not known to suffer from Lewy body or Parkinson's diseases. In their study, the researchers used unique Finnish forensic autopsy data, which consists of approximately 600 people aged 16-95 who died outside hospitals. Previous similar studies have investigated the occurrence of the disease markers in people over 60 years old. The researchers found that Lewy body disease changes may begin to develop in the brain already in middle age, even if there are no actual symptoms yet.

Link: https://www.helsinki.fi/en/news/healthier-world/common-degenerative-brain-disease-may-begin-develop-already-middle-age

The stem cell therapy industry is evolving. There are a few reasons for this. Firstly, cells remain hard to work with as a basis for therapy, and the level of standardization expected by regulators is very challenging to achieve, even for companies with very deep pockets. In the wilder world of stem cell therapies obtained via medical tourism, outcomes vary broadly from clinic to clinic and patient to patient for reasons that remain unclear. Secondly, stem cell transplantation produces benefits to aged patients primarily via the signaling produced by transplanted cells in a short time prior their destruction, rather than through any other activity of those cells.

Given these points, there is a slow shift away from using cells and towards the use of cell products such as harvested extracellular vesicles or, as in today's open access paper, the secretome of all molecules that exit the cell into extracellular medium, not just those encapsulated in vesicles. Immunis Biomedical is the company involved in the work reported here, working towards the clinical use of stem cell secretome therapies. Primarily this work involves standardization of cell lines and consistency of the resulting harvested secretome to a degree that will satisfy the regulators. Cells are still hard to manage, but compressing down that management into only the centralized process of manufacturing the therapy makes the goal attainable with a reasonable amount of funding.

Stem cell secretome treatment improves whole-body metabolism, reduces adiposity, and promotes skeletal muscle function in aged mice

Aging coincides with the progressive loss of muscle mass and strength, increased adiposity, and diminished physical function. Accordingly, interventions aimed at improving muscle, metabolic, and/or physical health are of interest to mitigate the adverse effects of aging. In this study, we tested a stem cell secretome product, which contains extracellular vesicles and growth factors, cytoskeletal remodeling factors, and immunomodulatory factors. We examined the effects of 4 weeks of 2×/week unilateral intramuscular secretome injections (quadriceps) in ambulatory aged male C57BL/6 mice (22-24 months) compared to saline-injected aged-matched controls.

Secretome delivery substantially increased whole-body lean mass and decreased fat mass, corresponding to higher myofiber cross-sectional area and smaller adipocyte size, respectively. Secretome-treated mice also had greater whole-body physical function (grip strength and rotarod performance) and had higher energy expenditure and physical activity levels compared to control mice. Furthermore, secretome-treated mice had greater skeletal muscle Pax7+ cell abundance, capillary density, collagen IV turnover, reduced intramuscular lipids, and greater Akt and hormone sensitive lipase phosphorylation in adipose tissue. Finally, secretome treatment in vitro directly enhanced muscle cell growth and IL-6 production, and in adipocytes, it reduced lipid content and improved insulin sensitivity. Moreover, indirect treatment with secretome-treated myotube culture media also enhanced muscle cell growth and adipocyte size reduction.

Together, these data suggest that intramuscular treatment with a stem cell secretome improves whole-body metabolism, physical function, and remodels skeletal muscle and adipose tissue in aged mice.

There is something of a tradition in the aging research community of writing reviews that attempt to summarize everything that is known of a single specific cellular behavior in the context of the panoply of cell and tissue dysfunction observed in aging. Today it is the turn of efferocytosis, the clearance of dying cells and their immediate debris by phagocytes such as macrophages of the innate immune system. It is fairly straightforward to mount an argument to suggest that more efficient efferocytosis is a good thing, as unwanted consequences attend the presence of lingering cell corpses cluttering up tissue. Like autophagy, the mechanisms making up efferocytosis are fairly well mapped, but unlike autophagy, there is no great effort underway in the research community to find ways to improve efferocytosis for functional benefit.

Efferocytosis is carried out by professional phagocytes, such as macrophages, dendritic cells, and other nonprofessional cells, to engulf apoptotic cells (ACs). Initially, phagocytes expeditiously and securely eliminate the membrane structure of the deceased cell before its disintegration and subsequent release into adjacent tissue. This process serves to safeguard the surrounding tissue against the deleterious effects induced by toxic enzymes, oxidants, and intracellular components, such as protease antibodies and caspases within ACs. Additionally, efferocytosis can generate a significant number of biological factors, including vascular endothelial growth factor (VEGF) and hepatocyte growth factor (HGF), which are hypothesized to facilitate cellular regeneration within the body. In addition, efferocytosis elicits subsequent intracellular signalling cascades, including anti-inflammatory, anti-protease, and growth-promoting actions.

The coordination of many processes is essential for the proper differentiation of ACs from healthy cells and their subsequent elimination through efferocytosis. When these deceased cells remain uninterrupted, they undergo a disruptive process, resulting in harm to the organism, triggering an inflammatory reaction, and perhaps giving rise to a range of ailments. Numerous human diseases, such as atherosclerosis, cancer, systemic lupus erythematosus, diabetes, obesity, rheumatoid arthritis, and aging, have been observed to exhibit associations with deficiencies or alterations in the processes of efferocytosis. Efferocytosis is a multistep physiological process and enhancing any one of these steps can promote efferocytosis while suppressing tissue inflammation.

Hence, the concurrent implementation of strategies aimed at augmenting efferocytic mechanisms and anti-aging treatments has the potential to serve as a potent intervention for extending the duration of a healthy lifespan. In this review, we comprehensively discuss the concept and physiological effects of efferocytosis. Subsequently, we investigated the association between efferocytosis and the hallmarks of aging. Finally, we discuss growing evidence regarding therapeutic interventions for age-related disorders, focusing on the physiological processes of aging and efferocytosis.

Link: https://doi.org/10.1016/j.jare.2024.03.008

Partial reprogramming by exposure to Yamanaka factors resets many of the epigenetic changes characteristic of cells in aged tissue. This is a potential approach to the production of future rejuvenation therapies. At present, some research groups are attempting to move away from genetic interventions to find small molecules that can provoke reprogramming. There are some avenues that seem promising. Here, researchers assess the effects of partial reprogramming by small molecules on a range of omics data and functional parameters for cells, finding that the outcomes are much as one would expect for a successful protocol.

Partial reprogramming by cyclic short-term expression of Yamanaka factors holds promise for shifting cells to younger states and consequently delaying the onset of many diseases of aging. However, the delivery of transgenes and potential risk of teratoma formation present challenges for in vivo applications. Recent advances include the use of cocktails of compounds to reprogram somatic cells, but the characteristics and mechanisms of partial cellular reprogramming by chemicals remain unclear.

Here, we report a multi-omics characterization of partial chemical reprogramming in fibroblasts from young and aged mice. We measured the effects of partial chemical reprogramming on the epigenome, transcriptome, proteome, phosphoproteome, and metabolome. At the transcriptome, proteome, and phosphoproteome levels, we saw widescale changes induced by this treatment, with the most notable signature being an upregulation of mitochondrial oxidative phosphorylation. Furthermore, at the metabolome level, we observed a reduction in the accumulation of aging-related metabolites.

Using both transcriptomic clock and epigenetic clock-based analyses, we show that partial chemical reprogramming reduces the biological age of mouse fibroblasts. We demonstrate that these changes have functional impacts, as evidenced by changes in cellular respiration and mitochondrial membrane potential. Taken together, these results illuminate the potential for chemical reprogramming reagents to rejuvenate aged biological systems and warrant further investigation into adapting these approaches for in vivo age reversal.

Link: https://doi.org/10.7554/eLife.90579.3