Fight Aging!

Atherosclerosis is the buildup of fatty plaques in the walls of blood vessels, impeding blood flow and eventually rupturing to produce a heart attack or stroke. It is the single largest cause of human mortality. Atherosclerosis is in part an inflammatory condition, accelerated by the state of chronic inflammation that arises in later life. In this context, levels of CCL17 have been shown to rise with age, while inhibition of CCL17 has been shown to reduce chronic inflammation and slow the progression of atherosclerosis. This outcome is achieved via effects on T cell behavior; CCL17 is expressed on the surface of dendritic cells and interacts with CCR4 on the surface of T cells. In doing so it represses the anti-inflammatory activity of regulatory T cells.

Researchers continue to investigate the biochemistry involved in this relationship. The authors of today's open access paper here report that CCR4 isn't the only receptor involved, and CCL17 also binds to CCR8. This sort of investigative work is necessary to understand how and where to target a specific mechanism. As researchers note, CCL17 does have a normal, useful role in coordinating transient immune activity where it is needed. As is the case for most age-related dysregulation of immune function, one can't just inhibit an overactive mechanism without consequences, as excessive immune activate uses the same pathways as normal immune activation. The aim of tracing the various interactions involved like this is to find a point of intervention that only affects pathology, rather than also suppressing necessary immune system activity. The results reported here are likely only one step of many needed to reach that goal, if it can be attained.

New signaling pathway uncovered, shedding fresh light on atherosclerosis

A chronic inflammatory disease of the inner walls of blood vessels, atherosclerosis is responsible for many cardiovascular conditions. Dendritic cells, which act to recognize foreign substances in the body and mount an immune response, play an important role in the disease. They produce the signaling protein CCL17, a chemokine, which influences the activity and mobility of T cells, which track down infected cells in the body and attack the pathogens. However, CCL17 can also promote cardiovascular pathologies. People who suffer from cardiovascular diseases, or are particular susceptible to such diseases, have elevated levels of the signaling protein. In humans and mice, elevated CCL17 serum levels are associated with increased risk of atherosclerosis and inflammatory diseases of the cardiovascular and digestive systems.

"We know from our previous work that a genetic deficiency or an antibody blockade of CCL17 impedes the progress of atherosclerosis." Before now, only one signal receptor was known to contribute to the recruitment and functions of T cells. If this receptor is lacking, however, the body is not protected from the negative effects of CCL17. Mice that did not possess the receptor in question continued to have the same extent of disease driven by CCL17. If the signaling protein acted directly and exclusively on this receptor, then silencing it should have the same effects as the absence of CCL17. Consequently, there must be another signaling pathway in which CCL17 is involved, and the researchers demonstrated and described just such a pathway in the course of the new study. "We furnish clear evidence that CCL17 acts through an alternative receptor with high affinity, thereby triggering a signaling pathway that results in the suppression of anti-inflammatory, so-called regulatory T cells."

Identification of a non-canonical chemokine-receptor pathway suppressing regulatory T cells to drive atherosclerosis

CCL17 is produced by conventional dendritic cells, signals through CCR4 on regulatory T (Treg) cells and drives atherosclerosis by suppressing Treg functions through yet undefined mechanisms. Here we show that conventional dendritic cells from CCL17-deficient mice display a pro-tolerogenic phenotype and transcriptome that is not phenocopied in mice lacking its cognate receptor CCR4. In the plasma of CCL17-deficient mice, CCL3 was the only decreased cytokine/chemokine. We found that CCL17 signaled through CCR8 as an alternate high-affinity receptor, which induced CCL3 expression and suppressed Treg functions in the absence of CCR4.

Genetic ablation of CCL3 and CCR8 in CD4+ T cells reduced CCL3 secretion, boosted FoxP3+ Treg numbers and limited atherosclerosis. Conversely, CCL3 administration exacerbated atherosclerosis and restrained Treg differentiation. In symptomatic versus asymptomatic human carotid atheroma, CCL3 expression was increased, whereas FoxP3 expression was reduced. Together, we identified a non-canonical chemokine pathway whereby CCL17 interacts with CCR8 to yield a CCL3-dependent suppression of atheroprotective Treg cells.

To the degree that senescent cells in a tissue exhibit distinctive surface features, one can deploy technologies such as chimeric antigen receptor T cells to selectively destroy them. T cells will destroy whatever cell binds to the chimeric antigen receptor they are equipped with. This approach has been used with great success to treat cancers, and may also see some use in the clearance of senescent cells provided that the cost is somehow greatly reduced. At present it is a very expensive therapeutic modality, given that a patient's cells must be extracted, genetically engineered, cultured for weeks or more to expand their numbers, and then reintroduced into the patient. The use of universal cells may allow a more efficient therapy, but a gene therapy that targets only T cells is perhaps a more plausible near term approach.

Senescent cells, which accumulate in organisms over time, contribute to age-related tissue decline. Genetic ablation of senescent cells can ameliorate various age-related pathologies, including metabolic dysfunction and decreased physical fitness. While small-molecule drugs that eliminate senescent cells ('senolytics') partially replicate these phenotypes, they require continuous administration. We have developed a senolytic therapy based on chimeric antigen receptor (CAR) T cells targeting the senescence-associated protein urokinase plasminogen activator receptor (uPAR), and we previously showed these can safely eliminate senescent cells in young animals.

We now show that uPAR-positive senescent cells accumulate during aging and that they can be safely targeted with senolytic CAR T cells. Treatment with anti-uPAR CAR T cells improves exercise capacity in physiological aging, and it ameliorates metabolic dysfunction (for example, improving glucose tolerance) in aged mice and in mice on a high-fat diet. Importantly, a single administration of these senolytic CAR T cells is sufficient to achieve long-term therapeutic and preventive effects.

Link: https://doi.org/10.1038/s43587-023-00560-5

Any sufficiently large set of biological data can be used to produce clocks that measure biological age, where a clock is some weighted combination of measurements that produces age as an output. At this point novel clocks are much less interesting than standardizing on one clock and working towards a better understanding of how exactly the clock measurements relate to underlying processes of aging. Without that understanding it is impossible to use clock assessments of biological age to accelerate research and development of therapies to treat aging as a medical condition. One has to know that they clock does in fact correctly assess the burden of damage that is targeted specifically by the therapy, whether it is senescent cells, or mitochondrial dysfunction, or any of the many other options, or the clock results are simply not actionable. Nonetheless, researchers continue to produce new clocks at a fair pace these days, with this paper being an example of the type.

Immune function and redox markers are used for estimating the aging rate, namely biological age (BA). However, it is unknown if this BA and its changes can be reflected in longevity. Thus, we must quantify BA in experimental animals. In peritoneal immune cells of 202 female mice (ICR/CD1) in different ages, 10 immune and 6 redox parameters were evaluated to construct two mathematical models for BA quantification in mice by multiple linear regression. Immune and redox parameters were selected as independent variables and chronological age as dependent, developing two models: the Immunity and the Redox Clocks, reaching both an adjusted coefficient of determination of 80.9% and a standard error of 6.38 and 8.57 weeks, respectively.

Both models were validated in a different group of healthy mice obtaining a Pearson's correlation coefficient of 0.844 and 0.800 between chronological age and BA. Furthermore, they were applied to adult prematurely aging mice, which showed a higher BA than non-prematurely aging mice. Moreover, after positive and negative lifestyle interventions, mice showed a lower and higher BA, respectively, than their age-matched controls. In conclusion, the Immunity and Redox Clocks allow BA quantification in mice and both the ImmunolAge and RedoxAge in mice relate to lifespan.

Link: https://doi.org/10.1038/s41598-024-51978-9

Alzheimer's disease is a complex degenerative failure of a complex system, the brain. This complexity is illustrated by the continuing debate over which of the many identified mechanisms are the primary cause. Is it amyloid-β aggregation, or some aspect of the halo of biochemistry associated with that aggregation, or is it chronic inflammation, or cellular senescence in supporting cells of the brain, or vascular dysfunction and leakage of the blood-brain barrier, or neurofibrillary tangles, or the presence of persistent viruses. All of these mechanisms interact with one another, and the direction of causation between any specific pair of mechanisms is also up for debate. Researchers are in many cases challenged by the inability to affect one mechanism in isolation of the others; even immunotherapies to clear amyloid-β have side-effects on tissues and the immune system.

In today's open access paper, researchers point out that most Alzheimer's patients exhibit cerebral amyloid angiopathy, deposition of amyloid-β into blood vessel walls leading to dysfunction, leakage, and rupture of microvessels. This results in damage to surrounding brain tissue and passage of inappropriate cells and molecules into the brain, provoking inflammation, among other consequences. The paper delves into mechanisms by which amyloid-β aggregation might cause dysfunction of the blood-brain barrier wrapping blood vessels in the brain and thus also the problems that arise from leakage of the blood-brain barrier. This is one example of an argument for a specific direction of causation between processes known to be involved in Alzheimer's disease. There are many such arguments, and not all of them agree with the one set out in this paper!

Endothelial leakiness elicited by amyloid protein aggregation

The most influential paradigm concerning Alzheimer's disease (AD) pathology is the amyloid cascade hypothesis and its modifications thereafter, where amyloid beta (Aβ) evolves from disordered monomers to toxic oligomers and amyloid fibrils through molecular self-assembly, modulated by environmental factors such as pH, temperature, metals, chaperones, and cell membranes. Accordingly, much effort over the past three decades has been made towards inhibiting or clearing the toxic Aβ aggregates, employing small molecules, peptidomimetics, antibodies, and, more recently, nanoparticles. A lack of clinical success, however, has shrouded these efforts, suggesting the pathophysiology of AD is multifactorial as its triggers.

Indeed, it has now been realized that, in addition to Aβ amyloidogenesis, tauopathies, apolipoprotein E, and neuroimmune activation are all causative to neurodegeneration in AD. The great (80-90%) correlation between AD subjects and patients carrying cerebral amyloid angiopathy (CAA) further suggests an important role of endothelial integrity in the development of AD pathogenesis, also evidenced by observations of cerebral endothelial dysfunction and microvascular injury induced by Aβ. Intriguingly, while Aβ originates from the proteolytic cleavage of amyloid precursor protein (APP) in endosomal membrane, deposits of Aβ are seen throughout the central nervous system, cerebral blood vessels, cerebrospinal fluid, and the plasma. Aβ-mediated vasoactivity, vascular capillary constriction, blood flow reduction, and paracellular transport have been reported with endothelial monolayers, blood-brain barrier (BBB), and biopsied human and rodent brain tissues, in connection with the production of reactive oxygen species (ROS), modified cytoskeletal network, altered tight-junction protein expression, and signaling to pericytes.

Here we show amyloid protein-induced endothelial leakiness (APEL) in human microvascular endothelial monolayers as well as in mouse cerebral vasculature. Using signaling pathway assays and discrete molecular dynamics, we revealed that the angiopathy first arose from a disruption to vascular endothelial (VE)-cadherin junctions exposed to the nanoparticulates of Aβ oligomers and seeds, preceding the earlier implicated proinflammatory and pro-oxidative stressors to endothelial leakiness. These findings were analogous to nanomaterials-induced endothelial leakiness (NanoEL), a major phenomenon in nanomedicine depicting the paracellular transport of anionic inorganic nanoparticles in the vasculature. As APEL also occurred in vitro with the oligomers and seeds of alpha synuclein, this study proposes a paradigm for elucidating the vascular permeation, systemic spread, and cross-seeding of amyloid proteins that underlie the pathogenesis of AD and Parkinson's disease.

Myelin acts as an insulating sheath for the axonal connections that exist between neurons, and is necessary for the correct function of these connections. Demyelinating diseases such as multiple sclerosis are particularly debilitating due to the spreading and progressively worsening failure of the nervous system caused by loss of myelin. Unfortunately myelin is also lost to a lesser degree with advancing age, one of many consequences of accumulated molecular damage and maladaptive reactions to that damage. Here, researchers report on efforts to better measure the loss of myelin that occurs with age, comparing established with novel approaches to the challenge of measuring specific structural aspects of the living brain via imaging technologies.

The study of myelination in the brain is essential due to its profound impact on neural function. Myelin acts as an insulator, significantly increasing the speed and efficiency of electrical signal transmission within the nervous system, facilitating information processing and precise neuron communication. Myelination is crucial during early development and continues to influence learning, memory, and cognitive function throughout life.

Recent studies showed that the myelin of the brain changes in the life span, and demyelination contributes to the loss of brain plasticity during normal aging. Diffusion-weighted magnetic resonance imaging (dMRI) allows studying brain connectivity in vivo by mapping axons in white matter with tractography algorithms. However, dMRI does not provide insight into myelin; thus, combining tractography with myelin-sensitive maps is necessary to investigate myelin-weighted brain connectivity. Tractometry is designated for this purpose, but it suffers from some serious limitations. Our study assessed the effectiveness of the recently proposed Myelin Streamlines Decomposition (MySD) method in estimating myelin-weighted connectomes and its capacity to detect changes in myelin network architecture during the process of normal aging. This approach opens up new possibilities compared to traditional Tractometry.

Our results show that the changes occurring in myelin network architecture due to aging have critical effects on network connection strength and efficiency. Specifically, we found that efficiency and mean strength extracted from myelin-weighted connectomes reach their highest point of development around 40 years of age; after this peak, the natural degeneration of axonal microstructure begins. In the broader context of our study, which explores the overall architecture of the myelin-weighted connectome, MySD outperforms traditional Tractometry-based approaches in detecting myelin network changes during normal aging.

Link: https://doi.org/10.3389/fnins.2023.1228952

The gut microbiome interacts with the body via a wide range of mechanisms, including induction of chronic inflammatory responses and delivery of both harmful and beneficial metabolites. With advancing age, the balance of populations making up the gut microbiome changes in ways that increase the harms while reducing the benefits. This may happen because the aged immune system becomes less able to clear problem microbes, but other mechanisms such as lifestyle changes and intestinal tissue aging may also contribute meaningfully. Fortunately, studies have demonstrated that making sizable, lasting changes to the gut microbiome is possible, such as via fecal microbiota transplant using a young donor. In animal studies, this can restore a more youthful balance of populations and thereby improve health and extend life.

Trillions of microbes live symbiotically in the host, specifically in mucosal tissues such as the gut. Recent advances in metagenomics and metabolomics have revealed that the gut microbiota plays a critical role in the regulation of host immunity and metabolism, communicating through bidirectional interactions in the microbiota-gut-brain axis (MGBA). The gut microbiota regulates both gut and systemic immunity and contributes to the neurodevelopment and behaviors of the host. With aging, the composition of the microbiota changes, and emerging studies have linked these shifts in microbial populations to age-related neurological diseases (NDs).

Preclinical studies have demonstrated that gut microbiota-targeted therapies can improve behavioral outcomes in the host by modulating microbial, metabolomic, and immunological profiles. In this review, we discuss the pathways of brain-to-gut or gut-to-brain signaling and summarize the role of gut microbiota and microbial metabolites across the lifespan and in disease. We highlight recent studies investigating 1) microbial changes with aging; 2) how aging of the maternal microbiome can affect offspring health; and 3) the contribution of the microbiome to both chronic age-related diseases (e.g., Parkinson's disease, Alzheimer's disease and cerebral amyloidosis), and acute brain injury, including ischemic stroke and traumatic brain injury.

Link: https://doi.org/10.1080/19490976.2024.2302801

One noted aspect of vascular aging is that the processes of angiogenesis become less effective with age, and as a consequence aged tissues lose capillary density. This harms function by reducing the supply of nutrients and oxygen to energy-hungry tissues such as muscles and brain, as well as putting stress on the remaining vasculature due to changes in the dynamics of blood flow. Accompanying this form of vascular aging is a progressive innervation, a loss of peripheral nervous system connections. These two complex processes interact strongly with one another, given the proximity of blood vessels and nerves, and signaling that passes back and forth between the cell types involved.

In today's open access commentary, researchers discuss recent findings regarding the interaction of blood vessel aging and peripheral nervous system aging, with a focus on the heart, where the consequences of these processes include various forms of arrhythmia. Interestingly, innervation precedes loss of capillary density, something that might form the basis for further investigation in and of itself, given the importance of this loss to tissue function. The primary result, however, is that researchers found one specific signal that appears to be released by endothelial cells in aged tissues, and which is disruptive to peripheral nerve formation and maintenance. This gives a target for drug development and further research into this form of degenerative aging.

Endothelial cell dysfunction: the culprit for cardiac denervation in aging?

During cardiac development, nerves grow in close anatomic proximity to blood vessels due to their need for oxygen and nutrients. Vice versa, blood vessels require closeness to nerves for tight control of vasodilation and vasoconstriction. However, their interdependence also means that malfunction of one cell type may result in dysregulation of the other. Two important sources of cardiac innervation are the parasympathetic and sympathetic nervous systems, and under- or hyper-activity of either system can lead to heart failure or arrhythmias. One common condition associated with autonomic nervous system deterioration and a predilection for cardiac arrhythmias is aging. Researchers recently demonstrated that aging-dependent vascular endothelial cell dysfunction reduces the density of neuronal axons in the heart, which in turn increases the risk of arrhythmias.

For these groundbreaking studies, researchers utilized 18-20-month-old male and female wild-type (WT) mice as the primary model of aging. Compared to young (3-month-old) mice, old mice exhibited ventricular diastolic dysfunction. Immunohistochemical staining of heart cross-sections revealed that all three major types of nerve fibers - parasympathetic, sympathetic, and sensory - were decreased in old vs. young mice. In conjunction, there was a higher incidence of inducible ventricular tachycardia in hearts isolated from old vs. young mice.

A time-course experiment revealed that nerve degeneration presented at 16 months prior to the onset of capillary rarefaction at 20 months - suggesting that nerve degeneration is not caused by loss of capillaries but rather may be due to alterations in vascular-derived neuroguidance cues. RNA sequencing (RNA-seq) of cardiac endothelial cells (ECs) isolated from old mice revealed upregulation of genes encoding pathways involved in neuronal death and axon injury, in particular semaphorin 3A (Sema3a). Interestingly, prior work had revealed that both deletion and overexpression of Sema3a can cause ventricular arrhythmias and sudden death in mutant mice. The researchers uncovered a new mechanism that involves aging ECs releasing more Sema3a, which reduces neuronal axon density in the heart, thereby promoting ventricular arrhythmias.

The vascular system responds favorably to exercise at any age. A large portion of the benefits of exercise derive from improvements to vascular function throughout the body, and physical fitness can be maintained further into old age than most people believe to be the case. The flip side of this point is that a sizable fraction of the declines of later life are a matter of disuse, people living a more sedentary life than is optimal for the health and function of muscles, heart, and brain. These the most energy-hungry tissues and those that see the worst outcomes from a decline in vascular function and consequently reduced delivery of nutrients and oxygen. Beyond the matter of blood supply, exercise is also protective against mechanisms involved in development of hypertension and atherosclerosis, as well as other conditions related to the vasculature. Overall, it is a good idea to maintain physical fitness for as long as possible in life, for these and other reasons.

Exercise-induced hemodynamic changes lead to mechanical stress of the vascular wall, the release of circulating growth factors from the endothelium, and the release of exerkines from the exercising skeletal muscle and other organs. These three main adaptive stimuli lead to an increased activity of several molecular pathways within the vascular endothelial and smooth muscle cells, culminating in a better vasodilation and vasoconstriction responsiveness, reduced arterial stiffness, arteriogenesis, and angiogenesis, higher antioxidative capacities, and reduced oxidative stress. Recent research revealed a potential role of enhanced mitochondrial biogenesis and mitophagy, substrate metabolism, and insulin sensitivity in the vascular smooth muscle cells for exercise-induced vascular adaptations.

Some vascular adaptations, such as a favorable balance of angiogenesis and angiostasis as well as of vasodilator and vasoconstrictor responsiveness, require regular exercise, ideally throughout the entire life span. Therefore, individualization of exercise according to objective and subjective factors should be sought to achieve the best possible long-term training adherence. Repeated stimuli, at least every other day at initial stages and progressively increasing to 5-7 days per week, might be necessary to use the full potential of favorable physiological alterations, such as elevated blood pressure and improved glycemic control, which last for about 24 hours post exercise.

The cumulative volume of elevated shear stress seems more important than peak shear stress in terms of stimulating vascular remodeling. Thus, prolonged moderate-intensity workouts may be favored over shorter sessions with very high intensities, especially if injury prevention and long-term training adherence are important. High-intensity interval training may have additional benefits in the long-term, such as increased antioxidative and metabolic capacities, and thus should also be part of vascular exercise training. Resistance and aerobic exercise induce distinct macro- and microvascular adaptations; thus, both types of exercise should be implemented in comprehensive training for optimal vascular health.

Link: https://doi.org/10.3390/cells12212544

Setting aside cases of vitamin deficiency, the consensus on supplement use (including vitamins) in essentially healthy individuals is that it does little to nothing, or is even mildly harmful to long-term health. That mild harm might include use of antioxidants that diminish the beneficial response to exercise that is mediated in part by oxidative stress. As a counterpoint to the consensus, researchers here provide evidence for multivitamin use to modestly improve cognitive function in later life. Whether this result will hold up in other study populations is a question, and we'll likely be waiting a while on the answer. It tends to take a long time for studies involving hundreds or thousands of participants to be organized, conducted, and analyzed.

The COcoa Supplement and Multivitamin Outcomes Study (COSMOS) is a large-scale, nationwide, randomized trial rigorously testing cocoa extract and multivitamin supplements. Two previously published studies of cognition in COSMOS suggested a positive effect for a daily multivitamin. COSMOS researchers now report the results of a third study of cognition in COSMOS, which focused on participants who underwent in-person assessments, together with the results of a combined analysis from the three separate studies.

In the in-clinic study the researchers administered detailed, in-person cognitive assessments among 573 participants in the subset of COSMOS known as COSMOS-Clinic. In their prespecified analyses of data from COSMOS-Clinic, investigators observed a modest benefit for the multivitamin, compared to placebo, on global cognition over two years. There was a statistically significant benefit of multivitamin supplementation for change in episodic memory, but not in executive function/attention. The team also conducted a meta-analysis based on the three separate studies, with non-overlapping COSMOS participants (ranging 2-3 years in treatment duration), which showed strong evidence of benefits for both global cognition and episodic memory. The authors estimate that the daily multivitamin slowed global cognitive aging by the equivalent of two years compared to placebo.

Link: https://www.massgeneralbrigham.org/en/about/newsroom/press-releases/multivitamins-improve-memory-and-slow-cognitive-aging

Geroscience is a philosophy of development, suggesting that aging can be slowed and we should work towards means to do so. In practice, geroscience is, more or less, the the name given to that part of the research and development community that aims to produce means to alter metabolism to modestly slow aging. It is best represented by the development of supplements and repurposing of very well studied drugs, near all of which produce smaller benefits to long-term heath than regular moderate exercise, and none of which can match the benefits provided by the practice of calorie restriction. It is entirely unambitious. This lack of ambition is one response to a regulatory environment that makes it very challenging and very expensive to produce entirely novel therapies that are capable of achieving sizable benefits. Many groups simply retreat to forms of development that are easier, even though the benefits will be small.

The current popularity of geroscience will be nothing more than a footnote in the history of aging research if it continues to produce supplement companies and interventions that achieve very little in the grand scheme of things. If the primary output of the Buck Institute for Research on Aging is supplement companies, as seems to be increasingly the case, then the Buck Institute for Research on Aging is irrelevant to the goal of treating aging as a medical condition. The research community knows more than enough about the causes of aging to produce therapies that are capable of far more than simply tweaking the operation of metabolism to age a little bit more slowly. We want more programs aimed at repair of the molecular damage that causes aging, and thus rejuvenation, and fewer programs aimed at characterizing metabolic changes that cannot even in principle achieve a greater slowing of aging than is produced by good lifestyle choices.

Is aging without illness possible?

Each morning after breakfast, Scott Broadbent takes a plastic bottle from the refrigerator in his home in Alameda, Calif., pops the top, and drinks the contents, 2.5 ounces of milky liquid. The bottle might contain ketone ester, a supplement meant to help the body burn fat instead of carbohydrates. Researchers are now testing whether it might also slow the aging process. Or Broadbent might instead be getting a placebo. He is part of a clinical trial at the nearby Buck Institute for Research on Aging to assess the supplement's safety and side effects in older adults.

A retired chemist who used to work for pharmaceutical companies, Broadbent is 70 and in excellent health today, but he worries about the future. He's not necessarily afraid of dying, but he doesn't want to be sick and in pain as he grows older. Some scientists think there's a better way. These researchers - part of a burgeoning field called "geroscience" - aren't seeking immortality. The focus is much more pragmatic: By addressing the root causes of aging, they hope to stave off the disability and diseases that can make old age so miserable. They want to help people feel healthy for longer, compressing the years of illness that often accompany old age into a much shorter time frame.

Though there are no proven therapies for people yet, geroscientists are eyeing several compounds that can slow the aging process, at least in worms, fruit flies, and mice. Some have already been tested in humans, and many more clinical trials are under way. Perhaps the best studied is rapamycin, a compound first discovered in a soil sample collected in 1964 from Rapa Nui, or Easter Island. Today, people who receive organ transplants take the drug to help keep their immune systems from rejecting the foreign tissue. But rapamycin also prolongs life in yeast, flies, and mice. And it's being tested in people in clinical trials. How it counters aging isn't entirely clear. The drug inhibits a protein complex called mechanistic target of rapamycin, mTOR for short, which plays a role in cell growth and protein synthesis. This inhibition appears to have wide-ranging effects, including reducing inflammation, clearing old and damaged cells, and altering cellular metabolism - some of the key processes that researchers think are to blame for the aging process.

Diet is also known to profoundly affect the aging process. Studies have found that the low-carb ketogenic diet, for example, can help mice live longer. But restrictive diets can be hard to follow and have side effects. Broadbent followed the ketogenic diet for a month or so, but his cholesterol levels went dramatically up. Ketone ester, the compound Broadbent might be downing each morning for the Buck Institute's clinical trial, may mimic the longevity benefits of such diets. When the body runs out of glucose to use for energy, the liver creates another source by converting fat into molecules called ketone bodies. These compounds are more than just fuel. They help regulate inflammation and control other cellular processes, many of them involved in the aging process. Drinking ketone esters, which quickly break down, is a way to deliver the ketone bodies without the diet.

It presently costs little to assess the transcriptomic state of a cell, the amounts and sequences of various RNA transcripts produced from DNA. Thus a fair amount of research into health, disease, and cell biochemistry is focused on this complex layer of cell behavior. It is comparatively easy to produce a great deal of data and identify differences between cells and cell states, but challenging to connect that to other mechanisms and higher level causes and consequences. The research here illustrates this point, in that the researchers can discuss changes in RNA transcripts observed in Alzheimer's disease, but do not discuss how this work might connect to, say, immune dysregulation or protein aggregation viewpoints of Alzheimer's disease - as it would be hard to make those connections.

A new study shows that RNA interference may play a key role in Alzheimer's. For the first time, scientists have identified short strands of toxic RNAs that contribute to brain cell death and DNA damage in Alzheimer's and aged brains. Short strands of protective RNAs are decreased during aging which may allow Alzheimer's to develop.

In addition to long coding RNAs in cells, there are large numbers of short RNAs (sRNAs) which do not code for proteins. They have other critical functions in the cell. One class of such sRNAs suppresses long coding RNAs through a process called RNA interference that results in the silencing of the proteins that the long RNAs code for. Researchers have now identified very short sequences present in some of these sRNAs that when present can kill cells by blocking production of proteins required for cells to survive. The data suggests that these toxic sRNAs are involved in the death of neurons which contributes to the development of Alzheimer's disease.

The toxic sRNAs are normally inhibited by protective sRNAs. One type of sRNA is called microRNAs. While microRNAs play multiple important regulatory roles in cells, they are also the main species of protective sRNAs. They are the equivalent of guards that prevent the toxic sRNAs from entering the cellular machinery that executes RNA interference. But the guards' numbers decrease with aging, thus allowing the toxic sRNAs to damage the cells. Adding back protective microRNAs partially protects brain cells engineered to produce less protective sRNAs from cell death induced by amyloid beta fragments (which trigger Alzheimer's). Enhancing the activity of the protein that increases the amount of protective microRNAs partially inhibits cell death of brain cells induced by amyloid beta fragments and completely blocks DNA damage (also seen in Alzheimer's patients).

Link: https://www.eurekalert.org/news-releases/1031412

The study noted here provides an interesting addition to the debate over whether time spent sitting is harmful to health independently of its contribution to time spent being sedentary. Time spent sitting increases mortality, while time spent active or undertaking exercise decreases mortality. The results of this large epidemiological study quantify how much additional exercise is required to mitigate the mortality increase resulting from time spent sitting. The results also have the look of common sense at the end of the day; the intuition that one should compensate for a desk job with additional exercise outside work turns out to be true.

To quantify health risks associated with prolonged occupational sitting and to determine whether there is a certain threshold of physical activity that may attenuate it. This prospective cohort study included participants in a health surveillance program in Taiwan who were followed-up between 1996 and 2017. Data on occupational sitting, leisure-time physical activity (LTPA) habits, lifestyle, and metabolic parameters were collected. The all-cause and cardiovascular disease (CVD) mortality associated with 3 occupational sitting volumes (mostly sitting, alternating sitting and nonsitting, and mostly nonsitting) were analyzed applying multivariable Cox regression models to calculate the hazard ratios (HRs) for all participants and by subgroups, including 5 LTPA levels and a personal activity intelligence (PAI)-oriented metric. Deaths occurring within the initial 2 years of follow-up were excluded to prevent reverse causality.

The total cohort included 481,688 participants (mean age 39.3 years). The study recorded 26,257 deaths during a mean follow-up period of 12.85 years. After adjusting for sex, age, education, smoking, drinking, and body mass index, individuals who mostly sat at work had a 16% higher all-cause mortality risk (HR, 1.16) and a 34% increased mortality risk from CVD (HR, 1.34) compared with those who were mostly nonsitting at work. Individuals alternating sitting and nonsitting at work did not experience increased risk of all-cause mortality compared with individuals mostly nonsitting at work (HR, 1.01). For individuals mostly sitting at work and engaging in low (15-29 minutes per day) or no (under 15 minutes per day) LTPA, an increase in LTPA by 15 and 30 minutes per day, respectively, was associated with a reduction in mortality to a level similar to that of inactive individuals who mostly do not sit at work. In addition, individuals with a PAI score exceeding 100 experienced a notable reduction in the elevated mortality risk associated with prolonged occupational sitting.

Link: https://doi.org/10.1001/jamanetworkopen.2023.50680

Those of us who have been involved in advocacy for aging research and the development of therapies to treat aging as a medical condition for long enough will remember the early 2000s, a time in which a million dollars of new funding for a specific project or specific non-profit was an amazing, novel, rare event. Given that $3 billion, a sizable fraction of all investment into all forms of medical biotech in 2022, was invested into one entity focused on one approach to the treatment of aging, Altos Labs, we might forgive advocates who think that the job is done, that the argument has been made and heard, that it is time to go home and watch the progress rolling in.

Sadly the job is never done. The difference between a few million dollars in a year and a few billion dollars in a year dedicated to aging research and the development of treatments targeting mechanisms of aging is vast. But it is only a step forward in the bigger picture. It remains the case that aging causes so much harm and death, a vast and ongoing toll, that the real goal here is to grow the entire medical research and development investment field a hundredfold, and all of that focused on age-related disease, rather than merely claiming a little more of the existing field.

Medical research is dramatically underfunded in comparison to the costs of disease, and nowhere is this more apparent than in the matter of degenerative aging. There must be a great changing of minds, an education of everyone who thinks that present investment is anywhere near adequate as a response to aging. The world up-ended itself over COVID-19, a condition that killed a tiny fraction of those who die due to aging. Yet aging has always been with us, and only now is there the real possibility of producing rejuvenation. People are accepting of a vast toll of death and suffering from aging. That must change.

Andrew Steele: "A Mindset Shift Is Required"

After spending about a decade in this field, are you now more optimistic or more pessimistic than you were in the beginning?

I think I'm a mixture of things. Scientifically, the last decade has been perhaps even more incredible than the decade that preceded it. The Hallmarks of Aging paper came out in 2013. It has provided a rallying point for geroscience and became one the most cited biology papers ever. We've seen many incredible things, like actual treatments progressing. We've got senolytics now, a whole class of treatments that simply didn't exist when I first started looking into longevity. We've got epigenetic reprogramming. We'd used it for individual cells, but we now have evidence that it can potentially improve aging in whole organisms. All those interventions are super exciting. The science is progressing. The respect in which I'm less optimistic is that making the case for longevity hasn't moved on as far. Yes, there has been some increase in public perception and longevity is a real buzzword, but the ways people get exposed to it are less than ideal.

Many of them come across news stories about incredibly rich people doing a variety of, frankly, quite strange interventions to try and extend their lifespan. If this is people's first exposure to aging biology, and they might start thinking that this is some kooky pastime for gajillionaires that isn't for the likes of you and me. They don't realize that a lot of what we're talking about is drugs that could cost pennies per pill while making all of us live healthier, longer lives without having to go to bed at a very prescribed time every night and do four hours of exercise a day and only eat the same food every single day and so on.

Another challenge is that although longevity and preventative medicine have really increased in their prominence, when you talk about this in policymaking circles, so much of that discussion focuses on diet, exercise, and other lifestyle stuff. While those things are very important, and I am a huge supporter of public health, I think that it's not as important as dramatically increasing the amount of money we spend researching aging. That's because while we know that you can add a decade of life by going from the least to the most healthy dietary patterns and so on, the potential of aging biology vastly outstrips that.

If you drill down to what goes into aging biology per se, it's about $350 million a year, which is a dollar per American. And this is for studying a process that kills 85% of Americans and is by far the largest cause of suffering in the United States. It just seems wildly disproportionate. Although it's very exciting to see a lot of private funding come into the field, this is still a drop in the ocean compared to US healthcare spending, which is four trillion - not four billion, but four trillion dollars every single year. Just think about the economic impact that investing in aging research could have. It's simply not being recognized. Although the scientific developments are exciting and cool and coming thick and fast, there's this weird tension between the amount of amazing stuff going on right now and the fact that the field is still dramatically underfunded. Trying to communicate that tension is probably the hardest part of my job.

After long years of failure, the treatment of Alzheimer's disease through clearance of protein aggregates in the brain has been reinvigorated by minor degrees of success. The results are poor in the grand scheme of things, and come with risk of severe side-effects, but once a disease can be at least slowed, there is a renewed interest in improving on that starting point. It remains the case that the contributing causes of Alzheimer's disease remain poorly understood, however, and it may turn out to be much more preventable than thought. Assays to detect the earliest stages of the condition are now demonstrated, and promising work suggests that persistent viral infection may be an important factor that could be addressed via more widespread use of existing antiviral therapies.

Alzheimer's disease (AD) is the most common neurodegenerative disease characterized by cognitive impairment with few therapeutic options. Amyloid-β (Aβ), tau, and neuroinflammation are immunotherapy targets focused on by industries for AD intervention. Passive immunotherapy targeting Aβ was launched decades ago and has reached milestone progress with full approval of lecanemab by the FDA very recently. While the development of monoclonal antibody (mAb) drugs targeting tau or immune modulators is at an early stage, several preclinical and clinical studies have shown promising results.

Here, we review characteristics, clinical trial data, and mechanisms of action for mAbs targeting key players in AD pathogenesis, including Aβ, tau, and neuroinflammation modulators. For the anti-Aβ strategy, it should be noted that even the mAbs (lecanemab and donanemab) only showed efficacy in patients with early AD. This may be because other factors, such as tau, have important contributions to neuronal loss in the later stages of AD. In support of this notion, donanemab only showed efficacy in AD patients with low/medium tau pathology.

Therefore, it is important to elucidate the clinical effect of anti-Aβ mAbs on neuronal loss, and it is worth testing the combined immunotherapy strategy targeting both Aβ and tau in patients with moderate symptoms or medium/severe tau pathology in the future. In addition, efficient Aβ-targeted immunotherapy is associated with a high incidence of ARIA and brain atrophy, and the underlying mechanisms need to be clarified. For anti-tau immunotherapy, most of the mAbs recognizing the N-terminal epitopes failed in clinical trials. The industries have now focused on developing mAbs targeting the tau mid-region or phosphorylated tau, which may be able to stop tau seeding and spreading.

Link: https://doi.org/10.1016/j.arr.2024.102192

Much of the communication that takes place between cells takes the form of secretion and uptake of extracellular vesicles, small membrane-wrapped packages of diverse molecules. Vesicles are currently categorized by size, for lack of a better taxonomy, and exosomes are one of the better studied size classes. It appears to be the case that much of the benefit of first generation stem cell therapies is produced by the signaling generated by transplanted cells, and thus the research community has started to focus on the logistically easier approach of harvesting and using extracellular vesicles rather than transplanting the cells themselves. While extracellular vesicle therapies are readily available via medical tourism, widespread use in the more regulated end of the medical community remains a work in progress.

Photoaging is a prominent manifestation of skin aging characterized by the appearance of mottled pigmentation, fine lines, and wrinkles. The main molecular mechanisms of photoaging are accumulation of reactive oxygen species, cellular senescence, inflammation, and collagen degradation. Targeting these pathways through novel therapeutics is an intriguing area of study in regenerative medicine.

Exosomes are tiny extracellular vesicles secreted by most cell types, which are filled with proteins, lipids, and nucleic acids (non-coding RNAs, mRNA, DNA), can be released by donor cells to subsequently modulate the function of recipient cells. Exosomes are able to regulate multiple cellular processes due to their important role in cellular communication.

In recent years, exosomes have emerged as a novel therapeutic option for treatment of many diseases. This review aims to summarize the current findings on the roles of exosomes, particularly those derived from stem cells, in the context of skin photoaging. In preclinical studies, stem cell-derived exosomes can restore skin physiological function and regenerate or rejuvenate damaged skin tissue through various mechanisms such as decreased expression of matrix metalloproteinase (MMP), increased collagen and elastin production, and modulation of intracellular signaling pathways as well as, intercellular communication. All these evidences are promising for the therapeutic potential of exosomes in skin photoaging.

Link: https://doi.org/10.1186/s12964-023-01451-3

Klotho is one of the few robustly longevity-associated genes discovered over the past few decades. Increased levels of the circulating α-klotho protein slows aging in mice and is associated with better late life health in humans. Additionally, more of this α-klotho appears to slow cognitive aging and also boost cognitive function in younger animals. While klotho is thought to be primarily active in the kidneys, and thus indicates the importance of declining kidney function in degenerative aging, researchers are discovering potentially relevant interactions in the brain. It remains an open question as to how exactly klotho produces its observed benefits, which potential mechanisms are most important, and whether there is more to be discovered yet.

This lack of knowledge hasn't prevented the research and development community from working on therapies based on delivery of optimized α-klotho variants. That is a work in progress, however, currently led by Unity Biotechnology and at a comparatively early preclinical stage. Other groups will no doubt join them as the possibilities for klotho-based therapies continue to attract further interest. Such therapies do not have to be limited to delivery of α-klotho as a protein. An increase in the levels of specific circulating proteins is one of the easier, more feasible prospects for gene therapies, as all it requires is delivery of the treatment to a small volume of fat tissue, turning it into a factory for the desired proteins, the effects lasting for years or more.

Klotho: a potential therapeutic target in aging and neurodegeneration beyond chronic kidney disease-a comprehensive review from the ERA CKD-MBD working group

Aging and neurodegenerative disorders are complex medical conditions with poorly understood underlying pathophysiology that may affect virtually all tissues and organs. A limited number of genes and their transcripts have been associated with either premature aging, as seen in progeria, or with longevity. The α-Klotho protein, first identified in mice studies in 1997, primarily functions as a co-receptor for fibroblast growth factor 23 (FGF23) in the kidneys and parathyroid gland and therefore has a crucial role in phosphate homeostasis, vitamin D metabolism, and vascular calcification. In addition, α-Klotho has been identified in a wide variety of tissues, consistent with its role in the aging process, including endocrine organs, arteries, and reproductive, epithelial, and neuronal tissue.

β-Klotho is primarily expressed in the liver, adipose tissue, and kidneys and plays a role in lipid and energy metabolism by acting as co-receptor for FGF15 and FGF21, while the γ-Klotho isoform is expressed in the brown adipose tissue, skin and kidneys with as yet poorly defined roles and by acting as co-receptor for FGF receptor 1b (FGFR1b), FGFR1c, FGFR2c and FGFR4 and are not discussed in the current review, which is focused on α-Klotho.

Nevertheless, preclinical studies conducted on Klotho knockout mice have revealed that Klotho deficiency is associated with impaired cognition, shorter lifespan, cardiac hypertrophy, vascular calcification, multi-organ atrophy, and fibrosis and growth retardation. Moreover, overexpression of the Klotho gene has been shown to lengthen lifespan in mice, which raises the potential question of whether Klotho may be utilized as a target to control or reverse aging and/or neurodegeneration. One drawback of such models is the lack of distinction between soluble and transmembrane Klotho molecules, which may potentially have distinct physiological roles in the human body. Whether such physiological and pathological outcomes of Klotho deficiency and/or overexpression may simply be attributable to the role of Klotho on phosphate metabolism is unclear and should be evaluated with caution with the discovery of multiple phosphate metabolism-independent functions of Klotho protein.

In this narrative review, our aim is to evaluate the potential pathophysiological and therapeutic role of Klotho protein in aging and neurodegenerative conditions. Emerging clinical and experimental insights suggest Klotho deficiency not only as a risk factor, but also a modifiable therapeutic target. Even though there is a clear need for future large-scale human studies in order to develop clinical and therapeutic strategies involving Klotho proteins in humans, this field appears to be promising.

Icariin supplementation has been shown to improve health and the state of the gut microbiome in mice, and appears to be neuroprotective in other studies. Here researchers show that icariin extends life in nematode worms by affecting the well-studied DAF-2 gene, and to a similar degree to DAF-2 mutation. Whether all of this will translate to an interesting effect size in humans remains to be seen; other interventions that alter metabolism, particularly this area of metabolic regulation, have produced diminishing returns in longer-lived species, where there is data to directly compare.

Aging presents an increasingly significant challenge globally, driven by the growing proportion of individuals aged 60 and older. Currently, there is substantial research interest in pro-longevity interventions that target pivotal signaling pathways, aiming not only to extend lifespan but also to enhance healthspan. One particularly promising approach involves inducing a hormetic response through the utilization of natural compounds defined as hormetins. Various studies have introduced the flavonoid icariin as beneficial for age-related diseases such as cardiovascular and neurodegenerative conditions.

To validate its potential pro-longevity properties, we employed Caenorhabditis elegans as an experimental platform. The accumulated results suggest that icariin extends the lifespan of C. elegans through modulation of the DAF-2, corresponding to the insulin/IGF-1 signaling pathway in humans. Additionally, we identified increased resistance to heat and oxidative stress, modulation of lipid metabolism, improved late-life healthspan, and an extended lifespan upon icariin treatment. Consequently, a model mechanism of action was provided for icariin that involves the modulation of various players within the stress-response network. Collectively, the obtained data reveal that icariin is a potential hormetic agent with geroprotective properties that merits future developments.

Link: https://doi.org/10.3390/ijms25010352

Researchers are coming to see chronic inflammation as an important driving mechanism of Alzheimer's disease, as well as many other age-related conditions. But inflammation is by no means a single, simple state. The immune system is complex, and inflammation is a complex collection of contributions and behaviors undertaken by varied cell populations. Researchers here find a way to gain some insight into which aspects of the inflammatory state are more or less important in the progression of Alzheimer's disease.

Inflammation is a central component of Alzheimer's disease (AD) pathophysiology, downstream of amyloid beta (Aβ) and tau pathology. Results become heterogeneous when one concentrates on single inflammatory markers, however. These variations may reflect different inflammatory mechanisms in different disease stages. However, a more parsimonious interpretation should take into account that cerebrospinal fluid (CSF) markers are only surrogate measures for an underlying construct, that is, inflammation, which cannot be directly observed in clinical studies.

Mathematically, one can express this epistemological reservation in the framework of structural equation models (SEM). We can construct the inflammatory response in the brain as a latent factor that eludes direct observation but can be assessed by observable proxy markers in the CSF. Confirmatory factor analysis is a readily available tool to form such latent factors. Here, we constructed latent factors for a priori defined inflammatory domains, including synaptic integrity, microglia, complement factors, adhesion, and cytokines/chemokines. We had two goals: First, to determine latent factors of neuroinflammation based on an a priori assignment of single inflammatory markers to certain inflammatory domains. Second, to characterize these neuroinflammation factors in relation to AD pathology markers from CSF and longitudinal rates of cognitive decline.

We studied 296 cases from the Deutsches Zentrum für Neurodegenerative Erkrankungen Longitudinal Cognitive Impairment and Dementia Study (DELCODE) cohort, and an extension cohort of 276 cases of the Alzheimer's Disease Neuroimaging Initiative study. Using Bayesian confirmatory factor analysis, we constructed latent factors for synaptic integrity, microglia, cerebrovascular endothelial function, cytokine/chemokine, and complement components of the inflammatory response using a set of inflammatory markers in CSF. We found strong evidence for an association of synaptic integrity, microglia response, and cerebrovascular endothelial function with a latent factor of AD pathology and with rates of cognitive decline. We found evidence against an association of complement and cytokine/chemokine factors with AD pathology and rates of cognitive decline.

Link: https://doi.org/10.1002/dad2.12510

There are any number of sizable gaps in the understanding of how aging progresses at the detail level, which processes are more or less important, the direct of causation for many different interactions, and so forth. Aging is very complex because a living organism is very complex. Even simply causes produce complex outcomes when operating in a complex system. The same sizable gaps in understanding exist when we ask how and why aging evolved to be near universal across the tree of life, given that physical immortality appears possible for lower animals, and for much the same reasons. The evolutionary landscape is a complicated environment.

The scientific impulse is to make progress towards full understanding of a system as it exists, but one can argue that finding answers to these questions will not actually be all that helpful when it comes to the near future production of the first generation of rejuvenation therapies. Those therapies must necessary address forms of molecular damage and disarray that cause degenerative aging, and which are already identified and well enough understood to allow meaningful progress towards interventions. Comprehensive lists of starting points and modes of therapy to be developed have existed for years, such as the Strategies for Engineered Negligible Senescence. The research community is nowhere near as ignorant of the causes of aging as it is of how exactly aging progresses in detail, and the human impulse is to change systems that are not ideal, such as the present state of degenerative aging, as soon as the tools exist to do so.

Today's open access paper is more reflective of the scientific impulse than the human impulse. It results from a narrow survey of researchers in the field, requesting commentary on unanswered important questions relating to aging. Thus we see a focus on the evolution of aging and why aging progresses differently between species and between individuals of the same species. This results from the urge to obtain a complete understanding, which remains somewhat distinct from what might be done effectively and soon to improve the state of aging. In fact, the state of research and development is one in which more might be learned, and more rapidly, by deploying the first rejuvenation therapies and observing the results, than by a more hands-off continued investigation of mechanisms without meaningful intervention.

Seven knowledge gaps in modern biogerontology

About a year ago, members of the editorial board of Biogerontology were requested to respond to a query by the editor-in-chief of the journal as to what one question within their field of ageing research still needs to be asked and answered. During the following couple of months, a majority of the editorial board members responded with their precise, and sometimes not-so-precise, questions, ideas and opinions. Based on those responses, this editorial article is my attempt to identify and compile a list of knowledge gaps in the biology of ageing research, and these are arranged under three main and general categories: (1) evolutionary aspects of longevity; (2) biological survival and death aspects; and (3) heterogeneity in ageing progression and phenotype. The implications of these knowledge gaps in biogerontology, especially in the context of ageing interventions for human health and longevity, are also discussed.

1. What are the evolved public (universal) and private (species-specific) longevity assurance genes for the essential lifespan of a species?

2. What is the nature of imperfections that limit the optimal functionality of the longevity assurance processes, and are they sex-specific?

3. With almost identical physical-time scales at the level of metabolic processes, how is the passage of biological-time regulated from one biological stage to the next through the life-cycle and until death?

4. What are the quantitative and qualitative features of the homeodynamic space in terms of the health and survival ability of a biological system?

5. What determines heterogeneity in the rate and extent of age-related changes at various levels of biological organization, from molecules to the whole body and population levels?

6. How to distinguish between harmful, useful, and neutral changes occurring during ageing?

7. How to identify and quantify the ability to tolerate, adapt, compensate and bypass age-related changes?

Since ageing is primarily a progressive loss of health, the focus of interventional strategies requires a shift from the treatment and prevention of diseases to the maintenance, recovery and enhancement of health. Such trends can already be seen emerging and being adopted.

Publicity materials here note a recent research initiative to produce pluripotent stem cell lines that will not be rejected when transplanted into other individuals, or even between species. This technological capability is necessary to the development of new forms of regenerative medicine, allowing the production of universal donor cells and tissues at reasonable cost. While the results sound impressive, it is worth noting that several large and well-funded pharma companies have been developing earlier, first generation versions of this technology for some years, accompanied by many smaller research groups and companies. A number of different approaches have been tried, but the broader goal of their use in cell therapies and tissue engineering remains challenging and expensive under the present system of medical regulation. Progress is slow and painstaking, and it remains unclear as to whether regulators consider this technology even in principle safe enough for the clinic, after years of intense investment. The approach noted here will still encounter these issues if it is further developed.

Pluripotent stem cells can turn into any type of cell in the body. The findings offer a viable path forward for pluripotent stem cell-based therapies to restore tissues that are lost in diseases such as Type 1 diabetes or macular degeneration. "There has been a lot of excitement for decades around the field of pluripotent stem cells and regenerative medicine. What we have learned from the experiences of organ transplantation is that you have to have matched donors, but the person receiving the transplant often still requires lifelong immune suppression, and that means there is increased susceptibility to infections and cancer. We've been trying to figure out what it is that you need to do to those stem cells to keep them from getting rejected, and it looks like we have a possible solution."

To test their hypothesis, researchers used CRISPR-Cas9 technology, "genetic scissors" that allow scientists to make precise mutations within the genome at extremely specific locations. Using human pluripotent stem cells, the team located the specific genes they believed were involved in immune rejection and removed them: β2M, TAP1, CIITA, CD74, MICA, and MICB. Prior research into pluripotent stem cells and immune rejection looked at different parts of the immune system in isolation. The researchers instead opted to test their genetically modified stem cells in a complete and functional immune system.

"Transplantation across species, across the xenogeneic barrier, is difficult and is a very high bar for transplantation. We decided if we could overcome that barrier, then we could start to have confidence that we can overcome what should be a simpler human-to-human barrier, and so that's basically what we did." The research team tested the modified human stem cells by placing them into mice with normal, fully functioning immune systems. The results were promising - the genetically engineered pluripotent stem cells were integrated and persisted without being rejected.

Link: https://healthsciences.arizona.edu/news/releases/researchers-genetically-modified-stem-cells-evade-immunological-rejection

Researchers here report on an epidemiological analysis of the effects of relative poverty and chronic inflammation on health and life span. It is well known that socioeconomic status correlates with mortality and life expectancy. There is a great deal of debate over which of the numerous mechanisms potentially involved in this correlation contribute the largest share of the effect size. Separately, chronic inflammation is disruptive to tissue structure and function, increases with age, and is known to increase risk and accelerate progression of all of the common age-related fatal conditions. As one might expect, the poverty and chronic inflammation together correlate with worse outcomes than either separately.

Chronic systemic inflammation and poverty are both linked to an increased mortality risk. The goal of this study was to determine if there is a synergistic effect of the presence of inflammation and poverty on the 15-year risk of all-cause, heart disease and cancer mortality among US adults. We analyzed the nationally representative National Health and Nutrition Examination Survey (NHANES) 1999 to 2002 with linked records to the National Death Index through the date December 31, 2019. Among adults aged 40 and older, 15-year mortality risk associated with inflammation, C-reactive protein (CRP), and poverty was assessed in Cox regressions. All-cause, heart disease, and cancer mortality were the outcomes.

Individuals with elevated CRP at 1.0 mg/dL and poverty were at greater risk of 15-year adjusted, all-cause mortality (hazard ratio [HR] = 2.45) than individuals with low CRP and were above poverty. For individuals with just one at risk characteristic, low inflammation/poverty (HR = 1.58), inflammation/above poverty (HR = 1.59) the mortality risk was essentially the same and substantially lower than the risk for adults with both. Individuals with both elevated inflammation and living in poverty experience a 15-year heart disease mortality risk elevated by 127% and 15-year cancer mortality elevated by 196%.

Link: https://doi.org/10.3389/fmed.2023.1261083

The primary focus of the Longevity Escape Velocity (LEV) Foundation is to demonstrate that therapies based on the repair of forms of underlying molecular damage that cause aging can be combined to produce greater rejuvenation. Research of recent years has demonstrated quite comprehensively that the alternative strategy for treating aging, to manipulate metabolism into a state in which aging occurs modestly more slowly, has so far produced therapies that largely cannot be combined. The combination of any two or more metabolic alterations, induced by supplements or other small molecules, that individually modestly slow aging in animal models will likely result in no effect or even a modest acceleration of aging. The advocacy community might do well to use this as a teaching moment, to refocus efforts on the better path of damage repair.

In this article the LEV Foundation staff discuss the use of senolytics to clear senescent cells in their combination studies in mice, and the relevance of this approach to the bigger picture of combined therapeutics to produce rejuvenation. Since aging is a condition caused by a number of interacting but quite different forms of molecular damage and disarray, it will require a panoply of different therapies to repair aged tissue. Reversing mitochondrial dysfunction, repairing stem cell populations, removing senescent cells, clearing intracellular and extracellular waste products, and so forth. Once widespread in the clinic, senolytic drugs to clear senescent cells will be the first rejuvenation therapy worthy of the name. It will be useful to have some degree of evidence in aged animal models to demonstrate that this treatment can combine well with other approaches.

The Case For: Senolytics

As of 2023, the flagship research program at LEVF is our Robust Mouse Rejuvenation (RMR) studies, the first of which (RMR-1) was initiated in early 2023. In this program, we seek to investigate the potential lifespan-enhancing effects of combining multiple interventions in middle-aged mice which have been previously shown to extend the lifespans of lab mice. For RMR-1, we decided to test a senolytic intervention as one of the four interventions administered in combination to our study mice at Ichor Life Sciences. Those four interventions are: (a) Senescent cell ablation via galactose-conjugated Navitoclax ("Nav-Gal"); (b) Rapamycin in food at 42 ppm; (c) Enhanced telomerase expression via repeated TERT gene therapy (via nasally administered AAV-mTERT); (d) Hematopoietic stem cell transplantation. In this essay, we hope to answer readers' questions about the role of cellular senescence in aging and the role of senolytic therapies in rejuvenation. We will further speculate on how reducing the burden of senescent cells might synergize with other rejuvenation therapies.

The word senolytics is a blend of two words - senescence and lysis. Lysis means "a process of disintegration or dissolution". So, the use of senolytics is an effort to selectively and deliberately induce disintegration or elimination of senescent cells. One could reasonably want to be cautious about purposefully inducing the death of cells in the body, but there have been multiple reports of health benefits associated with administration of senolytics, particularly when done in animals with elevated senescent cell burden such as animals that are older or have been treated with chemotherapy or radiation - both of which are known to elevate the prevalence of senescent cells. There appear to be multiple mechanisms by which senolysis can be accomplished. The most common mechanism is to inhibit proteins associated with cell survival during stressful situations. The survival of senescent cells is dependent on proteins and processes that are different than those used for survival by non-senescent cells. We can exploit these differences to specifically target senescent cells while leaving non-senescent cells relatively unaffected.

We found Navitoclax, also called ABT-263, particularly interesting for our first RMR study for several reasons. First, Navitoclax appears to be effective at inhibiting Bcl-2, Bcl-w, and Bcl-XL. Because different cell types can overexpress different survival proteins when they become senescent, the ability of Navitoclax to inhibit all three of these proteins means that it might be relatively more effective at reducing the elevated numbers of senescent cells in many different tissues in the body. Second, Navitoclax also seems to be increasingly well studied. There have been many scientific reports about its effects on both normal and senescent cells, and this gives us confidence about its possible effects in older animals. However, Navitoclax has a drawback: it has been shown to be toxic to normal, healthy platelets and other immune cells. Fortunately, some researchers have designed a method to substantially reduce the toxicity of Navitoclax to non-senescent cells. Attaching galactose to Navitoclax reduced the toxicity of Navitoclax for normal cells but retained its toxicity for senescent cells, as senescent cells contain a lot of beta-galactosidase, an enzyme that cleaves galactose molecules from the other molecules they are attached to.

There is evidence that a persistent, elevated prevalence of senescent cells inhibits wound healing, immune function, tissue maintenance, and possibly stem cell function, and that these effects might limit the lifespans of aged mice (and we suspect, humans). We imagine that the elimination of senescent cells will enable the more anabolic interventions - such as TERT gene therapy and hematopoietic stem cell (HSC) transplantation - to work more effectively. Particularly in the case of HSC transplantation, we suspect that ridding the body of excessive senescent cells and senescence-associated secretory phenotype (SASP) signaling might enable those transplanted HSC to function better than they otherwise would. For example, consider the case of the bone marrow, which houses both mesenchymal stem cells (MSC) and HSCs. There is some evidence that mesenchymal stem cells become senescent during aging and secrete proteins which alter the bone marrow microenvironment, which in turn impairs HSC function. We imagine that a senolytic intervention which reduces the prevalence of senescent MSCs in the bone marrow could enhance HSC function, which includes the generation of red blood cells and immune cells.

In addition, there is some evidence to suggest that rapamycin and senescent cell ablation might be synergistic. This comes from evidence that rapamycin inhibits a protein complex called mTOR and upregulates autophagy - a process by which tissues and cells recycle their molecular materials. A study found that senescent cells seem to upregulate autophagy, but then also upregulate mTOR to survive the upregulated autophagy. It may be that inhibiting mTOR and enhancing autophagy (both accomplished by rapamycin) might facilitate greater senolysis by making senescent cells more susceptible to cell death - they might experience elevated autophagy and will fail to survive it when pro-survival mTOR is inhibited by rapamycin. So, we'll be looking for this interaction between rapamycin and senolytics and should be evident by a greater reduction in senescent cell prevalence in the mice administered both a senolytic and rapamycin, relative to mice administered a senolytic alone.

Amyloid-β is found in the bloodstream and blood vessels as well as in the brain, and an increase in this peripheral amyloid-β is noted in Alzheimer's disease patients who exhibit the characteristic amyloid-β aggregates in their brains. Current thinking is that there is a dynamic equilibrium between amyloid-β in the brain and body, and based on this view some success has been achieved in reducing amyloid-β in the brain by clearing amyloid-β in the rest of the body. Does this peripheral amyloid-β contribute to the onset of Alzheimer's disease in other ways, however? Researchers here suggest that it may increase the burden of systemic chronic inflammation, known to be involved in Alzheimer's disease pathology.

A key pathological factor of Alzheimer's disease (AD), the most prevalent form of age-related dementia in the world, is excessive β-amyloid protein (Aβ) in extracellular aggregation in the brain. And in the peripheral blood, a large amount of Aβ is derived from platelets. So far, the causality between the levels of peripheral blood Aβ and its aggregation in the brain, particularly the role of the peripheral blood Aβ in the pathology of AD, is still unclear. And the relation between the peripheral blood Aβ and tau tangles of brain, another crucial pathologic factor contributing to the pathogenesis of AD, is also ambiguous.

More recently, the anti-Aβ monoclonal antibodies are approved for treatment of AD patients through declining the peripheral blood Aβ mechanism of action to enhance plasma and central nervous system (CNS) Aβ clearance, leading to a decreased Aβ burden in brain and improving cognitive function, which clearly indicates that the levels of the peripheral blood Aβ impacted on the Aβ burden in brain and involved in the pathogenesis of AD. In addition, the role of peripheral innate immune cells in AD remains mostly unknown and controversial.

In the present review, we summarize recent studies on the roles of peripheral blood Aβ and the peripheral innate immune cells in the pathogenesis of AD. In the early stage of disease, the peripheral Aβ is involved in the pathogenesis of AD through activating innate immune cells and promoting them to secretion of inflammatory cytokines and molecules leading to enhancing the blood-brain barrier (BBB) permeability or damage the BBB. In the late stage, the peripheral Aβ may activate the peripheral and central inflammatory processes by affecting the proliferation and differentiation of innate immune cells. The recruitment of the peripheral innate immune cells may lead to increased production of proinflammatory cytokines by microglia, promoting the recruitment of more peripheral innate immune cells to move to the Aβ plaques of brain.

Link: https://doi.org/10.1186/s12974-023-03003-5

One evolutionary perspective on life is that the individuals making up a species are secondary concerns, mere wrappers for the all-important germline cells. Evolution optimizes for success in propagation of the germline lineage, not the success of the individual. With that in mind, one might expect to find that the germline can influence the body. That influence doesn't have to be a net positive for the individual, as noted here. The individual is disposable, and health only matters insofar as it enhances reproductive fitness in the eternal, ever-shifting arms race that takes place over evolutionary time.

Classical evolutionary theories propose tradeoffs between reproduction, damage repair, and lifespan. However, the specific role of the germline in shaping vertebrate aging remains largely unknown. Here, we use the turquoise killifish (N. furzeri) to genetically arrest germline differentiation at discrete stages, and examine how different 'flavors' of infertility impact life-history.

We first constructed a comprehensive single-cell gonadal atlas, providing cell-type-specific markers for downstream phenotypic analysis. Next, investigating our genetic models revealed that only germline depletion enhanced female damage repair, while arresting germline differentiation did not. Conversely, germline-depleted males were significantly long-lived, indicating that the mere presence of the germline can negatively affect lifespan. Transcriptomic analysis highlighted enrichment of pro-longevity pathways and genes, with functional conservation in germline-depleted C. elegans. Finally, germline depletion extended male healthspan through rejuvenated metabolic functions.

Our results suggest that different germline manipulation paradigms can yield pronounced sexually dimorphic phenotypes, implying alternative mechanisms to classical evolutionary tradeoffs.

Link: https://doi.org/10.1101/2023.12.18.572041

It seems likely that researchers will still be debating the well-established difference in life expectancy between men and women long after the first rejuvenation therapies make that difference irrelevant. Of the many possible contributing causes, it at least seems reasonable to rule out the sociological explanations based on behavioral differences, given that sex differences in life span are observed in many species. That still leaves a great many possibly contributing mechanisms, and the observed outcome may well result from the combination of many individually small effects rather than any one dominant single cause.

Today's open access paper might be taken as an argument for that combination of small effects. The researchers note that genetic associations with longevity are stronger for women in their data set. This supports a viewpoint on the evolution of human longevity that looks something like the grandmother hypothesis, in that selection pressure emerged for women to live longer, driven by the support they provided to the reproductive fitness of their immediate descendants. Thus altered forms of a large number of diverse mechanisms of metabolism were selected to produce that outcome. Men were dragged along as many mechanisms relevant to life span are extremely similar between sexes, but did not obtain the full effect as their longevity was not under direct selection in the same way.

Genetic associations with longevity are on average stronger in females than in males

In this study, we discovered that genetic associations with longevity are on average stronger in females than in males through bio-demographic analyses of genome-wide association studies (GWAS) dataset of 2178 centenarians and 2299 middle-age controls of Chinese Longitudinal Healthy Longevity Study (CLHLS). This discovery is replicated across North and South regions of China, and is further confirmed by North-South discovery/replication analyses of different and independent datasets of Chinese healthy aging candidate genes with CLHLS participants who are not in CLHLS GWAS, including 2972 centenarians and 1992 middle-age controls. Our polygenic risk score analyses of eight exclusive groups of sex-specific genes, analyses of sex-specific and not-sex-specific individual genes, and Genome-wide Complex Trait Analysis using all SNPs all reconfirm that genetic associations with longevity are on average stronger in females than in males. Our discovery/replication analyses are based on genetic datasets of in total 5150 centenarians and compatible middle-age controls, which comprises the worldwide largest sample of centenarians.

Our results beg the question of why are genetic associations with longevity on average stronger in females than in males? The fact that females take much more care for childbearing and offspring than males may shed light on answering this question. Studies related to age-specific manifestation of genetic load suggest that fertility serves as the major factor of Darwinian natural selection for the accumulation of genetic mutation driving population survival and growth. The grandmother hypothesis proposed that postmenopausal longevity in human evolved from grandmothers' assistance with childcare, which prolonged females' lifespan.

A study reported that female centenarians were four times more likely to have children in their forties than females who lived only to age 73. Other studies (including analyses based on the CLHLS datasets) also found that females' late childbearing after ages 35 or 40 is positively and significantly associated with longevity. A study indicated that the longevity advantage of females over males may be a by-product of genetic evolution that maximizes the length of time during which females could bear and take care of children and contribute to human reproduction. The reproductive function of females might serve as a driving force for positive selection on the human genome and the related physiological features, such as immune response and metabolism. During periods of stress such as starvation, females use available amino acids to create deposits in the liver to support reproduction; conversely males slow down anabolic pathways and reserve carbohydrate stores for eventual use by the musculature.

Sex differences in genetics also affect innate and adaptive immunity. Various studies have reported a more progressive decline in immunity and dysregulated inflammatory response with increase of age in males than in females. In the current study, our pathway analysis revealed neuronal system, glycosaminoglycan biosynthesis-heparan sulfate, NABA ECM glycoproteins, and cell-cell junction organization are male-specific pathways, and neuroactive ligand receptor interaction is the female-specific pathway. Interestingly, it is previously reported that reductions of heparan sulfate biosynthetic gene function increased lifespan in Drosophila parkin mutants.

Researchers here employ a combination of genetic manipulation and calorie restriction in order to find mechanisms that might be important in aging. This leads them to retromer function, where the retromer is a complex system involved in recycling receptor proteins found in the cell membrane. Reduced retromer function leads to changes in cell behavior and survival that contribute to aging and disease. The gene OXR1 is necessary for retromer function, but its expression declines with age, suggesting it as a target for therapies to slow this aspect of age-related cellular dysfunction.

Dietary restriction (DR) delays aging, but the mechanism remains unclear. We identified polymorphisms in mtd, the fly homolog of OXR1, which influenced lifespan and mtd expression in response to DR. Knockdown in adulthood inhibited DR-mediated lifespan extension in female flies. We found that mtd/OXR1 expression declines with age and it interacts with the retromer, which regulates trafficking of proteins and lipids. Loss of mtd/OXR1 destabilized the retromer, causing improper protein trafficking and endolysosomal defects.

Overexpression of retromer genes or pharmacological restabilization with R55 rescued lifespan and neurodegeneration in mtd-deficient flies and endolysosomal defects in fibroblasts from patients with lethal loss-of-function of OXR1 variants. Multi-omic analyses in flies and humans showed that decreased Mtd/OXR1 is associated with aging and neurological diseases. mtd/OXR1 overexpression rescued age-related visual decline and tauopathy in a fly model. Hence, OXR1 plays a conserved role in preserving retromer function and is critical for neuronal health and longevity.

Link: https://doi.org/10.1038/s41467-023-44343-3

By now there are most likely dozens of published aging clocks constructed from various omics databases. The proliferation of new clocks isn't helping to solve the fundamental problem with this approach to assessing biological age, which is that the predicted biological age produced by a clock isn't actionable, as no-one yet understands how the clocks relate to causative processes of aging. Thus factions within the research community are arguing for standardization to a single clock, followed by focused effort on understand how those clock measurements relate to underlying processes of aging.

Using a large proteomic cohort in the UK Biobank, we aimed to develop a proteomic aging clock for all-cause mortality risk as a proxy of biological age (BA). Participants in the UK Biobank Pharma Proteomics Project were included with ages between 39 and 70 years (n = 53,021). We developed a proteomic aging clock (PAC) for all-cause mortality risk as a surrogate of BA using a combination of Least Absolute Shrinkage and Selection Operator (LASSO) penalized Cox regression and Gompertz proportional hazards models. The validation for PAC included assessing its age-adjusted associations with, and predictions for all-cause mortality and 18 incident diseases, and head-to-head comparisons with two biological age measures (PhenoAge and BioAge) and leukocyte telomere length (LTL). Additionally, a functional analysis was performed to identify gene sets and tissues enriched with genes associated with BA deviation, based on different BA measures.

The Spearman correlation between PAC proteomic age and chronological age was 0.76. 10.9% of the combined training and test samples died during a mean follow-up of 13.3 years, with the mean age at death 70.1 years. PAC proteomic age, after controlling for age and other covariates, showed stronger associations than PhenoAge, BioAge, and LTL, with mortality and multiple incident diseases in the test set sample and in disease-free participants, such as mortality, heart failure, pneumonia, delirium, Chronic Obstructive Pulmonary Disease (COPD), and dementia. Additionally, PAC proteomic age showed higher predictive power for the conditions above compared to chronological age, PhenoAge, and BioAge. Proteins associated with PAC proteomic age deviation (from chronological age) are enriched in various hallmarks of biological aging, including immunoinflammatory responses, cellular senescence, extracellular matrix remodeling, cellular response to stressors, and vascular biology.

Link: https://doi.org/10.1101/2023.12.19.23300228

Sarcopenia is the name given to the later stages of the characteristic loss of muscle mass and strength that occurs in every individual with aging, eventually leading to weakness and the state of frailty. There are many possible contributing mechanisms, and those mechanisms interact with one another. One important cause is loss of muscle stem cell activity, but this may be driven by any number of other aspects of aging. Another important contribution is dysfunction of neuromuscular junctions, as loss of innervation tends to have a negative impact on tissue maintenance. This again may be driven by any number of causative mechanisms of aging. Further, stem cell dysfunction may interact with neuromuscular junction dysfunction. The situation is complex.

Of the hallmarks of aging, both (a) loss of mitochondrial function and (b) sustained, unresolved inflammation receive a great deal of attention from the scientific community. Researchers here outline some of the interactions that take place between a state of chronic inflammatory signaling and a state of mitochondrial dysfunction that cause both sides to make the other worse. In turn, both chronic inflammation and mitochondrial dysfunction separately contribute to aspects of sarcopenia, harming the function of cells and structures that are necessary to the processes of muscle tissue maintenance.

The mediating role of inflammaging between mitochondrial dysfunction and sarcopenia in aging: a review

Sarcopenia, characterized by the insidious reduction of skeletal muscle mass and strength, detrimentally affects the quality of life in elderly cohorts. Present therapeutic strategies are confined to physiotherapeutic interventions, signaling a critical need for elucidation of the etiological underpinnings to facilitate the development of innovative pharmacotherapies. Recent scientific inquiries have associated mitochondrial dysfunction and inflammation with the etiology of sarcopenia. Mitochondria are integral to numerous fundamental cellular processes within muscle tissue, including but not limited to apoptosis, autophagy, signaling via reactive oxygen species, and the maintenance of protein equilibrium. Deviations in mitochondrial dynamics, coupled with compromised oxidative capabilities, autophagic processes, and protein equilibrium, result in disturbances to muscular architecture and functionality.

Mitochondrial dysfunction is particularly detrimental as it diminishes oxidative phosphorylation, escalates apoptotic activity, and hinders calcium homeostasis within muscle cells. Additionally, deleterious feedback loops of deteriorated respiration, exacerbated oxidative injury, and diminished quality control mechanisms precipitate the acceleration of muscular senescence. Notably, mitochondria exhibiting deficient energetic metabolism are pivotal in precipitating the shift from normative muscle aging to a pathogenic state.

This analytical review meticulously examines the complex interplay between mitochondrial dysfunction, persistent inflammation, and the pathogenesis of sarcopenia. It underscores the imperative to alleviate inflammation and amend mitochondrial anomalies within geriatric populations as a strategy to forestall and manage sarcopenia. An initial overview provides a succinct exposition of sarcopenia and its clinical repercussions. The discourse then progresses to an examination of the direct correlation between mitochondrial dysfunction and the genesis of sarcopenia. Concomitantly, it accentuates potential synergistic effects between inflammatory responses and mitochondrial insufficiencies during the aging of skeletal muscle, thereby casting light upon emergent therapeutic objectives.

Researchers here describe a G-quadruplex-related mechanism operating across diverse species that contributes to epigenetic change following cell replication, leading to the Hayflick limit on replication and subsequent cell death or cell senescence. G-quadruplexes form in telomeric regions at the ends of chromosomes, and their contributions to genomic structure, epigenetics, and aging are far from fully understood.

Insofar as the mechanism described in this paper is operating in organismal aging, it is worth bearing in mind that aging is accompanied by a reduction in stem cell activity, meaning a reduced supply of replacement somatic cells for tissues. Thus the average somatic cell in a tissue starts to be one that is more cycles of replication removed from the original daughter somatic cell created by a stem cell, and will be more affected by any replication-related mechanism.

Perhaps the more interesting result is the connection between this mechanism and a number of accelerated aging conditions, including Werner syndrome, in which mutations lead to an impairment of G-quadruplex removal. This implies that cell replication in affected individuals produces greater dysfunction than usual, leading to more cellular senescence and faster aging.

How cell replication ultimately results in aging and the Hayflick limit are not fully understood. Here we show that clock-like accumulation of DNA G-quadruplexes (G4s) throughout cell replication drives conserved aging mechanisms. G4 stimulates transcription-replication interactions to delay genome replication and impairs DNA re-methylation and histone modification recovery, leading to loss of heterochromatin. This creates a more permissive local environment for G4 formation in subsequent generations.

As a result, G4s gradually accumulate on promoters throughout mitosis, driving clock-like DNA hypomethylation and chromatin opening. In patients and in vitro models, loss-of-function mutations in the G4-resolving enzymes WRN, BLM and ERCC8 accelerate the erosion of the epigenomic landscape around G4. G4-driven epigenomic aging is strongly correlated with biological age and is conserved in yeast, nematodes, insects, fish, rodents, and humans. Our results revealed a universal molecular mechanism of aging and provided mechanistic insight into how G-quadruplex processor mutations drive premature aging.

Link: https://doi.org/10.1101/2024.01.06.574476

To what degree does the skin microbiome contribute to the aging of skin? This is an interesting question, but there is very little research on this topic. A growing body of work on the role of the gut microbiome in degenerative aging is leading to a greater interest in examining the microbial populations elsewhere in and on the body, however. Here, researchers note correlations between microbial populations on the skin and specific aspects of skin aging. The direct of causation is still to be determined, but it is reasonable to think that an aged skin changes in ways that might make it more or less hospitable for specific microbes.

Recent findings have identified an exciting potential new link to signs of skin aging - the skin microbiome, the collection of microorganisms that inhabits our skin. To the best of the team's knowledge, the study is the first to isolate microbes associated specifically with signs of skin aging and skin health, rather than chronological age. The study comprehensively examined data collected during 13 past studies, consisting of 16S rRNA amplicon sequence data and corresponding skin clinical data for over 650 female participants, aged 18 - 70. While each of the studies included in the analysis had focused on one particular area of interest - for example, crow's feet wrinkles or moisture loss - this multi-study analysis collated the data to search for trends related to specific microbes while accounting for other variables, such as age.

Two notable trends emerged from the analysis. First, the team found a positive association between skin microbiome diversity and lateral cantonal lines (crow's feet wrinkles), which are generally viewed as one of the key signs of skin aging. Second, they observed a negative correlation between microbiome diversity and transepidermal water loss, which is the amount of moisture that evaporates through the skin. In further exploring the trends, the researchers identified several potential biomarkers that warrant investigation as microorganisms of interest. It would be premature to infer causation or actionable insights, but the study's results have provided researchers with directions on the next steps to hone in on better understanding microbial associations with skin aging.

Link: https://today.ucsd.edu/story/researchers-discover-potential-microbiome-links-to-skin-aging

With advancing age, a wide range of mechanisms act to provoke the immune system into a state of constant inflammatory signaling and activation. Age-related mitochondrial dysfunction leads to mislocalized mitochondrial DNA fragments that trigger the cGAS-STING pathway to provoke inflammation. Senescent cells produce pro-inflammatory signaling, and their numbers increase with age. Visceral fat tissue produces signaling similar that resulting from infected cells. The increased presence of protein aggregates aggravates immune cells inside and outside of the brain. And so forth. Given all of this, actually fixing the issue of age-related chronic inflammation will likely require control over a great deal of the underlying biochemistry of aging itself.

Nonetheless, chronic inflammation is clearly a major problem that produces sizable downstream issues. It is highly disruptive to tissue function, accelerating all of the major fatal age-related conditions. If there are shortcuts to suppress excessive, chronic inflammation without affecting the necessary short-term inflammation required for the immune system to function, then pursing these shortcuts may turn out to be at least as beneficial as, say, control over raised blood pressure. Unfortunately, most of the approaches developed to date do poorly when it comes to avoiding suppression of necessary immune function.

As discussed in today's open access paper, there is the hope that targeting the immune sensors called inflammasomes will produce a better next generation of more discriminatory anti-inflammatory therapies. It remains the case that near all immune reactions, whether excessive and unwanted or transient and necessary, run through the same signaling pathways, however. At some point, given a greater understanding of the detailed mechanisms of immune reaction and signaling, a way to discriminate must emerge - but that has yet to happen and be demonstrated in practice.

The role of inflammasomes in human diseases and their potential as therapeutic targets

Inflammasomes are large protein complexes that play a major role in sensing inflammatory signals and triggering the innate immune response. Each inflammasome complex has three major components: an upstream sensor molecule that is connected to a downstream effector protein such as caspase-1 through the adapter protein ASC. Inflammasome formation typically occurs in response to infectious agents or cellular damage. The active inflammasome then triggers caspase-1 activation, followed by the secretion of pro-inflammatory cytokines and pyroptotic cell death. Aberrant inflammasome activation and activity contribute to the development of diabetes, cancer, and several cardiovascular and neurodegenerative disorders.

As a result, recent research has increasingly focused on investigating the mechanisms that regulate inflammasome assembly and activation, as well as the potential of targeting inflammasomes to treat various diseases. Multiple clinical trials are currently underway to evaluate the therapeutic potential of several distinct inflammasome-targeting therapies. Therefore, understanding how different inflammasomes contribute to disease pathology may have significant implications for developing novel therapeutic strategies. In this article, we provide a summary of the biological and pathological roles of inflammasomes in health and disease. We also highlight key evidence that suggests targeting inflammasomes could be a novel strategy for developing new disease-modifying therapies that may be effective in several conditions.

Researchers here describe a specific issue in the aging of metabolism connected to the activity of Ppp1r17 in the hypothalamus in the brain. This affects the sympathetic nervous system, leading to reduced innervation of fat tissue, which in turn negatively affects many tissues via altered availability of circulating nutrients, signal molecules, and the like. The researchers note a few points at which they can intervene to stop this decline, either Ppp1r17 in the brain, or the circulating molecule eNAMPT released by fat cells. The effect size on life span in mice is modest, and there is the remaining question of why this decline led by the hypothalamus starts to occur in the first place, but it is an interesting insight into one specific facet of the broader aging of metabolism.

Neurons in the dorsomedial hypothalamus, produce an important protein - Ppp1r17. When this protein is present in the nucleus, the neurons are active and stimulate the sympathetic nervous system. The neurons in the hypothalamus set off a chain of events that triggers neurons that govern white adipose tissue - a type of fat tissue - stored under the skin and in the abdominal area. The activated fat tissue releases fatty acids into the bloodstream that can be used to fuel physical activity. The activated fat tissue also releases another important protein - an enzyme called eNAMPT - which returns to the hypothalamus and allows the brain to produce fuel for its functions.

This feedback loop is critical for fueling the body and the brain, but it slows down over time. With age, the researchers found that the protein Ppp1r17 tends to leave the nucleus of the neurons, and when that happens, the neurons in the hypothalamus send weaker signals. With less use, the nervous system wiring throughout the white adipose tissue gradually retracts, and what was once a dense network of interconnecting nerves becomes sparse. The fat tissues no longer receive as many signals to release fatty acids and eNAMPT, which leads to fat accumulation, weight gain and less energy to fuel the brain and other tissues. When researchers used genetic methods in old mice to keep Ppp1r17 in the nucleus of the neurons in the hypothalamus, the mice were more physically active - with increased wheel-running - and lived 7% longer than control mice. They also used a technique to directly activate these specific neurons in the hypothalamus of old mice, and they observed similar anti-aging effects.

Researchers are continuing to investigate ways to maintain the feedback loop between the hypothalamus and the fat tissue. One route they are studying involves supplementing mice with eNAMPT, the enzyme produced by the fat tissue that returns to the brain and fuels the hypothalamus, among other tissues. When released by the fat tissue into the bloodstream, the enzyme is packaged inside compartments called extracellular vesicles, which can be collected and isolated from blood. "We can envision a possible anti-aging therapy that involves delivering eNAMPT in various ways. We already have shown that administering eNAMPT in extracellular vesicles increases cellular energy levels in the hypothalamus and extends life span in mice."

Link: https://medicine.wustl.edu/news/life-span-increases-in-mice-when-specific-brain-cells-are-activated/

Constant, unresolved inflammatory behavior in the supporting cells of the brain is implicated in the pathology of diverse neurodegenerative conditions. Here, researchers find that dampening this inflammation can help restore function in animal models of amyotrophic lateral sclerosis (ALS). This joins many other conceptually similar demonstrations conducted in the laboratory for a range of different neurodegenerative diseases. It remains to be seen as to how well these anti-inflammatory strategies will perform in human clinical trials.

ALS is caused by the loss of upper motor neurons, located in the brain, and lower motor neurons, which extend from the spinal cord to the muscles. Using a genetically modified mouse model, researchers found that structural changes in the upper neurons occurred prior to disease symptoms. The study suggests that these morphological changes send a signal to microglia and astrocytes, the immune cells of the central nervous system. When they arrive, their effect is protective, but if they stay too long, they become toxic to neurons. This leads to a reduction in synaptic connections between motor neurons in the brain and spinal cord, which in turn results in a reduction in synaptic connections with muscles. These changes lead to atrophy and loss of motor function.

Given this correlation between symptoms and immune response, the research team wondered whether it might be possible to restore synaptic connections by blocking inflammation. They tested a semi-synthetic drug based on Withaferin A, an extract of the Ashwagandha plant. The drug blocks inflammation and allows motor neurons to return to a more normal state. Neurons regenerate in the absence of activated immune cells. The dendrites of motor neurons start to grow and make connections again, increasing the number of synapses between motor neurons and muscles. This seems a promising way of improving ALS symptoms, whether the disease is familial or sporadic, since both types are associated with inflammation.

Link: https://www.eurekalert.org/news-releases/1030785

Senescent cells accumulate with age in tissues throughout the body, most likely in large part because the aging immune system becomes less efficient in removing these cell in a timely fashion. Senescent cells do perform useful functions when present in the short term, drawing the attention of the immune system to potentially cancerous or injured tissues, but when present for the long term they are increasingly disruptive to tissue structure and function. Their presence contributes to the dysfunctions of degenerative aging. Thus researchers are engaged in the development of senolytic drugs capable of selectively destroying senescent cells, and the first such drugs have been demonstrated to product rejuvenation and reversal of age-related conditions in mice.

In principle, many flavonoid compounds have the ability to put stress on senescent cells that their peculiar biochemistry is ill-equipped to handle. In practice near all of those flavonoid compounds are likely senolytic to a small, uninteresting degree, producing trivial degrees of cell death that make no real difference to health outcomes. Quercetin, for example, doesn't do much on its own, even though it combines with dasatinib to produce one of the first proven senolytic treatments. Fisetin, on the other hand, is meaningfully senolytic in mice on its own. It is interesting to ask whether we should expect many more flavonoids to be as senolytic as fisetin.

On this topic, today's open access paper assesses the senolytic ability of 4,4′-dimethoxychalcone (DMC), finding it worthy of note, though the animal data isn't as extensive as one would like. It is worth noting that the degree to which fisetin is senolytic in humans remains to be determined, as data from human trials has yet to be published. Further, while it is established to clear senescent cells in mice, the Interventions Testing Program found that fisetin treatment did not extend mouse life span, unlike the dasatinib and quercetin combination in other non-ITP studies. Whether flavonoids are a useful place to look for senolytic treatments remains under assessment.

Flavonoid 4,4′-dimethoxychalcone selectively eliminates senescent cells via activating ferritinophagy

4,4′-dimethoxychalcone (DMC) is a flavonoid previously reported as a small molecule promoting longevity and health. Our previous studies have shown that DMC functions as a ferroptosis inducer in cancer cells. However, there were no report on the function of DMC in senescent cells. Senotherapeutics consist of senolytics and senomorphics, which selectively eliminate senescent cells and reduce the senescence-associated secretory phenotype (SASP), respectively. Many flavonoids are senotherapeutics, and dasatinib + quercetin is so far the most commonly used senolytics. Dasatinib is a tyrosine kinase inhibitor, which inhibits cell proliferation and migration and induces apoptosis. Quercetin is a flavonoid that interacts with Bcl-2 family members to induce apoptosis. In the present study, we found that DMC, DMC + dasatinib, DMC + quercetin have a characteristic of senolytics. To investigate the senolytics effects, we employed replicative senescent cells and a DNA damage-induced senescent cells model. We found that DMC and its combination with dasatinib or quercetin selectively eliminated senescent cells, more effectively than using dasatinib + quercertin alone.

Senescent cells secrete a series of pro-inflammatory cytokines, chemokines, and growth factors, which is called SASP, to cause chronic inflammation and tissue dysfunction. In this study, we found that DMC reduced the SASP level in senescent cells. Furthermore, senescent cells enter irreversible cell cycle arrest, which involves the activation of p53/p21 and Rb/p16. In this study we found that the expression levels of p21 and p16 were decreased after DMC treatment. The downregulation of p21 may be attributed to the decrease of p53. In this study, we found that the mRNA level of p53 was reduced after DMC treatment.

Ferroptosis is an iron-dependent cell death process, which is accompanied by iron accumulation. Our previous study reported an important role of FECH, an enzyme inserts ferrous ion into PPIX, in ferroptosis, and showed that the inhibition of FECH by DMC led to iron accumulation in cancer cells. In this study, we found that the expression level of FECH increased in senescent cells, which may explain the sensitivity of DMC-induced ferroptosis in senescent cells. Senescent cells are associated with impaired ferritinophagy and ferroptosis. Interestingly, in our present study, we found that DMC could induce ferritinophagy, which may underlie DMC-induced ferroptosis in senescent cells.

There has been some work in recent years aimed at distinguishing subtypes of Alzheimer's disease that may respond quite differently to therapies. How much of the poor results in clinical trials is a matter of aiming too broadly, at patients who cannot respond well to a specific therapy? Of late, this attempt at categorization has focused on proteomic analyses of patient samples. Here find a paper covering results that were discussed late last year, in which researchers propose that there are five important subtypes of Alzheimer's disease.

Alzheimer's disease (AD) is heterogenous at the molecular level. Understanding this heterogeneity is critical for AD drug development. Here we define AD molecular subtypes using mass spectrometry proteomics in cerebrospinal fluid (CSF), based on 1,058 proteins, with different levels in individuals with AD (n = 419) compared to controls (n = 187).

These AD subtypes had alterations in protein levels that were associated with distinct molecular processes: subtype 1 was characterized by proteins related to neuronal hyperplasticity; subtype 2 by innate immune activation; subtype 3 by RNA dysregulation; subtype 4 by choroid plexus dysfunction; and subtype 5 by blood-brain barrier impairment. Each subtype was related to specific AD genetic risk variants, for example, subtype 1 was enriched with TREM2 R47H. Subtypes also differed in clinical outcomes, survival times, and anatomical patterns of brain atrophy.

These results indicate molecular heterogeneity in AD and highlight the need for personalized medicine. CSF-based subtyping may be useful to select individuals for a specific therapeutic treatment, either for a priori subject stratification or for responder and side effect analysis in clinical trials.

Link: https://doi.org/10.1038/s43587-023-00550-7

As is the case for the thymus, aging and loss of function in the ovaries is interesting for (a) occurring at an accelerated pace relative to the rest of the body, and (b) producing meaningful downstream consequences in later life. What causes this comparatively early loss of function? Here, researchers look at changes in the balance of microbial populations in the gut microbiome as a contributing factor. The gut microbiome also shows age-related changes comparatively early in adult life, in which pro-inflammatory microbes expand in number whilst those producing beneficial metabolites decline in number.

Altered composition and function of the gut microbiota play an important role in the pathogenesis of reproductive aging. Experimental and clinical studies have uncovered the relationship between gut dysbiosis and ovarian follicle development, as well as a disturbed immune response. Results from fecal microbiota transplant (FMT) studies provide a new insight to anti-ovarian aging, that is the maintenance of youthful gut microbiota helps to preserve ovarian function and prevent ovarian-related diseases. Microbiota-based intervention to delay or reserve ovarian aging is an appealing approach and may offer new therapeutic strategies for intestinal microbiota regulation to improve female fertility.

Furthermore, investigation of antiaging interventions such as antiaging drugs and calorie restriction may improve the gut microbial imbalance and promote a healthier intestinal ecological environment. However, evidence from the current scientific literature cannot offer direct conclusions regarding these measures. The majority of the relevant studies were conducted in animal models, which cannot simply apply to human beings. Therefore, future studies should shift from simple correlation analysis to large-scale cohort research and focus on the potential causes and underlying mechanisms to verify the beneficial effects of these interventions in ovarian aging.

Given the wide alterations in the gut microbiota composition and function throughout ovarian aging, it has been suggested that the gut microbiota may be suitable for deciphering the processes of expected and unexpected ovarian aging in women. Imbalance in the gut microbiota may lead to the progression of various ovarian aging-related conditions. Although ovarian aging is unavoidable, maintenance of a balanced gut microbiota is a potential way to delay ovarian aging and subsequent adverse outcomes.

Link: https://doi.org/10.1080/19490976.2023.2295394

The immune system recognizes flagellin as foreign. Flagellin is the protein found in flagellae, the whip-like structures that bacteria use to move around. Attacking and destroying these bacteria is very much a part of the immune system's portfolio of normal activities. Thus immunization with flagellin provokes the immune system into greater activity and responsiveness in the short term, and it has been tested in humans as a vaccine adjuvant, intended to make the immune system respond more effectively to the vaccine delivered alongside flagellin. Interestingly, flagellin immunization also makes the immune system clear out harmful microbes from the gut microbiome, improving the function of the gut microbiome by, for example, reducing its contribution to systemic inflammation. This effect has been demonstrated in mice, and in human self-experimentation, but has yet to be the subject of more rigorous research.

In that context, it is interesting to read today's open access paper, in which researchers demonstrate a modest extension of life span in mice to result from repeated flagellin immunization starting in late life. The researchers used a fusion protein made up of flagellin and another bacterial protein, presumably because one can patent such a novel formulation where one can't patent the use of flagellin. An observer might wager that the effect on life span is derived from changes in the gut microbiome, given other studies in mice demonstrating improved long-term health to result from improving the gut microbiome. The authors of this paper see it as more a matter of immunomodulation, however. The use of vaccines and immunization can produce a phenomenon called trained immunity, dampening age-related chronic inflammation spurred by the innate immune system.

Mucosal TLR5 activation controls healthspan and longevity

In advanced aging, innate immune activation has been viewed as an inducer of chronic inflammation, which promotes different signs of aging and age-related diseases. At the same time, numerous examples indicate that the innate immune system contributes to tissue homeostasis and repair. Toll-like receptors (TLRs) are crucial for the innate immune system's response to threats, primarily by regulating inflammation and activating immune responses. The reduction in TLR activity induced by aging leads to a decreased efficiency in immune responses, potentially lowering the body's resistance to infections.

TLR5 is a remarkably versatile receptor found on both epithelial and immune cells, and its functions are distributed throughout the body. One of its critical roles emerges in the respiratory tract, where TLR5 assumes a pivotal position in initiating protective immune responses, particularly when combating infections like Pseudomonas aeruginosa. It is well known that the reduction in TLR activity induced by aging leads to a decreased efficiency in immune responses, potentially lowering the body's resistance to infections. However, in our previous study, we discovered that TLR5 expression and signaling were relatively well-preserved in aged mice and older individuals compared to other TLRs. We also demonstrated that TLR5 effectively enhances vaccine efficacy against pneumonia, leading to increased survival rates from pneumococcal infection in old mice. Unlike other TLRs, TLR5 has been reported not only to induce pro-inflammatory signals essential for vaccine efficacy boosting but also to suppress inflammation in lesions, induce tissue regeneration in major disease models, and strengthen the barrier. This unique functionality underscores the diverse applicability and therapeutic potential of TLR5 in addressing age-related health issues and promoting longevity.

In our study, we show that stimulating toll-like receptor 5 (TLR5) via mucosal delivery of a flagellin-containing fusion protein effectively extends the lifespan and enhances the healthspan of aged mice of both sexes. This enhancement in healthspan is evidenced by diminished hair loss and ocular lens opacity, increased bone mineral density, improved stem cell activity, delayed thymic involution, heightened cognitive capacity, and the prevention of pulmonary fibrosis. Additionally, this fusion protein boosts intestinal mucosal integrity by augmenting the surface expression of TLR5 in a certain subset of dendritic cells and increasing interleukin-22 (IL-22) secretion. In this work, we present observations that underscore the benefits of TLR5-dependent stimulation in the mucosal compartment, suggesting a viable strategy for enhancing longevity and healthspan.

How exactly the extracellular matrix is involved in degenerative aging is a topic that remains understudied in comparison to the role of cellular biochemistry in aging. Clearly the matrix changes with age, such as by becoming less elastic, but a deeper understanding of the processes involved is a work in progress. Researchers here report on an investigation of age-related changes in the extracellular matrix, and how those changes are altered by interventions that slow aging. They worked with short-lived nematode worms, the starting point for a great deal of research into the mechanisms of aging, and found some interesting commonalities.

Dysfunctional extracellular matrices (ECM) contribute to aging and disease. Repairing dysfunctional ECM could potentially prevent age-related pathologies. Interventions promoting longevity also impact ECM gene expression. However, the role of ECM composition changes in healthy aging remains unclear. Here we perform proteomics and in-vivo monitoring to systematically investigate ECM composition (matreotype) during aging in C. elegans revealing three distinct collagen dynamics.

Longevity interventions slow age-related collagen stiffening and prolong the expression of collagens that are turned over. These prolonged collagen dynamics are mediated by a mechanical feedback loop of hemidesmosome-containing structures that span from the exoskeletal ECM through the hypodermis, basement membrane ECM, to the muscles, coupling mechanical forces to adjust ECM gene expression and longevity via the transcriptional co-activator YAP-1 across tissues. Our results provide in-vivo evidence that coordinated ECM remodeling through mechanotransduction is required and sufficient to promote longevity, offering potential avenues for interventions targeting ECM dynamics.

Link: https://doi.org/10.1038/s41467-023-44409-2

Researchers have found that deafness-associated gene TMTC4 causes pathology via an excessive increase in the unfolded protein response in sensory hair cells of the inner ear, and loud noise does much the same. This suggests that inhibition of the unfolded protein response in these cells might be a way to slow loss of hearing capacity, or protect against the effects of loud noise and drugs that can harm hair cells. Still, this isn't a path to restoration of hearing capacity. That would require some way to replace lost hair cells and their connections to the brain.

Mutations to the TMTC4 gene trigger a molecular domino effect known as the unfolded protein response (UPR), leading to the death of hair cells in the inner ear. Intriguingly, hearing loss from loud noise exposure or drugs such as cisplatin, a common form of chemotherapy, also stems from activation of the UPR in hair cells, suggesting that the UPR may underly several different forms of deafness. There are several drugs that block the UPR - and stop hearing loss - in laboratory animals. The new findings make a stronger case for testing these drugs in people who are at risk of losing their hearing, according to the researchers.

"As mice with TMTC4 mutations grew, we saw that they didn't startle in response to loud noise. They had gone deaf after they had matured." Researchers investigated what was happening to the mice, which looked like an accelerated version of age-related hearing loss in humans. They showed that mutations to TMTC4 primed hair cells in the ear to self-destruct, and loud noise did the same thing. In both cases, hair cells were flooded with excess calcium, throwing off the balance of other cellular signals, including the UPR.

Understanding TMTC4 mutations gives researchers a new way of studying progressive deafness, since it is critical for maintaining the health of the adult inner ear. The mutations mimic damage from noise, aging or drugs like cisplatin. Researchers envision a future where people who must take cisplatin, or who have to be exposed to loud noises for their jobs, take a drug that dampens the UPR and keeps hair cells from withering away, preserving their hearing.

Link: https://www.eurekalert.org/news-releases/1030451

The fasting mimicking diet resulted from efforts to understand how nutrient sensing systems in cells respond to a lower calorie intake. The question of interest was this: at what level of calorie intake do the benefits of fasting start to emerge, and at what level of calorie intake are most of the benefits present? Does one actually have to reduce calorie intake to zero to obtain all of the benefits? As it turns out, no. Low calorie intake, on the order of 600-750 calories per day, is almost as good as fasting when sustained for week or so.

On the basis of these results, a specific fasting mimicking medical diet was then commercialized and put through the FDA process as an adjuvant treatment for cancer patients, where it continues to show benefits in human trials. This is the usual consequence of the excessive costs of medical regulation, in that the only way for a cheap therapy to be used is to first turn it into a patented, expensive therapy, but it served to bring funding into a part of the field that usually lacks the incentives to attract investment. For the rest of us, it is easy enough to use the fasting mimicking approach to improve health and metabolism without the expensive, regulated diet. It is simply a set of targets for calorie and micronutrient intake over a period of time, and leads to sustained improvements in measures of metabolism.

Fasting-Mimicking Diet Inhibits Autophagy and Synergizes with Chemotherapy to Promote T-Cell-Dependent Leukemia-Free Survival

Fasting mimicking diets (FMDs) have the potential to enhance the efficacy of a wide variety of cancer treatments, weakening cancer cells by a process we termed differential stress sensitization (DSS) while strengthening normal cells by a response termed differential stress resistance (DSR). The effects of fasting/FMD in inducing DSS in both in vitro and in vivo models were previously shown to be mediated, in part, by the reduction of circulating IGF-1 and glucose levels. In a mouse leukemia model, fasting alone reversed the progression of both B cell and T cell acute lymphoblastic leukemia (ALL) but did not affect acute myeloid leukemia (AML).

Here we show that cycles of FMD induce significant anti-leukemia efficacy and cancer-free survival when combined with vincristine, in part by activating T-cell-dependent anti-cancer effects. Fasting/FMD alone causes a trend for increasing autophagy, but when fasting/FMD is combined with vincristine, a significant and consistent downregulation of autophagy markers is observed. This role of autophagy in the FMD/VC-dependent toxicity to ALL cells is confirmed by the effect of the combination of vincristine with the autophagy inhibitor chloroquine, which also promotes p53 modulation, apoptosis, and cancer-free survival in agreement with the established role of p53 in mediating cell death in AML and in solid malignancies.

Fasting/FMD and other dietary restrictions have also been tested clinically in a number of clinical trials. In a prospective, nonrandomized, controlled trial of 40 patients, the potential benefits of caloric restriction were shown (The Improving Diet and Exercise in ALL (IDEAL)) in the efficacy of chemotherapy in patients newly diagnosed with B-ALL. This intervention resulted in a low minimal residual disease risk, high-circulating adiponectin and low insulin resistance. In a randomized controlled study of 131 patients with HER2-negative early-stage breast cancer, FMD cycles significantly enhanced the effects of neoadjuvant chemotherapy on the radiological and pathological tumor response. A short-term fasting-mimicking diet was also well tolerated during chemotherapy in patients with ovarian cancers and appeared to improve quality of life and fatigue. In conclusion, FMD cycles have high potential to be effective in increasing the toxicity of a range of therapies against ALL and other blood cancers and should be tested in randomized clinical trials, especially in combination with immunotherapy and low toxicity cancer therapies.

In summary, we present a new strategy for improving leukemia treatment by combining FMD with chemotherapy to promote the killing of ALL cells in part by an immune-dependent mechanism. Fasting/FMD has been shown to reduce chemotherapy-associated toxicity in pre-clinical and clinical studies and thus represents a safe and potentially effective treatment adjunct for leukemia patients which should be tested clinically.

The regrowth of teeth - and the components of teeth, such as dental pulp, dentin, and enamel, that do not naturally exhibit sufficient regenerative capacity to address damage - has been a goal for researchers for some years now. Inroads have been made, but the research community is still some years from being able to sufficiently control the regrowth of entire teeth to produce more than technology demonstrations. Meanwhile, perhaps more meaningful advances have been made towards provoking the regeneration of damaged teeth in situ, finding ways to program cells in and around teeth into more regenerative modes of behavior.

Dentin is a complex mineralized tissue primarily composed of hydroxyapatite crystals, collagen fibers, and a fluid-filled tubular structure that extends from the pulp to the dentino-enamel or dentino-cementum junctions. Dentin is formed by highly specialized cells called odontoblasts, which secrete an extracellular matrix comprising collagen fibers and non-collagen proteins that serve as a scaffold for subsequent mineralization. Odontoblasts deposit dentin throughout the life of a tooth, albeit at a slower rate after early dentinogenesis, contributing to the thickening of dentin and potentially aiding in response of the tooth to external insults.

As a consequence of dentinal injury or decay, tertiary dentinogenesis of two different natures occur to protect and maintain dental pulp integrity. When secretory activities of quiescent odontoblasts are re-activated, reactionary dentin that is structurally and functionally similar to physiologic dentin is formed. On the other hand, newly differentiated odontoblast-like cells form pathologic reparative dentin, which is often less organized and more akin to bone-like tissue rather than dentin at the histological level. Likewise, physiologic dentin regeneration and pathologic dentin repair are two distinct processes aimed at restoring dentin functionality following damage, and re-establish a protective barrier for the pulp, alleviate sensitivity, and prevent further loss.

Physiologic dentin regeneration, in particular, seeks to recreate dentin that closely mimics its original, healthy state. This includes the reconstruction of dentinal tubules that integrate seamlessly with remaining dentin, the restoration of dentin-pulp complex, and the engagement of cellular and molecular pathways that govern dentinogenesis. The unique structure and function of true dentin, characterized by its distinctive tubular architecture housing odontoblasts and nerve endings, not only confers mechanical resilience to the tooth but plays a crucial role in the tooth's immune and sensitivity responses. A number of biological molecules that can direct the odontoblastic differentiation of dental pulp cells have been studied, most of which are part of key signaling pathways regulating dentinogenesis during tooth development. These include TGF-β, BMP, and Wnt/β-catenin signaling known to orchestrate the complex processes of cell differentiation, matrix deposition, and mineralization. The use of bioactive molecules in dentin regeneration has emerged as a promising approach, leveraging the biological cues to promote natural tissue regeneration.

Link: https://doi.org/10.3389/fphys.2023.1313927

The development of atherosclerosis leading to stroke or heart attack is the primary cause of human mortality, accounting for ~26% of deaths worldwide. It also contributes meaningfully to as much as another 15% of deaths through narrowing of blood vessels, heart failure, and so forth. It is well known that lowered LDL-cholesterol in the bloodstream, when maintained over a lifetime, pushes back the tipping point at which atherosclerotic lesions form. So genetic variants that affect LDL-cholesterol levels tend to also affect longevity to some degree, as demonstrated in this study. Unfortunately, therapies that lower LDL-cholesterol levels have nowhere near the same effect size, as (a) these treatments are not maintained over the full lifespan, and (b) lowering LDL-cholesterol has little effect on established atherosclerotic plaque in most patients.

It remains controversial whether the long-term use of statins or newer nonstatin drugs has a positive effect on human longevity. Therefore, this study aimed to investigate the genetic associations between different lipid-lowering therapeutic gene targets and human longevity. Two-sample Mendelian randomization analyses were conducted. The exposures comprised genetic variants that proxy nine drug target genes mimicking lipid-lowering effects (LDLR, HMGCR, PCSK9, NPC1L1, APOB, CETP, LPL, APOC3, and ANGPTL3). Two large-scale genome-wide association study (GWAS) summary datasets of human lifespan, including up to 500,193 European individuals, were used as outcomes.

Genetically proxied LDLR variants, which mimic the effects of lowering low-density lipoprotein cholesterol (LDL-C), were associated with extended lifespan. This association was replicated in the validation set and was further confirmed in the eQTL summary data of blood and liver tissues. Mediation analysis revealed that the genetic mimicry of LDLR enhancement extended lifespan by reducing the risk of major coronary heart disease, accounting for 22.8% of the mediation effect. The genetically proxied CETP and APOC3 inhibitions also showed causal effects on increased life expectancy in both outcome datasets. The lipid-lowering variants of HMGCR, PCKS9, LPL, and APOB were associated with longer lifespans but did not causally increase extreme longevity. No statistical evidence was detected to support an association between NPC1L1 and lifespan.

This study suggests that LDLR is a promising genetic target for human longevity. Lipid-related gene targets, such as PCSK9, CETP, and APOC3, might potentially regulate human lifespan, thus offering promising prospects for developing newer nonstatin therapies.

Link: https://doi.org/10.1186/s12944-023-01983-0

Cells contain many proteasomes, one portion of a broad array of repair and quality control mechanisms. The proteasome is a hollow, capped cylindrical structure made of many component proteins. It admits entry only to proteins that have been decorated with the addition of a ubiquitin molecule. Once inside the proteasome's central chamber, the ubiquinated protein is disassembled into short peptides suitable for reuse in the synthesis of other proteins. This ubiquitin-proteasome system is necessary to prevent the buildup of damaged, misfolded, unfolded, or otherwise unwanted proteins.

It has been noted that proteasomal function is impaired in Alzheimer's disease patients, and that inhibition of proteasomal function, such as by downregulating expression of specific proteasomal component proteins, produces symptoms akin to those of neurodegenerative conditions. In today's open access paper, researchers further explore this topic, showing that the amyloid-β associated with Alzheimer's disease is capable of inhibiting proteasomal function in the synapses that link neurons in the brain. This points to the merits of both clearance of amyloid-β and also the development of ways to augment proteasomal function, such as by increased expression of some of its component proteins.

Synaptic proteasome is inhibited in Alzheimer's disease models and associates with memory impairment in mice

The proteasome plays key roles in synaptic plasticity and memory by regulating protein turnover, quality control, and elimination of oxidized/misfolded proteins. Here, we investigate proteasome function and localization at synapses in Alzheimer's disease (AD) post-mortem brain tissue and in experimental models.

We found a marked increase in ubiquitinylated proteins in post-mortem human AD hippocampi compared to controls. Using several experimental models, we show that amyloid-β oligomers (AβOs) inhibit synaptic proteasome activity and trigger a reduction in synaptic proteasome content. We further show proteasome inhibition specifically in hippocampal synaptic fractions derived from Alzheimer's model mice.

Reduced synaptic proteasome activity instigated by AβOs is corrected by treatment with rolipram, a phosphodiesterase-4 inhibitor, in mice. Results further show that dynein inhibition blocks AβO-induced reduction in dendritic proteasome content in hippocampal neurons. Finally, proteasome inhibition induces AD-like pathological features, including reactive oxygen species and dendritic spine loss in hippocampal neurons, inhibition of hippocampal mRNA translation, and memory impairment in mice. Results suggest that proteasome inhibition may contribute to synaptic and memory deficits in AD.

The raised blood pressure of hypertension correlates with the development of atherosclerosis, a condition characterized by cholesterol-rich lesions that grow in blood vessel walls. Researchers have proposed mechanisms by which hypertension can cause cell dysfunction, such as by indirectly increasing circulating immune cell numbers, cells that are then drawn into the plaque and killed by it, increasing its mass. More directly, increased pressure on arterial walls causes them to become less permeable to cholesterol carried in the bloodstream, encouraging deposits to form in the inner blood vessel wall. As another potential mechanism, researchers here identify a way in which increased pressure can induced pathological dysfunction in the vascular smooth muscle cells that become involved in atherosclerosis.

Arterial vascular smooth muscle cells (VSMCs) play a central role in the onset and progression of atherosclerosis. Upon exposure to pathological stimuli, they can take on alternative phenotypes that, among others, have been described as macrophage like, or foam cells. VSMC foam cells make up more than 50% of all arterial foam cells and have been suggested to retain an even higher proportion of the cell stored lipid droplets, further leading to apoptosis, secondary necrosis, and an inflammatory response. However, the mechanism of VSMC foam cell formation is still unclear.

Here, it is identified that mechanical stimulation through hypertensive pressure alone is sufficient for the phenotypic switch. Hyperspectral stimulated Raman scattering imaging demonstrates rapid lipid droplet formation and changes to lipid metabolism and changes are confirmed in ABCA1, KLF4, LDLR, and CD68 expression, cell proliferation, and migration. Further, a mechanosignaling route is identified involving Piezo1, phospholipid, and arachidonic acid signaling, as well as epigenetic regulation, whereby CUT&Tag epigenomic analysis confirms changes in the cells (lipid) metabolism and atherosclerotic pathways.

Overall, the results show for the first time that VSMC foam cell formation can be triggered by mechanical stimulation alone, suggesting modulation of mechanosignaling can be harnessed as potential therapeutic strategy.

Link: https://doi.org/10.1002/advs.202308686

Physiological and other forms of stress are known to affect the immune system. Epigenetic age measured from a blood sample is an assessment of immune cells, not the organism as a whole. One might expect any sort of stress put on the immune system to alter measures of epigenetic age conducted on blood samples, but quite different results might emerge from an assessment of epigenetic age conducted on tissue biopsies.

This study used DNA methylation (DNAm)-based aging clocks to measure changes in biological age in response to diverse forms of stress. The researchers began with a laboratory experiment known to produce aged physiology in young mice or restore youthful physiology to old mice by surgically joining young, 3-month-old mice with older, 20-month-old mice, which allowed them to share their blood. At the molecular level, they found that the biological age of the young mice increased when measured with most aging clocks. Once the young mice were separated from the old mice and therefore were no longer experiencing the older mouse physiology, their biological age returned to youthful levels. This finding suggested that biological age is malleable and potentially reversible, and these changes are reported by DNAm aging clocks.

Next, the researchers examined blood samples from people who had recently experienced stressful situations, including surgery (emergency versus elective), pregnancy, or severe COVID-19. Analysis of blood samples from patients who underwent emergency surgery showed their biological age increased the morning after surgery and returned to pre-surgery levels four to seven days later. Elective surgeries, on the other hand, had less impact on biological age, which the authors attribute to pre-operative regimens known to aide recovery. Pregnancy in both mice and humans led to increased biological age at delivery, which reverted to lower biological age following delivery and recovery.

Link: https://www.nia.nih.gov/news/stress-induced-increases-biological-age-are-reversible

Cells maintain themselves against damage and stress via a range of maintenance processes. These include autophagy, in which proteins and structures are transported to the lysosome to be broken down by enzymes, and the ubiquitin-proteasome system, in which specific proteins are dismantled in the proteasome, among others. It is well demonstrated that upregulation of these processes improves resistance to cell stress, and can also improve long-term health, reducing risk of age-related disease and slowing progression of those conditions. Upregulation of autophagy, for example, is a feature of many interventions that modestly slow the progression of degenerative aging. Some approaches to improve proteasomal function have also been shown to slow aging and extend life in short-lived species. Thus a broad range of research is focused on increasing the efficiency or effectiveness of these processes.

In today's open access paper, researchers discuss upregulation of NRF1, also known as NFE2L1, as a way to improve proteasomal function. The specific focus is neurodegeneration rather than aging more generally, but it is still the case that greater resistance to the consequences of cell stress can preserve function in the face of many distinct and complex damaging processes. While the research community expends a great deal of time and effort on the question of how to improve the operation of systems of cell maintenance, it remains the case that few well developed therapies have shown any improvement over exercise in this respect. Large gains seem elusive, particularly as effect sizes appear to diminish with increased species life span. This perhaps suggests that many of the possible optimizations are already operating in long-lived species.

NFE2L1/Nrf1 serves as a potential therapeutical target for neurodegenerative diseases

Nuclear factor-erythroid 2 (NFE2)-related factor 1 (Nrf1, encoded by NFE2L1) acts as a transcription factor involved in multiple essential life processes, e.g., redox signaling, cellular metabolism, and proteasomal regulation. Of note, NFE2L1 binds to the promoter regions of its target genes through the antioxidant response elements (AREs), crucially to drive transactivation of those stress-responsive and cytoprotective genes, which are also present in the promoters of genes encoding proteasomal subunits. Further studies revealed that NFE2L1 regulates multiple antioxidant genes, such as HMOX1, SOD1, or GCLC; it has also been verified as a master regulator of the ubiquitin-proteasome system (UPS) by controlling the transcriptional expression of almost all proteasome subunits and relevant co-factors.

Multiple neuroprotective interventions, as aforementioned, rely mainly on increasing NFE2L1 activity in neurons, which enhances the cell survival ability to defend against various stressors. NFE2L1 is essential for the proper functioning of proteasomes, and its lack results in an aberrant accumulation of ubiquitinated proteins through the nervous system. Notably, the knockout of the NFE2L1 gene in animal models brings about severe pathology resembling human neurodegenerative diseases. In the postmortem analyses, reduced NFE2L1 levels were found in the substantia nigra region of patients with Parkinson's disease and in the hippocampus of patients with Alzheimer's disease. This presents a strong case of NFE2L1 deficiency involved in the pathogenesis of neurodegenerative diseases.

Therefore, it is plausible that NFE2L1 has significant potential in translational medicine to serve as a therapeutic target for these neurodegenerative diseases. Nevertheless, since NFE2L1 is widely expressed throughout a given organism's whole body, a neuron-specific activation of this transcription factor would be more beneficial to minimize off-target effects.

The immune system ages in ways that are harmful to tissue function and health, becoming both less effective and overly inflammatory. Not all of the observed changes in immune cell activities and immune cell population sizes are harmful, however. Some are compensatory, even though this compensation isn't enough to stop the overall decline. With that in mind, researchers here report on an analysis of the size of immune cell populations in old individuals, including centenarians. They find that natural killer cells increase in number with age, which they characterize as an adaptation to the aged environment.

The immune system of semi-centenarians and super-centenarians (i.e., the oldest centenarians) is believed to have peculiar characteristics that enable them to reach extreme longevity in a relatively healthy state. Therefore, in previous papers, we investigated, through flow cytometry, variations in the percentages of the main subsets of αβ T cells and γδ T cells in a Sicilian cohort of 28 women and 26 men (age range 19-110 years), including 11 long-living individuals (older than 90 years) and 8 oldest centenarians. These investigations suggested that some observed immunophenotypic changes may contribute to the extreme longevity of the oldest centenarians.

In the present study, to further characterize the immunophenotype of the oldest centenarians, we examined the percentages of Natural Killer (NK) cells identified as CD3-CD56+CD16+ in the previously described Sicilian cohort. We found a highly significant increase in NK cell percentages with age. When stratified by gender, this significant increase with age was maintained in both sexes, with higher significance observed in males.

Our findings on NK cells, together with the previously obtained results, discussed in the context of the literature, suggest that these changes are not unfavourable for centenarians, including the oldest ones, supporting the hypothesis that immune aging should be considered as a differential adaptation rather than a general immune alteration. These adapted immune mechanisms allow the oldest centenarians to successfully adapt to a history of insults and achieve remarkable longevity.

Link: https://doi.org/10.37825/2239-9747.1041

You might compare the research noted here with another similar study published a year ago. In both cases, data on hearing aid use in large patient populations is used to demonstrate that hearing loss contributes to the onset and progression of dementia. This data doesn't favor any specific theory regarding the mechanism, such as atrophy of brain structures resulting from disuse versus some form of maladaptive compensatory activity in the brain. Greater understanding of the mechanisms involved will require further research.

Hearing loss has been suggested as a risk factor for dementia, but there is still a need for high-quality research to better understand the association between these two conditions and the underlying causal mechanisms and treatment benefits using larger cohorts and detailed data. This population-based cohort study was conducted in Southern Denmark between January 2003 and December 2017 and included all residents 50 years and older. We excluded all persons with dementia before baseline as well as those who did not live in the region 5 years before baseline, with incomplete address history, or who had missing covariate information.

The study population comprised 573,088 persons (298,006 women [52%]; mean [SD] age, 60.8 [11.3] years) with 23,023 cases of dementia and mean (SD) follow-up of 8.6 (4.3) years. Having a hearing loss was associated with an increased risk of dementia, with an adjusted hazard ratio (HR) of 1.07 compared with having no hearing loss. Severe hearing loss in the better and worse ear was associated with a higher dementia risk, with an HR of 1.20 and 1.13, respectively, compared with having no hearing loss in the corresponding ear. Compared with people without hearing loss, the risk of dementia was higher among people with hearing loss who were not using hearing aids than those who had hearing loss and were using hearing aids, with HRs of 1.20 and 1.06, respectively.

The results of this cohort study suggest that hearing loss was associated with increased dementia risk, especially among people not using hearing aids, suggesting that hearing aids might prevent or delay the onset and progression of dementia. The risk estimates were lower than in previous studies, highlighting the need for more high-quality longitudinal studies.

Link: https://doi.org/10.1001/jamaoto.2023.3509

Chronological age is embedded in a great many standardized, widely-used protocols for patient risk assessment. Age-related diseases are, after all, age-related, and this use of chronological age has long seemed a reasonable choice. That said, we are now moving into an era in which novel means of measuring biological age are under development, such as epigenetic clocks.

Biological age is the burden of damage and dysfunction resulting from the causative processes of aging. Obviously, this should better reflect the odds of suffering age-related disease. While biological age correlates with chronological age, there is a great deal of room for differences between the two in any given individual. This development has also highlighted the point that a number of established functional measures, such as grip strength and other components of frailty assessment, particularly when these measures are combined together, might also be considered crude assessments of biological age.

This new knowledge regarding the measurement of age and processes of aging is making chronological age appear an ever worse choice for patient risk assessment. Different people age at meaningfully different rates. Today that occurs largely as the result of the combination of lifestyle choice, exposure to persistent pathogens, and the presence of environmental stressors such as particulate air pollution. In the decades ahead it will occur largely due to the use of interventions to repair and reverse causative processes of aging, progressively decoupling aging from the chronological passage of time.

Personalizing Cardiovascular Disease Risk Assessment: Is it Time to Forget About Chronologic Age?

It is commonly said that "age is just a number," and chronologic age, calculated as the time elapsed from birth, has been the primary way to define an individual's age. However, this method fails to account for the complex and diverse processes of aging. Indeed, a person's genetics along with their diet, lifestyle, and cumulative exposure to risk factors leads to significant heterogeneity in biologic age for persons of the same chronologic age. This creates a problem for cardiovascular risk calculators such as the Pooled Cohort Equation (PCE), because chronologic age is the most heavily weighted variable. Nearly all adults younger than 40 years have a low 10-year predicted risk of atherosclerotic cardiovascular disease (ASCVD), while most men older than 60 and women older than 65 years of age have at least an intermediate 10-year ASCVD risk from 7.5% to 20%, regardless of their traditional risk factor burden.

The shortcomings of chronologic age have led to an increased recognition that other measures are needed to better classify an individual's biologic age and ASCVD risk. Genetic biomarkers of DNA methylation and telomere length have been linked to acceleration of the aging processes, but the cost of testing and expertise needed for interpretation of the results limit their widespread use in clinical practice. Interestingly, even a subjective estimation of an individual's perceived age provides significant insight into their biologic age and survival. More direct quantification of arterial or vascular aging with the use of coronary artery calcium (CAC) scoring or noninvasive markers of arterial stiffness such as pulse-wave velocity (PWV) also better classify biologic age, which in turn improves ASCVD risk stratification relative to models that rely on chronologic age and may provide a more accurate and personalized estimate of ASCVD risk.

Compared with measuring systolic and diastolic blood pressure, measuring PWV provides distinct information on vascular health that is specifically related to vascular compliance and distensibility and is an early marker of poor vascular health, even before the development of hypertension. PWV is also strongly associated with cardiovascular outcomes and improves risk prediction beyond traditional cardiovascular risk factors, with a 30% increased risk for cardiovascular disease (CVD) for every 1 standard deviation higher PWV. As such, PWV is one simple method to improve the measurement of biologic age.

INDY is a well-studied longevity-associated gene. Reduced INDY expression extends life in a number of short-lived laboratory species. Here, researchers argue that INDY inhibition could form the basis for osteoporosis treatments. Osteoporosis is the condition resulting from age-related loss of bone density. Bone is constantly remodeled by osteoblasts that build bone extracellular matrix and osteoclasts that destroy it. With advancing age, the activity of osteoclasts steadily outpaces the activity of osteoblasts. This occurs for a variety of reasons, and much of the research into osteoporosis is conducted in search of ways to restore the balance in some way.

Reduced expression of the plasma membrane citrate transporter SLC13A5, also known as INDY, has been linked to increased longevity and mitigated age-related cardiovascular and metabolic diseases. Citrate, a vital component of the tricarboxylic acid cycle, constitutes 1-5% of bone weight, binding to mineral apatite surfaces. Our previous research highlighted osteoblasts' specialized metabolic pathway facilitated by SLC13A5 regulating citrate uptake, production, and deposition within bones. Disrupting this pathway impairs bone mineralization in young mice.

New Mendelian randomization analysis using UK Biobank data indicated that SNPs linked to reduced SLC13A5 function lowered osteoporosis risk. Comparative studies of young (10 weeks) and middle-aged (52 weeks) osteocalcin-cre-driven osteoblast-specific Slc13a5 knockout mice (Slc13a5cKO) showed a sexual dimorphism: while middle-aged females exhibited improved elasticity, middle-aged males demonstrated enhanced bone strength due to reduced SLC13A5 function. These findings suggest reduced SLC13A5 function could attenuate age-related bone fragility, advocating for SLC13A5 inhibition as a potential osteoporosis treatment.

Link: https://doi.org/10.3390/metabo13121186

Evidence strongly suggests that failing drainage of cerebrospinal fluid contributes to neurodegeneration, as the flow of fluid from the brain into the body carries metabolic waste with it. This metabolic waste, such as misfolded amyloid-β, becomes more prone to accumulate given the reduced drainage that occurs in later life, and this accumulation contributes to the onset and progression of neurodegenerative conditions. One of the pathways for drainage is the comparatively recently discovered glymphatic system. Here, researchers discuss a way to measure the flow of cerebrospinal fluid through the glymphatic system. Putting numbers to the problem of reduced drainage is an important step on the way to doing something about it.

Glymphatic clearance dysfunction may play an important role in a variety of neurodegenerative diseases and the progression of ageing. However, in vivo imaging of the glymphatic system is challenging. In this study, we describe an MRI method based on chemical exchange saturation transfer (CEST) of the Angiopep-2 probe to visualize the clearance function of the glymphatic system.

We injected rats with Angiopep-2 via the tail vein and performed in vivo MRI at 7 T to track differences in Angiopep-2 signal changes; we then applied the same principles in a bilateral deep cervical lymph node ligation rat model and in ageing rats. We demonstrated the feasibility of Angiopep-2 CEST for visualizing the clearance function of the glymphatic system. Finally, a pathological assessment was performed. Within the model group, the deep cervical lymph node ligation group and the ageing group showed higher CEST signal than the control group. We conclude that this new MRI method can visualize clearance in the glymphatic system.

Link: https://doi.org/10.18632/aging.205322

Aging is characterized by constant sterile inflammation, a state that is disruptive to tissue structure and function. A number of forms of molecular damage have been shown via various mechanisms to provoke this inflammation. Mitochondrial dysfunction, for example causes mitochondrial DNA to mislocalize to the cytoplasm, where it triggers an innate immune response that evolved to recognize the presence of bacterial DNA. Mitochondria are the evolved descendants of ancient symbiotic bacteria, and their remnant DNA is close enough to bacterial genomes for this to occur.

In today's open access paper, researchers discuss a different direct link between mutational damage to the genome and inflammation. It nonetheless also involves mitochondria and triggering of the cGAS-STING pathway that recognizes mislocalized DNA fragments. The authors of the paper consider this mechanism in the context of senescent cells, which actively generate inflammatory signaling. Senescent cells are also characterized by DNA damage, and undergo a significant amount of that damage in the process of becoming senescent. Research into the mechanisms driving senescent cell inflammatory signaling may lead to ways to suppress this damaging contribution to the inflammation of aging.

A mitochondria-regulated p53-CCF circuit integrates genome integrity with inflammation

Genomic instability and inflammation are distinct hallmarks of aging, but the connection between them is poorly understood. Understanding their interrelationship will help unravel new mechanisms and therapeutic targets of aging and age-associated diseases. Here we report a novel mechanism directly linking genomic instability and inflammation in senescent cells, through a mitochondria-regulated molecular circuit that connects the p53 tumor suppressor and cytoplasmic chromatin fragments (CCF), a driver of inflammation through the cGAS-STING pathway.

Activation or inactivation of p53 by genetic and pharmacologic approaches showed that p53 suppresses CCF accumulation and the downstream inflammatory senescence-associated secretory phenotype (SASP), independent of its effects on cell cycle arrest. p53 activation suppressed CCF formation by promoting DNA repair, reflected in maintenance of genomic integrity, particularly in subtelomeric regions, as shown by single cell genome resequencing. Activation of p53 by pharmacological inhibition of MDM2 in old mice decreased features of SASP in liver, indicating a senomorphic role in vivo. Remarkably, mitochondria in senescent cells suppressed p53 activity by promoting CCF formation and thereby restricting ATM-dependent nuclear DNA damage signaling.

This data provides evidence for a mitochondria-regulated p53-CCF circuit in senescent cells that controls DNA repair, genome integrity and inflammatory SASP, and is a potential target for senomorphic healthy aging interventions.

Researchers have implicated numerous mechanisms in the age-related loss of muscle mass and strength leading to the condition known as sarcopenia. While not everyone arrives at a diagnosis of sarcopenia, everyone is subject to the progressive deterioration of muscle tissue. One of the challenges facing attempts to understand age-related disease in detail is that the noteworthy mechanisms of aging form a complex, interacting web of cause and consequence. It is next to impossible to determine which mechanisms are more or less important from observation alone. So while one can mount a good argument for sarcopenia to be driven by reduced stem cell activity, proving that would require interventions that do not at present exist. One is further left struggling to explain how exactly that loss of stem cell function takes place: which of the mechanisms of aging are most important in driving it?

Ageing is a complex biological process associated with increased morbidity and mortality. Nine classic, interdependent hallmarks of ageing have been proposed involving genetic and biochemical pathways that collectively influence ageing trajectories and susceptibility to pathology in humans. Ageing skeletal muscle undergoes profound morphological and physiological changes associated with loss of strength, mass, and function, a condition known as sarcopenia. The aetiology of sarcopenia is complex and whilst research in this area is growing rapidly, there is a relative paucity of human studies, particularly in older women.

Here, we evaluate how the nine classic hallmarks of ageing: genomic instability, telomere attrition, epigenetic alterations, loss of proteostasis, deregulated nutrient sensing, mitochondrial dysfunction, cellular senescence, stem cell exhaustion, and altered intercellular communication contribute to skeletal muscle ageing and the pathophysiology of sarcopenia. We also highlight five novel hallmarks of particular significance to skeletal muscle ageing: inflammation, neural dysfunction, extracellular matrix (ECM) dysfunction, reduced vascular perfusion, and ionic dyshomeostasis, and discuss how the classic and novel hallmarks are interconnected. Their clinical relevance and translational potential are also considered.

We conclude that there is strong evidence for epigenetic alteration, mitochondrial dysfunction, neural dysfunction, and moderate evidence for inflammation, deregulated nutrient sensing, immunoaging, ECM dysfunction, and reduced vascular perfusion as hallmarks for skeletal muscle ageing, with their relevance for sarcopenia evolving.

Link: https://doi.org/10.1042/CS20230319

Researchers here report that HKDC1 is important in the autophagic processes that remove worn and damaged mitochondria, sending them to be recycled in the lysosome. Mitochondrial function declines with age, and this is thought to result in large part due to this decline in mitophagy, the name given to mitochondria-specific autophagy. Finding novel targets for therapies that might enhance mitophagy is a popular topic, despite the comparatively poor results obtained to date. Few of the existing approaches are better than exercise. Much more is needed if the objective is to significantly slow aging.

Mitochondria power the cell and lysosomes keep the cell tidy. Although damage to these two organelles has been linked to aging, cellular senescence, and many diseases, the regulation and maintenance of these organelles has remained poorly understood. There was evidence that a protein called TFEB is involved in maintaining the function of both organelles, but no targets of this protein were known. By comparing all the genes of the cell that are active under particular conditions, and by using a method called chromatin immunoprecipitation, which can identify the DNA targets of proteins, researchers have shown that the gene encoding HKDC1 is a direct target of TFEB, and that HKDC1 becomes upregulated under conditions of mitochondrial or lysosomal stress.

One way that mitochondria are protected from damage is through the process of "mitophagy", the controlled removal of damaged mitochondria. There are various mitophagy pathways, and the most well-characterized of these depends on proteins called PINK1 and Parkin. "We observed that HKDC1 co-localizes with a protein called TOM20, which is located in the outer membrane of the mitochondria. Through our experiments, we found that HKDC1, and its interaction with TOM20, are critical for PINK1/Parkin-dependent mitophagy."

"HKDC1 is localized to the mitochondria, right? Well, this turns out to also be critical for the process of lysosomal repair. Lysosomes and mitochondria contact each other via proteins called VDACs. Specifically, HKDC1 is responsible for interacting with the VDACs; this protein is essential for mitochondria-lysosome contact, and thus, lysosomal repair." These two diverse functions of HKDC1, with key roles in both the lysosome and the mitochondria, help to prevent cellular senescence by simultaneously maintaining the stability of these two organelles.

Link: https://www.eurekalert.org/news-releases/1029874

In the past year or two, a great deal of effort on the part of leading researchers has gone into trying to standardize the use of a single epigenetic clock based on DNA methylation status of CpG sites on the genome. Suitable candidate universal mammalian clocks now exist. There are good reasons for standardization. Given that any large amount of omics data can be used to produce aging clocks, where "clock" in this context means a weighted combination of measured values that correlates well with chronological age or biological age, there is an essentially infinite number of potential clocks. People can build or cherry pick clocks that are optimized to produce large numbers for their specific therapeutic approach to age-slowing or age-reversing intervention. Further, comparing results obtained with different clocks is essentially impossible. This leads to wasted effort.

As an example of why standardization is important, we might look at today's open access paper, in which researchers pick a clock that isn't one of the proposed standards, uses only four CpG sites (a tiny number!) and show large differences between study groups. One wonders if they picked the clock because the numbers are large. One can't really do anything to compare this data with data obtained from different clocks: this paper is thus unlikely to contribute meaningfully to the advance of knowledge. Further, we should probably assume that any epigenetic clock built using such a small number of CpG sites is reflecting only a very narrow slice of the full panoply of processes of degenerative aging. It is reasonable to think that no such clock will be able to usefully assess the results of interventions that target only a subset of the processes of aging. All in all, this isn't helpful.

Decelerated Epigenetic Aging in Long Livers

Epigenetic aging is a hot topic in the field of aging research. The present study estimated epigenetic age in long-lived individuals, who are currently actively being studied worldwide as an example of successful aging due to their longevity. We used Bekaert's blood-based age prediction model to estimate the epigenetic age of 50 conditionally "healthy" and 45 frail long-livers over 90 years old. Frailty assessment in long-livers was conducted using the Frailty Index. The control group was composed of 32 healthy individuals aged 20-60 years.

The DNA methylation status of the 4 CpG sites (ASPA CpG1, PDE4C CpG1, ELOVL2 CpG6, and EDARADD CpG1) included in the epigenetic clock was assessed through pyrosequencing. According to the model calculations, the epigenetic age of long-livers was significantly lower than their chronological age (on average by 21 years) compared with data from the group of people aged 20 to 60 years. This suggests a slowing of epigenetic and potentially biological aging in long livers.

At the same time, the obtained results showed no statistically significant differences in delta age (difference between the predicted and chronological age) between "healthy" long livers and long livers with frailty. We also failed to detect sex differences in epigenetic age either in the group of long livers or in the control group. It is possible that the predictive power of epigenetic clocks based on a small number of CpG sites is insufficient to detect such differences. Nevertheless, this study underscores the need for further research on the epigenetic status of centenarians to gain a deeper understanding of the factors contributing to delayed aging in this population.

A sizable fraction of the benefits to health and life span resulting from the practice of calorie restriction derive from regulatory systems that are triggered by nutrient sensing mechanisms focused on specific amino acids, primarily methionine. Thus a lowered dietary methionine intake produces health benefits even when overall calorie intake remains the same. This is well demonstrated in animal models, but not well tested in humans, despite the existence of low methionine medical diets. This may be because the medical diet are expensive, and it is neither straightforward nor easy to plan and eat a low methionine diet. Guides exist, but as a practical matter it is challenging to implement.

Methionine restriction (MetR) extends lifespan in various organisms, but its mechanistic understanding remains incomplete. Whether MetR during a specific period of adulthood increases lifespan is not known. In Drosophila, MetR is reported to extend lifespan only when amino acid levels are low. Here, by using an exome-matched holidic medium, we show that decreasing Met levels to 10% extends Drosophila lifespan with or without decreasing total amino acid levels. MetR during the first four weeks of adult life only robustly extends lifespan.

MetR in young flies induces the expression of many longevity-related genes, including Methionine sulfoxide reductase A (MsrA), which reduces oxidatively-damaged Met. MsrA induction is foxo-dependent and persists for two weeks after cessation of the MetR diet. Loss of MsrA attenuates lifespan extension by early-adulthood MetR. Our study highlights the age-dependency of the organismal response to specific nutrients and suggests that nutrient restriction during a particular period of life is sufficient for healthspan extension.

Link: https://doi.org/10.1038/s41467-023-43550-2

Dysfunction of the salivary gland is an underappreciated and unpleasant age-related condition. Researchers here demonstrate that injection of platelet rich plasma into the salivary gland can rescue function in old mice by promoting regrowth of lost cells, reducing inflammation, and reducing the burden of cellular senescence in this tissue. As noted in the paper, platelet rich plasma is fairly widely used in the regenerative medicine industry, and this sort of result in an animal model is one of the reasons why this is the case.

Saliva, synthesized and secreted by the salivary glands (SGs), plays an essential role in the oral cavity by maintaining oral homeostasis, protecting against infection, and promoting digestion. A dysfunction of the SG leads to xerostomia or dry mouth, sialadenitis or salivary gland inflammation, worsening of dental caries, and periodontal diseases. Furthermore, xerostomia reduces overall health or the quality of patient's life. Temporal xerostomia is caused by acute infection or dehydration. On the other hand, permanent xerostomia is caused by autoimmune inflammatory diseases such as Sjogren syndrome, radiation therapy in head and neck cancer patients, xerogenic medication, or aging.

Platelet derivatives such as platelet-rich plasma (PRP), platelet-rich fibrin (PRF), and plasma rich in growth factor (PRGF), are used widely in different areas of regenerative medicine to enhance the wound healing processes. This study examined whether the local injection of the supernatant of activated PRP (saPRP) into the salivary gland (SG) could help prevent aging-induced SG dysfunction and explored the mechanisms responsible for the protective effects on the SG hypofunction.

Human salivary gland epithelial cells (hSGEC) were treated with saPRP or PRP after senescence through irradiation. The significant proliferation of hSGEC was observed in saPRP treated group compared to irradiation only group and irradiation + PRP group. Cellular senescence, apoptosis, and inflammation were significantly reduced in the saPRP group.

The SG function and structural tissue remodeling by the saPRP were investigated with naturally aged mice. The mice were divided into three groups: 3 months old (3 M), 22 months old (22 M), and 22 months old treated with saPRP (22 M + saPRP). Salivary flow rate and lag time were significantly improved in 22 M + saPRP group compared to 22 M group. The histologic examinations showed the significant proliferation of acinar cells in the SG of the 22 M + saPRP group. A decrease of senescence, apoptosis, and inflammation was observed by western blot in the 22 M + saPRP group.

Link: https://doi.org/10.1038/s41598-023-46878-3

One long-lasting result of the hype engineered over sirtuin 1 overexpression as a possible avenue to modestly slow aging is a continued focus on other sirtuins in the context of aging. Sirtuin 1 overexpression turned out to be entirely unimpressive, a dead end. Sirtuin 6, however, is more interesting, and overexpression in mice does modestly extend life span, possibly by improving DNA repair efficiency. It may also be the case that sirtuin 3 overexpression can improve mitochondrial function to a great enough degree to also be interesting.

On the whole, however, this sort of approach to manipulating metabolism has yet to produce gains in mouse life span that come close to that achieved by calorie restriction. And gains in mouse life span dwindle when the same strategies are applied to longer-lived species, in which evolution has already implemented many of the gains that can be achieved in short-lived species. Still, the research community continues down this road, and sirtuins remain on the agenda. That leads to studies such as the one reported in today's open access paper, in which researchers rule out sirtuin 2 upregulation as an area of interest.

SIRT2 transgenic over-expression does not impact lifespan in mice

The sirtuin NAD+-dependent deacylase family of enzymes contains seven members, playing diverse roles in epigenetic regulation, DNA repair, and metabolic homeostasis. Interest in these proteins was sparked by initial findings on the role of Sir2 in yeast replicative lifespan, and subsequent interest in the mammalian homologue SIRT1. This was further compounded by the identification of small molecule allosteric activators for SIRT1, with these compounds demonstrating potential in preclinical models of disease. Whole-body transgenic over-expression of SIRT1 impacts some aspects of late-life health, it does not increase overall lifespan in mice, unlike the transgenic over-expression of another nuclear sirtuin, SIRT6. This may be complicated by tissue specific effects, as unlike whole-body overexpression, tissue specific SIRT1 overexpression in the hypothalamus results in increased overall lifespan. It is currently unknown whether altered activity of other members of this family can impact mammalian ageing.

One member of this family, sirtuin-2 (SIRT2) was previously found to regulate stability of BubR1, which has been implicated in maintaining accurate chromosome segregation during mitosis to prevent cellular senescence during ageing. Transgenic over-expression of BubR1 extends lifespan, while its under-expression results in the accelerated onset of age-related pathologies and shortened overall lifespan. Previously, we showed that SIRT2 transgenic over-expression (SIRT2-Tg) in the context of BubR1 under-expression partially rescued the lifespan of male, but not female mice. Further, we showed that this same SIRT2-Tg allele on a non-progeroid wild-type (WT) C57BL6 background could delay reproductive ageing in mice, with an extended period of functional fertility.

While members of the sirtuin family have been classically studied as NAD+-dependent deacetylase enzymes, SIRT2 is also capable of removing other acyl modifications on lysine residues, including lactylation, crotonylation, myristoylation, and benzoylation. Well-studied substrates for SIRT2 include tubulin, histones, glucose-6phospohate dehydrogenase (G6PD), Foxo1, Foxo3a, p65, IDH1, APCCDH1 and others. SIRT2 has been proposed as a therapeutic target in neurodegenerative disease, though a number of these findings are contradictory. For example, SIRT2 inhibitors can provide neuroprotection against models of Huntington's disease, Alzheimer's disease, and Parkinson's disease; however, SIRT2 deletion impairs axonal energy metabolism, resulting in locomotor disability, with SIRT2 also playing a putative role in reducing neuroinflammation. Similarly, there is evidence for SIRT2 as both a suppressor and promoter of tumour growth, though these roles are likely to be context dependent.

Given this previous work, the aim of this investigation was to establish whether SIRT2 could impact overall lifespan on a non-progeroid background in mice. Here, we characterized aspects of metabolism, development, motor coordination, mitochondrial function, bone health, fertility and overall lifespan in a previously described mouse strain over-expressing SIRT2. While SIRT2 over-expression had impacts on levels of certain metabolites in the brain, we found no impact of SIRT2 overexpression any aspect of overall health or lifespan, suggesting that levels of this protein are not relevant to functional biological ageing and lifespan under standard, non-progeroid conditions.

A great deal of research and development effort is now focused on finding ways to reduce the contribution of senescent cells to degenerative aging. Initiatives range from fundamental research into the biochemistry of senescent cells to clinical trials of early senolytic therapies capable of selectively destroying senescent cells. A growing burden of senescent cells is a feature of all organs and tissues in the body, the skin included. Researchers here discuss what is known of the role of cellular senescence in aging and dysfunction of skin, and what might be done about it.

The skin is the largest organ of the human body, and the site where signs of aging are most visible. These signs include thin and dry skin, sagging, loss of elasticity, wrinkles, as well as aberrant pigmentation. The appearance of these features is accelerated by exposure to extrinsic factors such as ultraviolet (UV) radiation or pollution, as well as intrinsic factors including time, genetics, and hormonal changes.

At the cellular level, aging is associated with impaired proteostasis and an accumulation of macromolecular damage, genomic instability, chromatin reorganization, telomere shortening, remodelling of the nuclear lamina, proliferation defects and premature senescence. Cellular senescence is a state of permanent growth arrest and a key hallmark of aging in many tissues. Due to their inability to proliferate, senescent cells no longer contribute to tissue repair or regeneration. Moreover, senescent cells impair tissue homeostasis, promote inflammation and extracellular matrix (ECM) degradation by secreting molecules collectively known as the "senescence-associated secretory phenotype" (SASP).

Senescence can be triggered by a number of different stimuli such as telomere shortening, oncogene expression, or persistent activation of DNA damage checkpoints. As a result, these cells accumulate in aging tissues, including human skin. In this review, we focus on the role of cellular senescence during skin aging and the development of age-related skin pathologies, and discuss potential strategies to rejuvenate aged skin.

Link: https://doi.org/10.3389/fphys.2023.1297637

It remains unclear as to why apolipoprotein E (APOE) variants are associated with longevity in humans. The gene has a well-studied role in Alzheimer's disease, but the reasons why APOE variants are associated with aging remain to be determined. The most likely mechanisms involve (a) interactions with age-related disruptions of lipid metabolism, both in the brain and elsewhere, and (b) indirect effects on the inflammatory behavior of innate immune cells such as microglia. There are plenty of other interactions to further study, however, such as in bone tissue, or effects on the gut microbiome. As is often the case, a great deal of data exists, but making sense of that data lags far behind the ability to generate more of it.

The APOE variants, respectively ε2 ε3, ε4, and ε3r, are determined by four haplotypes at the APOE locus (19q13.32). These four APOE alleles are probably the most investigated variants in the human genome. Remarkably, the APOE exon 4 region, encompassing the ε2/ε3/ε4 allele variants, is a well-defined CpG islands-rich area. Moreover, the two common SNPs rs429358 and rs7412 are CpG-altering and modify the CpG content of this area. This APOE CpG island-rich area is a transcriptional enhancer with a specificity linked to the ε4 allele and cell-type.

A genetic association of APOE with both human longevity and Alzheimer's disease (AD) was found, but the mechanistic contribution of APOE in aging and long life is largely under investigation. APOE pleiotropic roles may be explained by its exceptional epigenetic properties. In the AD brain, these epigenetic changes could contribute to neural cell dysfunction. Additionally, DNA methylation modifications have been found on specific genes associated with AD pathology such as APOE. In the AD brain, it was shown that APOE CpG islands were differentially methylated in an APOE-genotype and tissue-specific way.

In the lipid metabolism pathophysiology, ApoE may be related with normal/pathological aging, while its function in CNS pathophysiology needs further clarification. In fact, in the CNS, there was about a quarter of total body cholesterol that may exert a significant impact on synaptic plasticity. With advancing age, cholesterol metabolism may modify, and its related brain changes may be associated with the pathophysiology of AD. So, in longevity and healthy aging, lipid and cholesterol maintenance are a critical factor also from an interventional point of view.

Studies on longevity and healthy aging are related because subjects who live longer tend to be healthier for a greater part of their lives. Healthy aging can be described as achieving older age maintaining intact cognition and/or mobility and without disabilities or multimorbidity. This last can be defined as the coexistence of two or more chronic diseases in the same subjects. The detrimental effects of the APOE ε4 allele on longevity could influence the probability of a long human lifespan. The APOE ε2 allele has a greater frequency in long-lived individuals than the ε4 allele. Thus, the main longevity factor is the APOE ε3/ε3 genotype. The greater frequency of the ε3 allele in older individuals and their offspring than in controls derives from the higher amount of the homozygous APOE ε3/ε3 genotype in comparison with the ε2/ε3 or ε3/ε4 genotypes

Link: https://doi.org/10.3390/biology12121529

A gene sequence consists of a mix of shorter sequences, only some of which are used to manufacture the protein encoded in that gene. Exon sequences are included and intron sequences are excluded. Nothing is ever quite that simple, of course, but changes in which exons and introns end up in a protein enable multiple proteins to be produced from a single gene sequence. Sometimes this is an accident, as some genes are prone to accidental production of truncated or extended proteins that are toxic. Sometimes this is an evolutionary reuse in which a gene produces several different vital proteins with quite different functions.

The process by which a gene sequence is interpreted to manufacture messenger RNA (mRNA) molecules for a given protein (some or all exons, none of the introns) is called RNA splicing. Alternative splicing is what happens when the dominant protein is not produced, but rather some other protein is made instead. Splicing is a complex and highly regulating process, and like all such processes in the cell, it runs awry with age. Changes in the gene expression of splicing factors and other forms of change and damage in the cell can alter the distribution of different mRNAs produced from a given gene, or lead to a greater production of malformed, toxic proteins.

As for all of the changes taking place in the machinery of gene expression, we might well ask where alternative splicing fits into the complex web of interacting causes and consequences of degenerative aging. Are these changes closer to being a root cause of aging, with many harmful downstream effects resulting from disruption of RNA splicing? Or are these changes far downstream, with little further damage and dysfunction resulting from dysregulated RNA splicing? There is a sea of data, but it remains hard to argue for a given position without acknowledging the surplus of evidence that supports all of the other positions. For what it is worth, methods of slowing aging tend to correlate with lesser disruption of RNA splicing. The most interesting research here is by groups like SENISCA that are attempting to restore youthful organization of RNA splicing, and have achieved some success on this front. It remains to be seen as to how this will turn out, given that it remains a comparatively new area of research and development.

Age-Related Alternative Splicing: Driver or Passenger in the Aging Process?

A wide range of changes in cellular mechanisms involving both transcriptional and post-transcriptional regulation have been linked to normal aging. While age-related variations in the cellular environment lead to eventual molecular changes, it is also possible that the molecular changes accelerate aging and age-related disorders (ranging from hypertension to cardiovascular disease, cancer, and neurodegeneration). Furthermore, different tissues and organs may experience different age-related alterations in transcriptional and post-transcriptional regulation. In higher eukaryotic genomes, alternative splicing (AS) of both protein and non-coding genes not only profoundly contributes to increasing the functional diversity and complexity of the whole transcriptome, but it also seems to be a master regulator of cellular and individual aging.

Although the majority of variations in alternative splicing events occur during development, it is estimated that approximately 30% of all alternative splicing alterations occur during aging. As rodents and humans consistently exhibit age- and tissue-related variations in the expression of genes involved in splicing, age-related changes in splicing may be caused by the age-related decline in splicing factor expression. On the other hand, the main categories of genes with age-related altered splicing include those encoding genes with neuronal-specific activities such as synaptic transmission in the human brain, as well as those implicated in collagen production and post-translational modification in the human Achilles tendon. These observations suggest that age-dependent splicing changes are more likely to occur in at least some of the same categories of tissue-specific genes that show transcriptional decline with aging.

Aging-dependent splicing alterations can explain why some genes show a tissue-specific decrease in expression. Splicing errors during pre-mRNA processing can result in the incorrect usage of alternative splice sites, leading to intron retention in the mature mRNA transcript rather than proper exon joining. Intron retention introduces premature termination codons that target the aberrant transcripts for degradation through nonsense-mediated decay (NMD). This differs from frameshift mutations caused by small insertions or deletions during splicing, which can also introduce premature stop codons but do not always trigger transcript degradation by NMD, and may allow some protein production from the altered transcripts.

The interplay between splicing and aging has major implications for aging biology, though differentiating correlation and causation remains challenging. Declaring a splicing factor or event as a driver requires comprehensive evaluation of the associated molecular and physiological changes. A greater understanding of how RNA splicing machinery and downstream targets are impacted by aging is essential to conclusively establish the role of splicing in driving aging, representing a promising area with key implications for understanding aging, developing novel therapeutic options, and ultimately leading to an increase in the healthy human lifespan.

Microglia, the innate immune cells of the central nervous system, can enter an aggressive, inflammatory state in response to the presence of molecular waste, inflammatory signaling, mitochondrial damage, and so forth. They can also become senescent, which is also a pro-inflammatory state. The aging brain, and particularly the brains of patients with neurodegenerative conditions, exhibit a state of chronic inflammation, producing dysfunction, cell stress, and cell death. It remains to be seen as to how effective anti-inflammatory therapies targeting microglia will be in the treatment of neurodegenerative conditions and the slowing of brain aging. Comparatively simple approaches already exist, such as the use of CSF1R inhibitors to clear existing maladaptive microglia and thereby allow a new population to emerge lacking the damage and inflammatory behavior of the preexisting cells. Time will tell as to their utility.

Current evidence demonstrates that human microglial cells are a hugely varied and heterogeneous population. Microglial heterogeneity is crucial for neurodegeneration, although at the moment it was demonstrated mainly in neurodegenerative mice models. These animal models can only partially clarify what happens in humans due to the fact that Alzheimer's disease (AD) is a proper human disease which is complex and related to both genetic and environmental factors, with a trajectory of evolution that is different and peculiar for each patient. Just think of the association recently demonstrated between imaging markers of microglial reaction and behavioral symptoms in Alzheimer's disease, which is certainly not transferable to mouse models. Thus, the role of microglia in human healthy aging and in AD presents multiple aspects, complex and interconnected.

Although there are huge differences between humans and rodents, mouse models have been very useful to shed light on the microglial role in AD. From our systematic review emerges that microglia have a fundamental role in removing phosphorylated tau protein and harmed synapses and in the phagocytosis and compaction of amyloid-β deposits. All these actions represent the protective aspects of microglia that are crucial to prevent neurodegeneration. This neuroprotective role may become less efficient with advancing age, primarily due to increased oxidative stress and mitochondrial dysfunction. Probably, the loss of efficiency of microglia and the accumulation of protein debris ends up determining a persistent mild inflammation. Therefore, in the brain areas where neurodegenerative phenomena are concentrated, possibly also associated with chronic hypoxia, a pathological context is created in which microglia lose their homeostatic role and become exhausted or dystrophic, otherwise they can become aggressive enhancing neurodegenerative phenomena and synapse loss.

Thus, microglia may contribute to the progression of AD pathology in two ways: through functional exhaustion, with less efficiency in the removal of metabolic waste, or through neurotoxic phenomena due to an excess level of inflammation. Arguably, physiological aging and the maintenance of a healthy brain depends on establishing a balance between the actions and reactions of microglia. These lines of evidence suggest that microglia play a pivotal role in the pathogenesis of AD.

Link: https://doi.org/10.3390/cells12242824

Myelin sheathes axons, the connections between neurons. This sheath is essential to nervous system function, and a range of unpleasant diseases result from loss of myelin, such as through the autoimmune activity of multiple sclerosis. Demyelination occurs to a lesser degree over the course of aging, the standard problem of a complex system becoming disarrayed as the result of various forms of molecular damage and maladaptive reactions to that damage. Here, as elsewhere, chronic inflammation appears to be a contributing cause. Calorie restriction is known to dampen chronic inflammation and favorably alter the behavior of cells such as microglia and astrocytes that might otherwise be promoting inflammatory signaling. Thus the panoply of calorie restriction mimetic drugs is also a topic of interest - though none of these recaptures more than a fraction of the effects of the actual practice of calorie restriction, more is the pity.

The dysfunction of myelinating glial cells, the oligodendrocytes, within the central nervous system (CNS) can result in the disruption of myelin, the lipid-rich multi-layered membrane structure that surrounds most vertebrate axons. This leads to axonal degeneration and motor/cognitive impairments. In response to demyelination in the CNS, the formation of new myelin sheaths occurs through the homeostatic process of remyelination, facilitated by the differentiation of newly formed oligodendrocytes. Apart from oligodendrocytes, the two other main glial cell types of the CNS, microglia and astrocytes, play a pivotal role in remyelination. Following a demyelination insult, microglia can phagocytose myelin debris, thus permitting remyelination, while the developing neuroinflammation in the demyelinated region triggers the activation of astrocytes.

Modulating the profile of glial cells can enhance the likelihood of successful remyelination. In this context, recent studies have implicated autophagy as a pivotal pathway in glial cells, playing a significant role in both their maturation and the maintenance of myelin. In this review, we examine the role of substances capable of modulating the autophagic machinery within the myelinating glial cells of the CNS. Such substances, called caloric restriction mimetics, have been shown to decelerate the aging process by mitigating age-related ailments, with their mechanisms of action intricately linked to the induction of autophagic processes.

Link: https://doi.org/10.3390/cimb45120596

Every one of our cells contains hundreds of mitochondria, the descendants of ancient symbiotic bacteria now fully integrated into our biochemistry. Mitochondria contain their own small remnant genome, the mitochondrial DNA, replicate like bacteria, and toil to produce adenosine triphosphate (ATP), a chemical energy store molecule used to power cell processes. Mitochondrial function declines with age, unfortunately, and our cells suffer for it. This contributes meaningfully to many age-related conditions. This decline appears to result in large part from changes in gene expression that impair the various quality control processes that (a) ensure mitochondrial proteins are correctly formed, and (b) that damaged mitochondria are recycled. Those changes in gene expression are maladaptive responses to other aspects of aging, perhaps in part the shift to an inflammatory environment, perhaps in part due to changes in nuclear structure resulting from cycles of double strand DNA repair, and so forth.

The search for ways to improve mitochondrial function in old age is an area of considerable focus in the aging research community and longevity industry. Partial reprogramming is perhaps the most well funded approach, but numerous efforts are being undertaken to find ways to improve mitochondrial quality control to greater degrees than can be achieved via supplements and exercise. Beyond this, a number of groups are building the infrastructure needed to manufacture large amounts of mitochondria for transplantation. This latter approach seems the most viable path if the goal is near term success; researchers have demonstrated that mitochondrial can be delivered into tissues and taken up to improve cell function. It is just a matter of being able to cost-effectively manufacture very large numbers of these organelles.

Mitochondrial Quality Control via Mitochondrial Unfolded Protein Response (mtUPR) in Ageing and Neurodegenerative Diseases

Mitochondria play a key role in cellular functions, including energy production and oxidative stress regulation. For this reason, maintaining mitochondrial homeostasis and proteostasis (homeostasis of the proteome) is essential for cellular health. Therefore, there are different mitochondrial quality control mechanisms, such as mitochondrial biogenesis, mitochondrial dynamics, mitochondrial-derived vesicles (MDVs), mitophagy, or mitochondrial unfolded protein response (mtUPR). The last item is a stress response that occurs when stress is present within mitochondria and, especially, when the accumulation of unfolded and misfolded proteins in the mitochondrial matrix surpasses the folding capacity of the mitochondrion. In response to this, molecular chaperones and proteases as well as the mitochondrial antioxidant system are activated to restore mitochondrial proteostasis and cellular function.

In disease contexts, mtUPR modulation holds therapeutic potential by mitigating mitochondrial dysfunction. In particular, in the case of neurodegenerative diseases, such as primary mitochondrial diseases, Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), Amyotrophic Lateral Sclerosis (ALS), or Friedreich's Ataxia (FA), there is a wealth of evidence demonstrating that the modulation of mtUPR helps to reduce neurodegeneration and its associated symptoms in various cellular and animal models. These findings underscore mtUPR's role as a promising therapeutic target in combating these devastating disorders.

The burden of senescent cells in tissues throughout the body increases with age, as the immune system becomes ever less capable of clearing such cells in a timely fashion. Senescent cells do not replicate, but instead devote their energies to the production of pro-growth, pro-inflammatory signaling that is disruptive to tissue structure and function when maintained for the long term. These cells actively contribute to degenerative aging in this way. Senescent cells are not just produced by reaching the Hayflick limit, or by damage of some sort. They can also become senescent in response to the signaling of other senescent cells, or via other forms of stress signaling that are far from fully understood at this time. Researchers here delve into what is know of the signaling that can produce what is known as bystander senescence.

Current data suggest that senescence is neither entirely intrinsic nor simply time-dependent. Certain soluble elements present in the systemic milieu - proteins, lipids, and reactive oxygen species (ROS) - can induce bystander senescence, but there are likely others, as yet unidentified, that are also capable of accomplishing this result, either individually or in combination. Extracellular vesicles (EVs) can induce bystander senescence, but only a few components of these vesicles that are responsible for this result are specifically known. Many of these components are microRNAs (miRNAs); however, hundreds of miRNAs have been identified, and we still have much to learn about their functions. Whether nuclear DNA or mitochondrial DNA in apoptotic bodies contributes to senescence in the healthy cells that engulf them is a tantalizingly unexplored frontier. The same is true for non-vesicular multi-component macromolecules that are known to be taken up by non-senescent cells. Our knowledge of the systemic components that provoke senescence in healthy cells remains incomplete, and the importance of this paradigm demands further investigation.

The characterization of age-altered contents - proteins, lipids, and nucleic acids - of vesicles and aggregates, as well as the identification of the senescent cells that release them and the mechanisms of their uptake, is an enormous but essential endeavor. A deeper understanding of this field will be invaluable to the development of senolytics that can prevent an organism-wide loss of health due to the propagation of senescence from a pathological tissue to healthier tissues. Notably, it is important to confirm the many in vitro studies using in vivo paradigms. In vivo studies will not only confirm the physiological relevance of senescence but also provide insights into whether senescence is induced directly by interactions between the inducing factor and the target cell or mediated indirectly by other cell types (e.g., macrophages and microglia) whose secretions may change when they are affected by the inducing factor. Moreover, it is necessary to employ multiple assays to reach reliable conclusions. When asserting that a cell is senescent, for example, this should be demonstrated by morphology, a lack of proliferation, an increase in cyclin-dependent kinase inhibitor production, senescence-assocated-β-gal, phosphorylated histone γH2AX, and a change in secretions, or a comparable set of assays appropriate to the cell type and senescence classification. Armed with such information, we should be able to develop new strategies that will inform us regarding physiological senescence, helping to ameliorate the adverse systemic effects of damaged tissues on an organism.

Link: https://doi.org/10.3390/cells12242769

Researchers here discuss the use of aptamers that can bind to advanced glycation endproducts (AGEs). This prevents the AGEs from themselves binding to the receptor for AGEs (RAGE), an interaction that provokes inflammation. A sizable presence of circulating, short-lived AGEs is characteristic of the abnormal metabolism of obesity and obesity-related conditions such as type 2 diabetes. It is an open question as to how much of a contribution to the chronic inflammation of aging is provided by AGEs in people of a normal weight, eating a basically sensible diet, however. The only way to find out is to test a therapy of this nature, in which only the contribution of AGEs is suppressed, and then observe the results.

As AGEs have been considered a promising target for therapeutic intervention in various diseases, a large number of compounds have been proposed as AGE formation inhibitors or AGE-RAGE interaction blockers. However, owing to their limited efficacy or potential adverse side effects in vivo, none of these compounds have reached clinical application. DNA aptamers are short single-stranded DNA sequences that can selectively bind to target molecules. Compared with protein antibodies, DNA aptamers have several advantages, including short generation time, low costs of manufacturing, no batch-to-batch variability, and high modifiability and thermal stability. RNA aptamers that can inhibit vascular endothelial growth factors are clinically approved for the treatment of age-related macular degeneration, and a number of aptamers have entered clinical trials, including for ocular diseases, hematologic diseases, and cancer. Recently, we have innovatively developed DNA aptamers raised against AGEs (AGE-Apts) that can inhibit the toxic effects of AGEs.

We herein evaluated the effects of AGE-Apts on muscle mass and strength in senescence-accelerated mouse prone 8 (SAMP8) mice. Eight-month-old male SAMP8 mice received subcutaneous infusion of control DNA aptamers (CTR-Apts) or AGE-Apts. Mice in an age-matched senescence-accelerated mouse resistant strain 1 (SAMR1) group were treated with CTR-Apts as controls. The soleus muscles were collected after the 8-week intervention for weight measurement and histological, RT-PCR, and immunofluorescence analyses. Grip strength was measured before and after the 8-week intervention.

AGE-Apt treatment inhibited the progressive decrease in the grip strength of SAMP8 mice. SAMP8 mice had lower soleus muscle weight and fiber size than SAMR1 mice, which was partly restored by AGE-Apt treatment. Furthermore, AGE-Apt-treated SAMP8 mice had a lower interstitial fibrosis area of the soleus muscle than CTR-Apt-treated SAMP8 mice. The soleus muscle levels of AGEs, oxidative stress, receptor for AGEs, and muscle ring-finger protein-1 were increased in the CTR-Apt-treated mice, all of which, except for AGEs, were inhibited by AGE-Apt treatment. Our present findings suggest that the subcutaneous delivery of AGE-Apts may be a novel therapeutic strategy for aging-related decrease in skeletal muscle mass and strength.

Link: https://doi.org/10.3390/biomedicines11123112

There are medical conditions that occur only in old age, and there are medical conditions, such as cancer, that can occur at any point in life, but more so in the old. Then there are grey area conditions that may occur to some greater degree in later life, or be worse in later life, but this is by no means widely appreciated. Where does the autoimmune condition of rheumatoid arthritis sit in this spectrum? Unlike cancer, it is not commonly thought of as an age-related disease, even though it is certainly affected and made worse by the processes of aging. This point is discussed in today's open access commentary and the paper to which it refers.

One of the more interesting aspects of this work is the background of poor mechanistic understanding that attends research into the treatment of rheumatoid arthritis. Despite considerable effort, it remains a poorly understood condition. The immune system is complex, and there as, as of yet, no very straightforward evidence for a specific malfunction of the immune system to trigger the condition. Available treatments take the form of quite blunt approaches to the suppression of chronic inflammatory dysfunction of the immune system, such as TNFα inhibition, and have meaningful long-term side-effects related to impairment of the necessary immune response to infection and damage.

Biological ageing: a promising target for prevention and management of rheumatoid arthritis

Researchers have used US National Health and Nutrition Examination Survey and UK Biobank to show that people with accelerated biological ageing had an increased risk of rheumatoid arthritis compared with people without accelerated biological ageing. Accelerated biological ageing particularly increased the risk among people with a high genetic predisposition for rheumatoid arthritis, suggesting a joint effect on the risk of incident disease. The life expectancy at age 45 years of people with both rheumatoid arthritis and accelerated biological ageing was 2.4-5.7 years lower than that of people with rheumatoid arthritis who did not have accelerated biological ageing. The findings support the significant effects of biological ageing on the development and progression of rheumatoid arthritis.

The pathogenesis of accelerated biological ageing in rheumatoid arthritis is complex and not fully understood. The high prevalence of comorbidities and associated polypharmacy in rheumatoid arthritis is a potential pathway by which biological ageing is accelerated and life expectancy is reduced. Besides the genetic factors associated with rheumatoid arthritis, molecular mechanisms, including epigenetic modifications and telomere attrition, are interrelated with biological ageing and thus might increase susceptibility to rheumatoid arthritis. Regarding immune ageing, T cells are particularly susceptible to ageing-related changes. Treatment with biological and targeted synthetic disease-modifying antirheumatics might be effective in restoring the functional intactness of aging T cells in rheumatoid arthritis. Since the advent of these drugs, life expectancy and quality of life have increased in patients with rheumatoid arthritis. Whether these drugs have a favourable effect on biological ageing in rheumatoid arthritis should be investigated.

Life expectancy is a key indicator reflecting the mortality associated with a disease. Diverging from previous research that primarily focused on the effects of novel treatments, this study has shifted attention to an important and potentially reversible factor: loss of life expectancy resulting from accelerated biological ageing. Notably, the authors found that the absolute loss in life expectancy attributed to ageing characteristics did not differ significantly across age groups. These results suggest that the effects of reducing or reversing accelerated biological ageing on increasing life expectancy could be similar across different age groups, highlighting the importance of management of biological ageing at every life stage. Thus, controlling biological ageing could be an effective way to enhance quality of life and extend the lifespan of people with rheumatoid arthritis, irrespective of chronological age. However, given that rheumatoid arthritis primarily affects women and the inherent sex-based differences in life expectancy and in the speeds and processes of ageing, it remains unclear whether accelerated biological ageing affects life expectancy differently for men and for women with rheumatoid arthritis. Therefore further investigation is needed.

A compelling range of evidence links greater particulate air pollution to a greater incidence of age-related disease and mortality. The primary mechanism is considered to be induction of chronic inflammation via the interaction of particulates with lung tissue. Constant, unresolved inflammatory signaling is disruptive to cell and tissue function throughout the body, accelerating the onset and progression of all of the most common disabling and ultimately fatal age-related conditions.

Growing evidence suggests that exposure to fine particulate matter (PM2.5) may reduce life expectancy; however, the causal pathways of PM2.5 exposure affecting life expectancy remain unknown. Here, we assess the causal effects of genetically predicted PM2.5 concentration on common chronic diseases and longevity using a Mendelian randomization (MR) statistical framework based on large-scale genome-wide association studies (GWAS) employing a total of more than 400,000 participants.

After adjusting for other types of air pollution and smoking, we find significant causal relationships between PM2.5 concentration and angina pectoris, hypercholesterolaemia, and hypothyroidism, but no causal relationship with longevity. Mediation analysis shows that although the association between PM2.5 concentration and longevity is not significant, PM2.5 exposure indirectly affects longevity via diastolic blood pressure (DBP), hypertension, angina pectoris, hypercholesterolaemia and Alzheimer's disease, with a mediated proportion of 31.5%, 70.9%, 2.5%, 100%, and 24.7%, respectively. Our findings indicate that public health policies to control air pollution may help improve life expectancy.

Link: https://doi.org/10.1038/s41514-023-00126-0

Life lived on a comparatively high calorie diet is both shorter and less healthy than a life lived on a comparatively lower calorie diet, so long as one still obtains all of the necessary micronutrients needed to avoid malnutrition. This is clearly the case in near all species in which the outcome of calorie restriction has been assessed. Human trials of even modest calorie restriction have demonstrated a panoply of improvements to long term health. A great deal of overfeeding and calorie restriction research is conducted in short-lived species, however, such as the study here in flies. The principle remains the same, though: it is never too late to try a lower intake of calories as a lifestyle choice intended to improve health.

Many animal studies have shown that eating less - meaning sharply restricting calories without malnutrition - lengthens lifespan. While human trials have shown evidence of beneficial effects of eating less on health, especially in healthy obese individuals, studies examining effects on lifespan have been unrealistic for humans.

Fruit flies live short and fast - the lifespan of flies raised on a high calorie diet is less than 80 days, while the longest lived on a low calorie diet can reach 120 days. In this study, researchers looked specifically at male flies. Young flies switched from a high calorie to a low-calorie diet at 20 days old lived very long lives, similar to the flies fed a low-calorie diet from day one. What surprised the researchers was that switching the flies' diet to a low calorie one remained a reliable way to extend lifespan even for old flies in ill health. The older insects raised on the high calorie diet had more lipids in their bodies, and they expended more energy defending their bodies from reactive oxygen species. They also had a higher death rate than flies raised on the low-calorie diet. But when the surviving high calorie flies were switched to a low-calorie diet at 50 or even 60 days (when most of the high calorie flies had already died) their metabolisms changed, their death rate plummeted, and their lifespans lengthened.

The team's results show that flies' metabolisms can adapt to a change in diet even in old age. Since many basic metabolic pathways in fruit flies are shared with humans, this study suggests that human metabolism may respond the same way, and individuals eating a high calorie diet could benefit from reducing their calorie intake at old age. The researchers are currently analyzing data from female fruit flies to see if there are any sex-related differences in response to diet shifting.

Link: https://today.uconn.edu/2023/12/fat-flies-live-longer-on-a-diet-at-any-age/