Fight Aging!

Adoptive cell therapies involve introducing immune cells to attack a specific issue in the body, most often cancer. The earliest forms of adoptive cell therapy used immune cells from another individual, but more modern approaches use a patient's own cells, expanded in culture and potentially engineered in various ways. Think of chimeric antigen receptor T cell (CAR-T) therapies, for example. Both T cells and natural killer (NK) cells have been employed as a basis for adoptive cell therapies targeted at cancer.

In today's open access paper, researchers consider another potential use for adoptive NK cell therapy, as a way to produce lasting clearance of senescent cells in aged tissues. It is clear that NK cells, along with several other immune cell types, are involved in the normal processes of destruction of senescent cells as they show up in the body. Unfortunately, this immune mediated clearance of senescent cells slows down with advancing age, allowing the build up of lingering senescent cells throughout the body. Senescent cells produce signaling that is useful under various circumstances, such as suppression of potentially cancerous damage and coordination in wound healing, but when sustained for the long term becomes highly disruptive to tissue structure and function.

Researchers have already demonstrated that CAR-T therapies can be adapted to target senescent cells. It is plausible that NK cell therapies can also serve this purpose. The question is whether the cost is worth it, when other forms of senolytic therapy that are capable of training the immune system to more aggressively attack senescent cells, including the Deciduous Therapeutics approach, are far cheaper. The primary issue with adoptive cell therapies at the present time is their high cost, an unavoidable outcome of any therapy that requires weeks or months of effort to grow, engineer, and quality control large numbers of cells from a patient sample. That doesn't compete well with the need to treat every older individual on some intermittent, recurring basis.

Adoptive NK cell therapy: a potential revolutionary approach in longevity therapeutics

As the global population ages, the prevalence of associated diseases becomes increasingly apparent. The pursuit of healthy aging, characterized by heightened resistance to lethal diseases, is the cornerstone of preventive medicine. The aging process is a complex process involving cellular senescence and inflammation, with the immune system playing a pivotal role in managing these aspects. Timely clearance of senescent cells (SNCs) is central to maintaining tissue and organismal homeostasis. Unfortunately, immunosenescence, a progressively dysregulated immune state with age, fails to eliminate SNCs, leading to their accumulation. This often coincides with the release of senescence-associated secretory phenotypes (SASPs), inhibiting immunity and increasing vulnerability to aging-associated diseases (AADs).

Consequently, targeting immunosenescence and SNCs emerges as a crucial therapeutic strategy to preserve and extend healthy aging. While adaptive immunity has traditionally taken center stage in immunogerontological studies, growing evidence underscores the substantial impact of innate immunity in AADs. Natural killer (NK) cells, integral to the innate immune system, uniquely identify and eliminate aberrant cells such as tumor cells and virus-infected cells. Moreover, NK cells promptly address SNCs, and coordinate with other immune components through cytokine and chemokine production to surveil and eliminate cancer cells. Although whether the same occurs against SNCs remains to be determined.

Evidence from healthy elderly individuals, especially those exhibiting physical fitness, independence in daily activities, or adequate cognitive function, the number and function of NK cells are highly preserved. Conversely, diminished NK cell activity in elderly individuals is associated with disorders such as atherosclerosis and an elevated risk of mortality. Accordingly, preserving NK cell function during aging is deemed crucial for healthy aging and longevity. Alternatively, NK-cell-based therapies, notably adoptive NK cell therapy, aligning with their established role in cancer and viral infection treatments, show promise in rejuvenating immunosenescence, eliminating SNCs and alleviating SASPs, that lead to AADs.

The practice of calorie restriction, reducing calorie intake by up to 40% while still obtaining a sufficient level of micronutrients necessary to good health, is well demonstrated to slow aging. It slows near all aspects of aging and progression of near all age-related conditions, and so the literature is packed with papers that investigate just one of those line items. Here, the focus is on loss of bone mineral density with age, a phenomenon that leads to osteoporosis and eventual fracture and incapacity. This is one of the few age-related conditions for which there is some debate over whether moderate or greater calorie restriction is a net benefit, based on apparently contradictory animal data. My impression of the literature, reinforced here, is that the weight of evidence leans towards calorie restriction as a benefit in this matter.

Caloric restriction (CR) is a nutritional intervention that increases life expectancy while lowering the risk for cardiometabolic disease. Its effects on bone health, however, remain controversial. For instance, CR has been linked to increased accumulation of bone marrow adipose tissue (BMAT) in long bones, a process thought to elicit detrimental effects on bone. Qualitative differences have been reported in BMAT in relation to its specific anatomical localization, subdividing it into physiological and potentially pathological BMAT. We here examine the local impact of CR on bone composition, microstructure, and its endocrine profile in the context of aging.

Young and aged male C57Bl6/J mice were subjected to CR for 8 weeks and compared to age-matched littermates with free food access. CR increased tibial BMAT accumulation and adipogenic gene expression. CR also resulted in elevated fatty acid desaturation in the proximal and mid-shaft regions of the tibia, thus more closely resembling the biochemical lipid profile of the distally located, physiological BMAT. In aged mice, CR attenuated trabecular bone loss, suggesting that CR may revert some aspects of age-related bone dysfunction. Cortical bone, however, was decreased in young mice on CR and remained reduced in aged mice, irrespective of dietary intervention. No negative effects of CR on bone regeneration were evident in either young or aged mice.

Our findings indicate that the timing of CR is critical and may exert detrimental effects on bone biology if administered during a phase of active skeletal growth. Conversely, CR exerts positive effects on trabecular bone structure in the context of aging, which occurs despite substantial accumulation of BMAT. These data suggest that the endocrine profile of BMAT, rather than its fatty acid composition, contributes to healthy bone maintenance in aged mice.

Link: https://doi.org/10.3389/fendo.2024.1394263

The measurement of life span is self-evident and obvious, but is little consensus on how to measure healthspan, the length of life spent in good health. Good health is like art, we know it when we see it, but that isn't helpful when trying to compare the effects of interventions where the studies were conducted by different researchers with different ideas as what constitutes good health in an older individual. This issue exists for both human and animal studies, and the lack of consistency makes it hard to make comparisons based on the existing literature on the topic. Researchers are starting to propose rigorous definitions of healthspan, but it seems that we stand some distance removed from any great agreement as to which of these definitions is the one to adopt as a standard.

Unlike lifespan, which has a universal definition, there is no consensus on the definition of healthspan. Previous research has suggested characterizing healthy aging in five domains: physical capability, cognitive function, physiological and musculoskeletal, endocrine, and immune functions. For practical purposes, healthspan typically refers to the period of life spent in good health, free from the chronic diseases and disabilities of aging. Studies aiming to evaluate the effects of interventions on healthspan are challenging due to the need for long follow-up lengths and large sample sizes of healthy individuals to observe the outcomes of interest. Thus, developing surrogate biomarkers that can predict healthspan is crucial for improving the feasibility of clinical trials to test interventions to prolong healthspan and lifespan.

Composite biomarkers incorporating multiple measures are more robust in predicting age-related outcomes than single biomarkers. Several composite biomarkers for predicting lifespan or mortality have been developed using clinical biomarkers or omics data. However, to date, no composite biomarker measures have been developed based on a healthspan definition. To mitigate this gap, we developed a proteomics-based healthspan biomarker (healthspan proteomic score, HPS) using chronological age and expression data of 2,920 proteins at the UK Biobank baseline/recruitment (2006-2010).

A lower HPS was associated with higher mortality risk and several age-related conditions, such as COPD, diabetes, heart failure, cancer, myocardial infarction, dementia, and stroke. HPS showed superior predictive accuracy for these outcomes compared to chronological age and biological age measures. Proteins associated with HPS were enriched in hallmark pathways such as immune response, inflammation, cellular signaling, and metabolic regulation. Our findings demonstrate the validity of HPS, making it a valuable tool for assessing healthspan and as a potential surrogate marker in geroscience-guided studies.

Link: https://doi.org/10.1101/2024.06.26.24309530

What are the biological mechanisms by which centenarians manage to reach 100 years of age or more, significantly outliving near all of their birth cohort peers? This is a question that receives a great deal of interest in the research community and among the public at large. The answer that aging is a stochastic process of damage accumulation that produces a distribution of outcomes, and that some people are lucky, is not very satisfying. So a sizable amount of funding is directed towards analysis of factors that might robustly contribution to the longevity of centenarians: cultural transmission of good practices in long-lived families, longevity-promoting genetic variants, and the topic for today, longevity-promoting variations in the composition of the gut microbiome.

Amidst all of this, it is perhaps worth considering whether finding out why centenarians are so long-lived is actually worth all of the effort. Centenarians are frail, a shadow of their younger selves, and exhibit a sizable mortality rate. Is this really a desirable state to aim for? The research community has a very good list of the causative processes of degenerative aging, the forms of molecular damage that accumulate in aged bodies to produce dysfunction. It requires exactly zero further knowledge of centenarian biochemistry to be able put a great deal of effort into the development of potential rejuvenation therapies that are capable of repairing this damage. The end result of successful, comprehensive rejuvenation via damage repair will not be people who are as damaged and frail as today's centenarians.

Gut microbiota in centenarians: A potential metabolic and aging regulator in the study of extreme longevity

Diverse factors have been associated with healthy or unhealthy aging such as demographic factors; prosociality level, physical and organic health status, mental health, lifestyle factors, and genetics. This converges in the concept of biological aging (BA), defined as the set of processes that cause organ deterioration over time. BA depends on the complex interaction of these factors, which can lead to a heterogeneous aging process across multiple organic systems, and correlate with a specific survival time and health or disease phenotype even in advanced ages. To deeply understand the mechanisms associated with aging and to identify potential targets for intervention to control or delay BA and the onset of diseases, it is necessary to study successful BA models. These models reflect phenotypes that are resistant to external stress factors with a favorable organic response. Centenarians, individuals with a chronological age (CA; defined as the number of years an individual has lived) equal to or greater than 100 years, constitute one such model of successful aging.

Currently, there is a significant knowledge gap from the translational perspective due to the evolutionary and exhaustive nature of aging research, which requires robust and reproducible omics studies on populations (specially in centenarians). These studies would aid in understanding precisely how modifiable and nonmodifiable factors impact the organic evolution of centenarians. Cellular senescence, epigenetic clocks, and alterations in stem cells, are some of the cellular and molecular processes that could theoretically reflect cellular proteodynamics, adaptation to aging, and the development of health phenotypes and prognosis during longevity. Having specific data on these mechanisms could facilitate the identification of aging biomarkers for cells, tissues, organs, or diseases, and predict the onset of age-related chronic diseases. However, there are not enough, studies to corroborate these hypotheses based on centenarians as a model of successful aging. Therefore, evidence regarding possible interventions to delay aging and prevent the onset of age-related chronic diseases into extreme ages remains weak and speculative.

The gut microbiota (GM) has been described as a biological and metabolic regulator of various organs and diseases. Age and diet, determinants in aging, are two factors directly related to the establishment and modification of the composition of the GM. To date, little discussion has taken place regarding the specific changes that occur in the long-lived population, which allow the establishment of an antioxidant system with characteristics similar to those of a young population, as a result of successful evolutionary adaptation. Although the specific mechanisms are unknown, this may possibly be one of the strongest reasons influencing life expectancy and healthy lifespan during aging.

To understand the possible impact generated by the GM, its changes, and the probable causes for successful aging, the aim of this review was to synthesize evidence on the role of the GM as a potential protective factor for achieving extreme longevity, using its relationship with centenarians. Evidence suggests that there are significant changes in the composition of the GM of centenarians, compared to other age groups, which could be associated with specific phenotypes of healthy aging, and be determinants in extreme longevity. However, numerous factors condition the establishment of the GM over time. The origin of the data is limited to certain countries with some blue zones. This field should be extensively studied in regions lacking data and determine the possible specific causal association between genera and species of microorganisms, and extreme longevity.

Researchers here describe an injected immunomodulatory peptide that reduces migration of adaptive immune cells in response to inflammatory signaling. They mount the argument that excessive immune cell migration is a sizable part of the problem in the chronic inflammation of aging, and arises due to age-related changes in immune cell behavior. Delivering the peptide is intended to restore a more youthful regulation of this immune cell behavior.

Growing evidence suggests that the ageing process significantly impacts leukocyte trafficking dynamics during inflammation, thereby compromising protective immunity. We have previously reported that ageing increases homeostatic leukocyte trafficking to the peritoneal cavity in mice through pro-inflammatory mediators and enhanced vascular permeability. Whilst ageing increases neutrophil and monocyte trafficking in response to peritonitis, patterns of lymphocyte trafficking are still unknown in this model.

Here, we investigated how ageing changes leukocyte trafficking dynamics and the impact of a novel immunopeptide (PEPITEM) has on this using an inflammation model of zymosan-induced peritonitis in young (3-month) and aged (21-month) male mice. Zymosan-induced peritonitis typically represents a simplified model of the disease, focusing primarily on the early inflammatory events. It may not adequately capture the later stages of human peritonitis development, including tissue damage and organ dysfunction. Nonetheless, it remains a highly reproducible and robust model, characterised by significant recruitment of various immune cells.

We previously identified PEPITEM as a key regulator of leukocyte trafficking. Indeed, through action of adiponectin on its receptors (AdipoR1 and AdipoR2) on B-cells, PEPITEM is released to then stimulate endothelial production of spingosine-1-phosphate (S1P). S1P will in turn inhibit leukocyte trafficking through modulation on integrin signalling. We analysed whether intraperitoneal injection of PEPITEM could modulate leukocyte migration in older mice. We observed a loss of functionality in the PEPITEM pathway, which normally controls leukocyte trafficking in response to inflammation, in older adults and aged mice and show that this can be rescued by supplementation with PEPITEM. Thus, leading to the exciting possibility that PEPITEM supplementation may represent a potential pre-habilitation geroprotective agent to rejuvenate immune functions.

Link: https://doi.org/10.1038/s41514-024-00160-6

The aging brain malfunctions in complex ways, giving rise to a range of poorly categorized end states beyond the most prevalent, well known neurodegenerative conditions. As an example of research in this part of the field, scientists here discuss a form of age-related memory loss that they call limbic-predominant amnestic neurodegenerative syndrome. Interestingly, this condition appears to be associated with TDP-43 pathology, a comparatively recently discovered form of harmful protein aggregation in the aging brain that is now known to contribute to some forms of neurodegeneration.

Researchers have established new criteria for a memory-loss syndrome in older adults that specifically impacts the brain's limbic system. It can often be mistaken for Alzheimer's disease. Limbic-predominant Amnestic Neurodegenerative Syndrome, or LANS, progresses more slowly and has a better prognosis. Prior to the researchers developing clinical criteria the hallmarks of the syndrome could be confirmed only by examining brain tissue after a person's death. The proposed criteria provide a framework for neurologists and other experts to classify the condition in patients living with symptoms, offering a more precise diagnosis and potential treatments. They consider factors such as age, severity of memory impairment, brain scans, and biomarkers indicating the deposits of specific proteins in the brain.

"Historically, you might see someone in their 80s with memory problems and think they may have Alzheimer's disease, and that is often how it's being thought of today. With this paper, we are describing a different syndrome that happens much later in life. Often, the symptoms are restricted to memory and will not progress to impact other cognitive domains." Without signs of Alzheimer's disease, the researchers looked at the involvement of one possible culprit - a buildup of a protein called TDP-43 in the limbic system that scientists have found in the autopsied brain tissue of older adults. Researchers have classified the build-up of these protein deposits as limbic-predominant age-related TDP-43 encephalopathy, or LATE. These protein deposits could be associated with the newly defined memory loss syndrome, but there are also other likely causes and more research is needed.

Link: https://newsnetwork.mayoclinic.org/discussion/mayo-clinic-scientists-define-new-type-of-memory-loss-in-older-adults/

Senescent cells accumulate with age throughout the body. Cellular senescence occurs most often at the end of a cell's replicative life span, but can also be provoked by damage, a toxic environment, or the signaling of other nearby senescent cells. Senescent cells are metabolically active and secrete a potent mix of pro-inflammatory, pro-growth signals. This state has a number of useful functions, such as coordination of wound healing and elimination of potentially cancerous cells. In youth senescent cells are promptly destroyed by the immune system or programmed cell death processes, but with age this clearance becomes impaired. The signaling of senescent cells, useful in the short term, becomes disruptive to tissue function and structure when sustained over the long term by a growing population of lingering senescent cells.

While much of the research and development of anti-senescence therapies involves the production of senolytic treatments that can selectively destroy these cells, there is some interest in trying to find ways to suppress the harmful signaling of of senescent cells instead. This seems likely to be more challenging and less effective as a strategy, as the regulation of the senescent state is complex, and any one intervention is likely to only affect a modest fraction of the whole. Nonetheless, see today's open access paper as an interesting example of the research taking place into means to reduce senescent cell signaling. Unlike most such research at the present stage of development, the authors did actually test their work in mice, and demonstrated a small extension in life span to result from their approach to suppression of senescent cell signaling.

PKM2 aggregation drives metabolism reprograming during aging process

Aging is a progressive process characterized by the systemic deterioration of organs and tissues, often culminating in chronic diseases such as diabetes, cancer, cardiovascular disorders, and neurodegenerative diseases. In recent years, the disruption of proteostasis has emerged as a well-recognized hallmark of aging. It is principally guarded by the chaperone-mediated folding system and degradation pathways involving lysosomes or proteasome. Dysfunction in either of these systems can precipitate the accumulation of aberrant protein aggregates within cells, thereby contributing to the onset and progression of aging-related pathologies.

In this study, we conducted an analysis of lysosomal proteomics from young and senescent cells, leading us to uncover the role of Pyruvate Kinase M2 (PKM2) aggregates in the aging process. In senescent cells, PKM2 tends to aggregate along with other glycolytic enzymes, such as Glyceraldehyde-3-phosphate dehydrogenase (GAPDH), α-Enolase (ENO1), and others. Furthermore, we found that PKM2 aggregation accompany with impairment of PKM2 enzymatic activity and glycolytic flux in senescent cells, exacerbating senescent phenotypes.

To identify compounds capable of dissolving PKM2 aggregates and alleviating senescence, we conducted a series of screenings. K35 and its analog K27 were identified as compounds capable of inhibiting the formation of PKM2 aggregates. Treatment with K35 or K27 restored PKM2 enzymatic activity and glycolytic flux. Further studies demonstrated that K35 or K27 not only alleviated cellular senescence but also extended the lifespan of both naturally and prematurely aged mice.

Mitochondria are the power plants of the cell, their production of the chemical energy store molecule adenosine triphosphate (ATP) essential to cell function. With advancing age mitochondria become dysfunctional for reasons that in part involve damage to mitochondrial DNA and in part involve changes in gene expression that harm mitochondrial structure and the quality control processes of mitophagy. Mitochondrial dysfunction places stress on cells in a number of ways, from loss of ATP production to increased generation of oxidative molecules. What might be fixed if mitochondria could be restored to a more youthful state of function, and how might that goal be achieved? Researchers here look at these questions in the context of the aging of the ovaries.

Ovarian aging is a complex process characterized by a gradual decline in both the quantity and quality of oocytes. This age-related decline in ovarian function not only results in reduced fertility and an increased risk of pregnancy complications but also significantly impacts critical elements like hormonal balance, bone health, cardiovascular well-being, and cognitive function.

Mitochondria assume a fundamental role in energy generation through oxidative phosphorylation. Considering that the oocyte is the body's most mitochondria-rich cell, these organelles bear significant responsibility in fostering its development, promoting follicular growth, and orchestrating hormone regulation - all crucial factors in ensuring successful reproduction. While several other factors, such as vascular network defects, hormonal dysregulation, genetic and epigenetic alterations, and environmental and lifestyle influences, have been identified as contributing to the aging of the ovary, mitochondrial dysfunction appears to be a more central and significant driver of this process. Moreover, preserving mitochondrial function not only holds promise for enhancing reproductive outcomes but also for delaying aging in women. Exploring therapeutic strategies targeted at maintaining mitochondrial health could offer significant opportunities for addressing age-related fertility decline and promoting reproductive and overall well-being in women.

In this review, we focus on the intricate interplay between mitochondrial function and ovarian aging, and the mechanisms through which mitochondrial health affects oocyte and ovarian follicle quality, and how it contributes to age-related fertility decline. Furthermore, we explore potential therapeutic strategies aimed at preserving mitochondrial function to enhance reproductive outcomes for women as they age.

Link: https://doi.org/10.3389/fendo.2024.1417007

Here find a SENS Research Foundation article covering some of the specifics of progress towards messenger RNA (mRNA) therapies capable of breaking down harmful age-related intracellular protein aggregates, with a focus on those involved in neurodegenerative conditions. Delivery of synthetic mRNA into cells by lipid nanoparticle is an active area of gene therapy development. Once inside cells, mRNA molecules are processed by ribosomes to produce proteins for a short period of time. A range of biochemical problems in the cells of aged tissues can only be solved by expressing suitable proteins inside those cells, such as clearance of protein aggregates. This sort of repair task is well suited to mRNA gene therapies that produce only short-term expression of therapeutic proteins. When damage accumulates slowly, only intermittent and short periods of treatment are needed.

Rejuvenation biotechnologies targeting aberrant tau are in development, ranging from the earliest cell studies all the way up to Phase III clinical trials. In part, this ambition to clear out tau started off as a hedge against the unfounded skepticism about the role of beta-amyloid in Alzheimer's disease. Although biotech companies were forced to abandon many of their first attempts to target tau (often because they interfered with the physiological function of the healthy, non-aggregated tau protein), clinical trials are presently testing numerous therapies targeting tau. Most of these potential therapies are in Phase II.

An important limitation of these candidate therapies is that most of them only clear tau aggregates located outside of cells - in the spaces where neurons interact with one another or in the wider fluid that bathes the brain. Such therapies should do some good, most notably by slowing down the rate at which "seeds" of aberrant tau "infect" other neurons in their network. But they would do nothing to clear existing aberrant tau in the location where those seeds form and where they inflict most of their harm: inside of neurons.

In recent years, scientists began targeting tau inside neurons using functional fragments of antibodies with key subunits that target different segments of the tau protein. When they treated animals that carry forms of mutated human tau that aggregate and drive neurodegenerative disease in humans, these antibody fragments lowered the burden of soluble aberrant tau in these animals' brains - and the effect was almost entirely the result of clearing it from inside the neurons. Scientists then pitted different tau-targeting antibody fragments against each other, and also against the same fragments after further modifying them to turn them into intrabodies. Intrabodies are antibody fragments that have been engineered to remain within and function inside cells, sometimes including targeting them to specific locations within the cell.

But how would we deliver these intrabodies to aging humans? Researchers have seized on the recent revolution of mRNA technology. Researchers realized that they could use mRNA to deliver the instructions for tau-targeting intrabodies into neurons. The cells would then produce free, active antibodies inside of themselves from scratch, avoiding the entire fraught journey required for conventional antibody infusions to reach and become active in the cell without requiring gene therapy. This research is promising, but is still in a very preliminary stage. While the potential of an mRNA vaccine against aberrant tau is exciting, hurdles remain to be overcome.

Link: https://www.sens.org/get-the-message-mrna-to-target-intracellular-aggregates/

Atherosclerosis is the development of fatty plaques in blood vessel walls. It is a universal condition of aging, present to some degree in every older individual. Atherosclerosis contributes to many age-related diseases via narrowing of vessels and reduced blood flow on the one hand, and on the other causing more than a quarter of all human mortality via the stroke and heart attack that can follow rupture of an unstable plaque. We might think of atherosclerosis as a condition of macrophage dysfunction. Macrophages are innate immune cells responsible for clearing excess cholesterol from blood vessel walls. These cells ingest cholesterol and the LDL particles that transport cholesterol from the liver to the rest of the body. Then then hand off that cholesterol to HDL particles for transport back to the liver.

Considered at a high level, and skipping some of the complexities, atherosclerotic plaque develops when the influx of LDL-cholesterol exceeds the capacity of macrophages to clean it up. The research community is near entirely focused on the LDL-cholesterol side of the question, but as a result of decades of such work has now comprehensively demonstrated that even dramatic reductions in circulating LDL-cholesterol only modestly reduce the risk of heart attack and stroke, and cannot reliably or sizeably reverse established atherosclerotic plaque. It is past time to focus on the other side of the equation, the capacity of macrophages to remove cholesterol from blood vessel walls, and even survive and continue this work in the hostile environment of an established plaque in order to reduce its size. Today's open access paper is an example of this sort of work, the search for proximate causes of macrophage dysfunction in the context of atherosclerosis that may form a basis for later drug development.

Mitochondrial dysfunction and metabolic reprogramming induce macrophage pro-inflammatory phenotype switch and atherosclerosis progression in aging

Immune cells, including the circulating monocytes that will transform into macrophages, are recruited to the vascular wall in atherogenesis and play a critical role in sustaining oxidative stress, inflammation, and extracellular matrix degradation. Atherosclerotic lesion macrophages can maintain several phenotypes, including classically activated (M1 or M[IFNγ+LPS]) pro-inflammatory macrophages and alternatively activated (M2 or M[IL4]) pro-resolving macrophages. Macrophage metabolic reprogramming, with pro-inflammatory cells relying on glycolysis and pro-resolving cells on oxidative phosphorylation for energy production, is closely related to the changes in atherosclerotic plaque environment and morphology. Nevertheless, the mechanisms of metabolic reprogramming of macrophages in atherosclerosis and its effects on plaque morphology are incompletely understood.

Mitochondrial dysfunction in macrophages in aging results in reduced ATP production, elevated reactive oxygen species (ROS) generation, and compromised mitochondrial quality control, features that are intricately linked to the shift in metabolism from oxidative phosphorylation to glycolysis and pro-inflammatory phenotype. Consequently, aging-associated atherosclerotic plaque mitochondrial oxidative stress and dysfunction result in increased lesion volume and vulnerable plaque features. Expression of mitochondria-localized NOX4 NADPH oxidase is increased with age in human and mouse vasculature and is associated with increased oxidative stress, vascular inflammation, aortic stiffness, and atherosclerotic lesion size and severity. Similarly, increased NOX4 expression in atherosclerotic plaque was associated with plaque instability and rupture, while direct inhibition, genetic downregulation of NOX4, or blockade of NOX4-dependent signaling pathways inhibited atherogenesis. In human coronary atherosclerotic lesions increased NOX4 expression was observed in nonphagocytic vascular cells, contributing to increased ROS levels, while increased NOX4-derived ROS in human monocytes was associated with higher metabolic priming, vascular recruitment, and atherosclerosis progression.

Targeting NOX4-dependent mitochondrial ROS holds promise in atherosclerosis management. However, the precise mechanisms of mitochondrial dysfunction in aging-associated atherosclerosis, its impact on plaque progression and phenotype, and therapeutic potential are not fully elucidated. Here, we tested the hypothesis that mitochondrial oxidative stress associated with increased NOX4 levels in aging results in metabolic priming in monocytes/macrophages to a pro-inflammatory phenotype switch, fostering atherosclerotic lesion progression. We used Apoe-/- mice as they have high cholesterol levels when fed a Western diet, leading to human-like atherosclerosis progression with similar lesion cellular composition, a prominent inflammatory profile, and aging-related phenotype useful for aging studies. Effects of aging were examined in 16-month-old mice, which represent the age equivalent of humans with exponentially increasing coronary heart disease incidence, making them a useful model to study the pathogenesis of atherosclerosis. Using aged Nox4-deficient Apoe-/- mice, mice we showed that reduced mitochondrial ROS in macrophages preserves mitochondrial function and is associated with pro-resolving phenotype attenuating atherosclerotic disease. We recapitulated our findings by inhibiting NOX4 activity in aged Apoe-/- mice.

Our findings suggest that increased NOX4 in aging drives macrophage mitochondrial dysfunction, glycolytic metabolic switch, and pro-inflammatory phenotype, advancing atherosclerosis. Inhibiting NOX4 or mitochondrial dysfunction could alleviate vascular inflammation and atherosclerosis, preserving plaque integrity.

At present, researchers consider there to be a bidirectional relationship between aging of the gut microbiome and aging of the immune system. The immune system gardens the microbial populations of the gut to minimize the number of problematic microbes, but growth in number of those inflammatory, disruptive microbes can contribute to loss of immune function. As is the case for many processes in aging, interactions between systems are as important as problems that occur within systems. Improving late life immune function should improve the gut microbiome. Conversely, restoring a more youthful balance of microbial populations in the gut microbiome should improve late life immune function.

The gut microbiome has come to prominence across research disciplines, due to its influence on major biological systems within humans. Recently, a relationship between the gut microbiome and hematopoietic system has been identified and coined the gut-bone marrow axis. It is well established that the hematopoietic system and gut microbiome separately alter with age; however, the relationship between these changes and how these systems influence each other demands investigation.

Since the hematopoietic system produces immune cells that help govern commensal bacteria, it is important to identify how the microbiome interacts with hematopoietic stem cells (HSCs). The gut microbiota has been shown to influence the development and outcomes of hematologic disorders, suggesting dysbiosis may influence the maintenance of HSCs with age. Short chain fatty acids (SCFAs), lactate, iron availability, tryptophan metabolites, bacterial extracellular vesicles, microbe associated molecular patterns (MAMPs), and toll-like receptor (TLR) signalling have been proposed as key mediators of communication across the gut-bone marrow axis and will be reviewed in this article within the context of aging.

Link: https://doi.org/10.1016/j.heliyon.2024.e32831

Senescent cells accumulate with age to secrete disruptive inflammatory signaling. Clearing even as few as a third of these cells in some tissues using senolytic therapies has proven to be very beneficial in mice. Senescent cells are not as uniform in their biochemistry as once thought, however, and a primary focus in the development of second generation senolytic therapies is to categorize different types of senescent cells and understand their meaningful differences. For future senolytic therapies, this will allow greater selectivity regarding which senescent cells to clear, but also the ability to remove more senescent cells from more tissue types.

Cellular senescence has been strongly linked to aging and age-related diseases. It is well established that the phenotype of senescent cells is highly heterogeneous and influenced by their cell type and senescence-inducing stimulus. Recent single-cell RNA-sequencing studies identified heterogeneity within senescent cell populations. However, proof of functional differences between such subpopulations is lacking. To identify functionally distinct senescent cell subpopulations, we employed high-content image analysis to measure senescence marker expression in primary human endothelial cells and fibroblasts.

We found that senescent cells arrested in the G2 phase of the cell cycle feature higher senescence marker expression than G1-arrested senescent cells. To investigate functional differences, we compared IL-6 secretion and response to ABT263 senolytic treatment in G1 and G2 senescent cells. We determined that G2-arrested senescent cells secrete more IL-6 and are more sensitive to ABT263 than G1-arrested cells. We hypothesize that cell cycle dependent DNA content is a key contributor to the heterogeneity within senescent cell populations. This study demonstrates the existence of functionally distinct senescent subpopulations even in culture. This data provides the first evidence of selective cell response to senolytic treatment among senescent cell subpopulations. Overall, this study emphasizes the importance of considering the senescent cell heterogeneity in the development of future senolytic therapies.

Link: https://doi.org/10.1101/2024.06.22.600200

The blood-brain barrier is a specialized layer of cells surrounding blood vessels that pass through the central nervous system. It serves to separate the metabolism of the brain from the metabolism of the rest of the body by permitting passage of only certain molecules and cells to and from the brain. It is a complex system, and like all complex systems in biology, it falls apart with advancing age. This manifests as leakage, allowing inappropriate cells and molecules into the brain where they can provoke inflammation and other downstream issues. A growing consensus in the research community places blood-brain barrier dysfunction as an early contributing cause of neurodegenerative conditions and loss of cognitive function.

There is a weight of evidence in favor of the view presented above, obtained from a great many databases of human epidemiological data, as well as animal studies in which blood-brain barrier leakage is assessed. In today's open access paper the authors report on a human study that was set up to generate confirming data for the connection between blood-brain barrier dysfunction and cognitive decline. The results fall into line with other data indicating the importance of blood-brain barrier dysfunction in neurodegeneration.

Blood-Brain Barrier Permeability Is Associated With Cognitive Functioning in Normal Aging and Neurodegenerative Diseases

Vascular risk factors, such as hypertension, high cholesterol, diabetes, and obstructive sleep apnea, have a well-established link to cerebrovascular pathology and accelerated cognitive decline. Vascular risk factors have been hypothesized to cause cerebrovascular disease via chronic hypoperfusion, which leads to a cascade of events that includes blood vessel injury (eg, fibrosis, hyalinosis), hypoxia, and ischemia. These mechanisms cause inflammation that disrupts the blood-brain barrier (BBB), resulting in white matter damage.

Some theories suggest that BBB permeability manifests earlier than structural brain changes and therefore may serve as an early marker of emerging neuropathological processes and cognitive dysfunction. This is supported in rodent models, in which BBB dysfunction has been linked to inflammation and precedes neuropathological processes, including neurodegeneration and cognitive decline and accumulation of β-amyloid, a protein associated with Alzheimer's disease (AD). Ultimately, cognitive dysfunction is a common end point of neurodegeneration that clinically manifests as a neurocognitive disorder. However, few studies have examined theoretical models of the involvement of BBB permeability in the cascade of events leading to neurocognitive impairment, including the relationships between vascular risk factors, BBB permeability, and cognitive dysfunction.

The purpose of this study was to investigate the relationship between blood-brain barrier (BBB) permeability and cognitive functioning in healthy older adults and individuals with neurodegenerative diseases. A total of 124 participants with Alzheimer disease, cerebrovascular disease, or a mix of Alzheimer's and cerebrovascular diseases, and 55 control participants underwent magnetic resonance imaging and neuropsychological testing. BBB permeability was measured with dynamic contrast-enhanced magnetic resonance imaging and white matter injury was measured using a quantitative diffusion-tensor imaging marker of white matter injury. Structural equation modeling was used to examine the relationships between BBB permeability, vascular risk burden, white matter injury, and cognitive functioning.

Vascular risk burden predicted BBB permeability and white matter injury. BBB permeability predicted increased white matter injury and increased white matter injury predicted lower cognitive functioning. The study provides empirical support for a vascular contribution to white matter injury and cognitive impairment, directly or indirectly via BBB permeability. This highlights the importance of targeting modifiable vascular risk factors to help mitigate future cognitive decline.

Long term memories must be maintained by retrieval and update of their storage. Researchers here demonstrate that pharmacological inhibition of HDAC3 reduces issues with maintenance of memories in old mice. Interestingly the strategy is disruptive to initial memory formation in young mice, and this provides some additional insight into how this mechanisms of neurological aging functions. Understanding a great deal more of the fine detail regarding the functioning of mammalian memory will likely prove necessary to make large strides towards addressing this aspect of brain aging.

Long-term memories are not stored in a stable state but must be flexible and dynamic to maintain relevance in response to new information. Existing memories are thought to be updated through the process of reconsolidation, in which memory retrieval initiates destabilization and updating to incorporate new information. Memory updating is impaired in old age, yet little is known about the mechanisms that go awry.

One potential mechanism is the repressive histone deacetylase 3 (HDAC3), which is a powerful negative regulator of memory formation that contributes to age-related impairments in memory formation. Here, we tested whether HDAC3 also contributes to age-related impairments in memory updating using the Objects in Updated Locations (OUL) paradigm. We show that blocking HDAC3 immediately after updating with the pharmacological inhibitor RGFP966 ameliorated age-related impairments in memory updating in 18-month-old male mice. Surprisingly, we found that post-update HDAC3 inhibition in young (3-month-old) male mice had no effect on memory updating but instead impaired memory for the original information, suggesting that the original and updated information may compete for expression at test and HDAC3 helps regulate which information is expressed.

To test this idea, we next assessed whether HDAC3 inhibition would improve memory updating in young male mice given a weak, subthreshold update. Consistent with our hypothesis, we found that HDAC3 blockade strengthened the subthreshold update without impairing memory for the original information, enabling balanced expression of the original and updated information. Together, this research suggests that HDAC3 may contribute to age-related impairments in memory updating and may regulate the strength of a memory update in young mice, shifting the balance between the original and updated information at test.

Link: https://doi.org/10.3389/fnmol.2024.1429880

This open access paper represents a great deal of scientific work. Researchers analyzed transcriptomics from all of the successful Interventions Testing Program (ITP) mouse studies, a very large number of mice, in multiple tissues, to produce clocks for aging and mortality. They then pulled in single cell transcriptomics and human data to validate the clocks for broader use, and assessed the utility of these clocks in states of progeria and rejuvenation via reprogramming. The next decade is going to see the data associated with clock-like measures of biological age expand enormously. We might hope to also see meaningful progress toward connecting specific clock components with the underlying mechanisms of aging - this is much needed in order to be able to use aging clocks to speed up the assessment of potential rejuvenation therapies.

The development of mortality transcriptomic clocks based on gene expression profiles and their functional components across organs and mammalian species could reveal universal and specific molecular mechanisms of the established and novel models of healthspan regulation, rejuvenation and aging. Here, we conducted an RNA-seq analysis of mice subjected to 20 compound treatments in the Interventions Testing Program (ITP). By integrating it with the data from over 4,000 rodent tissues representing aging and responses to genetic, pharmacological, and dietary interventions with established survival data, we developed robust multi-tissue transcriptomic biomarkers of mortality, capable of quantifying aging and change in lifespan in both short-lived and long-lived models.

These tools were further extended to single-cell and human data, demonstrating common mechanisms of molecular aging across cell types and species. Via a network analysis, we identified and annotated 26 co-regulated modules of aging and longevity across tissues, and developed interpretable module-specific clocks that capture aging- and mortality-associated phenotypes of functional components, including, among others, inflammatory response, mitochondrial function, lipid metabolism, and extracellular matrix organization. These tools captured and characterized acceleration of biological age induced by progeria models and chronic diseases in rodents and humans. They also revealed rejuvenation induced by heterochronic parabiosis, early embryogenesis, and cellular reprogramming, highlighting universal signatures of mortality, shared across models of rejuvenation and age-related disease. They included Cdkn1a and Lgals3, whose human plasma levels further demonstrated a strong association with all-cause mortality, disease incidence and risk factors, such as obesity and hypertension.

Overall, this study uncovers molecular hallmarks of mammalian mortality shared across organs, cell types, species and models of disease and rejuvenation, exposing fundamental mechanisms of aging and longevity.

Link: https://doi.org/10.1101/2024.07.04.601982