Fight Aging! Newsletter, October 28th 2024
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- The Interactions Between Aging and Autophagy are Complicated
- CD47 Inhibition to Slow Atherosclerosis is Entering an Initial Clinical Safety Trial
- Dysregulation in "Eat Me" and "Don't Eat Me" Signals in the Aging Brain Contributes to Loss of Myelination
- A Biomarker of Aging Built from the Senescence-Associated Secretory Phenotype of Monocytes
- An Approach to Reducing the Senescence-Associated Secretory Phenotype in Aged Tissues
- Liver Inflammation Contributes to Brain Inflammation
- Assessing Optimal Lifestyle Choices from UK Biobank Data
- Advocating for More Careful Use of the Term "Biological Age"
- Fluid Homeostasis is Disrupted by Aging
- An Aged Gut Microbiome Increases Susceptibility of Arrhythmia in a Mouse Model
- The Two Phases of Alzheimer's Disease
- Regeneration of the Atrophied Thymus is a Growing Field Once Again
- Novel Omics Assessments of the Burden of Age-Related Inflammation Correlate with Mortality Risk
- Mitochondrial Dysfunction in the Aging Heart
- Towards Lipid-Based Senolytics
The Interactions Between Aging and Autophagy are Complicated
https://www.fightaging.org/archives/2024/10/the-interactions-between-aging-and-autophagy-are-complicated/
Autophagy is a collection of processes responsible for recycling protein structures in the cell. There are numerous moving parts, not all of which are fully understood or characterized. Firstly, there is the question of how structures are identified for recycling, a process that is quite different on a structure by structure basis. Mitophagy, autophagy targeted to mitochondria, is very different in its opening stages to ribophagy, autophagy targeted to ribosomes, to pick one comparison of many. Secondly, there is the engulfment of the structure to be recycled into an autophagosome, a membrane assembled specifically for this purpose. Thirdly, there is the transport of that autophagosome to a lysosome where it merges to deliver its cargo to the lysosome interior. Lastly, there is the internal lysosomal activity in which enzymes break down the delivered structure into amino acids for reuse.
Autophagy is clearly important to aging, in that interventions known to modestly slow aging tend to upregulate autophagic activity. Autophagy is difficult to measure, however, and there is some debate over whether and how it slows with advancing age. One can pick any given molecular aspect of autophagy to measure, but it will not be clear as to whether an increase or decrease of that measure reflects an overall enhancement or decine of autophagy. A decreased measure could mean that efficiency has increased, while an increased measure could mean that some dysfunction is leading to futile overactivity in one part of the process. Further, aging could affect autophagy very differently in different tissues or even different cell populations in the same tissue. Average measures may blur out useful information, or a measure obtained in one place may provide misleading data. Most studies of autophagy make only one measure, and are thus subject to this sort of criticism.
Longitudinal autophagy profiling of the mammalian brain reveals sustained mitophagy throughout healthy aging
Once thought to be an acute stress response, our previous work established that mitophagy is a basal, homeostatic process that operates during normal physiology to clear damaged mitochondria through the autophagic pathway. This steady-state mitochondrial turnover occurs independently of mitochondrial stress-induced PINK1-Parkin signaling in a cell- and tissue-specific fashion with a complex regulatory network. In short-lived model organisms such as yeast and nematodes, mitophagy levels decrease with age, leading to the widely held hypothesis that mitophagic capacity may also decline in aged mammalian tissues and could contribute to age-related neurodegeneration. Significant translational efforts are underway to enhance or restore mitophagy levels in these pathological contexts. However, because short-lived and long-lived species have distinct evolutionary pressures, it remains unclear whether lessons learned from short-lived organisms and cell lines actually translate to mammalian physiology - a question that has great translational significance. Mammalian postmitotic neurons survive for decades, have high energy demands and are particularly sensitive to homeostatic impairments. Understanding organelle homeostasis in long-lived mammals is crucial, given how aging accelerates cognitive decline and disease.
How natural aging modifies mammalian mitophagy in distinct brain regions and cellular subtypes remains to be examined, because profiling mitophagy within intact tissues and brain circuits is not straightforward using conventional techniques. Thus, while major insights have been possible from tractable short-lived model organisms, the question of how autophagy pathways are modulated in natural mammalian aging has remained an intractable question. Overcoming these limitations, genetically encoded optical reporter mouse models have recently emerged as powerful tools to monitor specific stages of physiological autophagy and mitophagy in intact tissues at high resolution with cell-specific precision.
Here, using two genetically encoded reporter mouse strains, we tracked mitophagy and autophagy longitudinally throughout the mouse lifespan in several pathophysiologically important brain regions, with cell types including dopaminergic neurons, cerebellar Purkinje cells, astrocytes, microglia, and interneurons. We defined aging-related dynamics in mitophagy and autophagy, providing strong evidence that decreased mitophagy and autophagy are not general features of healthy mammalian brain aging. We also find that healthy aging is hallmarked by the dynamic accumulation of differentially acidified lysosomes in several neural cell subsets. Our findings argue against any widespread age-related decline in mitophagic activity, instead demonstrating dynamic fluctuations in mitophagy across the aging trajectory, with strong implications for ongoing theragnostic development.
CD47 Inhibition to Slow Atherosclerosis is Entering an Initial Clinical Safety Trial
https://www.fightaging.org/archives/2024/10/cd47-inhibition-to-slow-atherosclerosis-is-entering-an-initial-clinical-safety-trial/
Atherosclerosis, the growth of fatty plaques in blood vessel walls, is the single largest cause of human mortality. More novel approaches to treatment are welcome, as the present standard of care, involving reduction of circulating LDL-cholesterol in the bloodstream, is nowhere near effective enough. It only modestly reduces plaque growth, and cannot regress existing plaque. Atherosclerotic plaques are fat-laden cell graveyards, regions of disrupted metabolism and inflammation. The innate immune cells called macrophages are drawn there or created locally to attempt to repair the lesion, but are overwhelmed by the toxic environment and become dysfunctional and die, adding their mass to the plaque. Eventually a plaque ruptures, to cause a heart attack or stroke.
Some years back, researchers reported that CD47 is abundant in atherosclerotic plaque, decorating the surface of dying and dead cells. CD47 is a "don't eat me" marker that prevents cells from being destroyed by local immune cells as they interact with tissue. Normally this and other other protective markers are lost when a cell approaches death, but for yet to be fully explored reasons this is not the case in the toxic environment of an atherosclerotic plaque. This unwanted overabundance of CD47 prevents some of the clearance of cell debris in the plaque that would otherwise happen. Using techniques developed in cancer research, where anti-CD47 therapies are now well established to try to prevent cancerous cells from abusing CD47 to protect themselves from immune cells, researchers have shown that delivering CD47 to atherosclerotic plaque can slow its progression in mouse models of atherosclerosis.
This research, starting a decade ago or so, led to the formation of Bitterroot Bio, a company now starting an initial phase 1 safety trial of a CD47 inhibitor targeted to macrophages. Today's open access paper reports on earlier tests of their drug in pigs, one of the many steps along the way to the regulatory approval needed to test in human volunteers. Reading through the various published papers on this approach, it seems the case that this therapy only slows progression of plaque, but it hopefully turns out to be better at doing that than the present approach of lowering LDL cholesterol in the bloodstream.
Pro-efferocytic nanotherapies reduce vascular inflammation without inducing anemia in a large animal model of atherosclerosis
Among the many emerging translational targets in the field of cardiovascular medicine, a phenomenon known as efferocytosis has recently been prioritized for study. Efferocytosis refers to the engulfment and clearance of pathological cells by professional phagocytes such as macrophages. Within the atherosclerotic plaque, enlargement of the necrotic core is, in part, a consequence of impaired removal of apoptotic vascular cells, which have upregulated the key anti-phagocytic 'don't-eat-me' molecule CD47 on their surface. The growth of a necrotic core contributes to plaque instability and eventual rupture, which serves as a nidus for subsequent acute thrombosis.
Antibodies (Ab) which block the binding of CD47 to its receptor SIRPα potently reduce plaque vulnerability and lesion size by preventing the accumulation of apoptotic debris in murine models of atherosclerosis. These pre-clinical observations were recently extended in a phase I trial of the first humanized anti-CD47 Ab. Subjects receiving 'macrophage checkpoint inhibitors' experienced a dramatic reduction in vascular inflammation of the carotid artery scans. Unfortunately, anti-CD47 Ab treatment in both mouse models and humans has been shown to induce anemia due to the non-specific erythrophagocytosis of aged red blood cells (RBCs) in the spleen.
Studies demonstrating toxicity of anti-CD47 antibody-mediated blockade therefore prompted a search for methods which could reactivate efferocytosis in a precision-targeted manner. To do this, we generated a macrophage-specific nanotherapy loaded with a chemical inhibitor of Src homology 2 domain-containing phosphatase-1 (SHP-1), a small molecule downstream of the CD47-SIRPα signaling axis. This 'Trojan horse' nanoparticle selectively delivered drug to inflammatory monocytes and macrophages within the atherosclerotic plaque, potently augmented phagocytosis, and reduced atherosclerosis as effectively as gold-standard Ab therapies in mouse models. Most notably, this therapy did not cause any hematological toxicity.
Accordingly, the aim of this study was to test our targeted nanoparticles in a large animal model of cardiovascular disease (CVD) to determine if additional translation of our nanotherapy toward human clinical trials is justified.
Dysregulation in "Eat Me" and "Don't Eat Me" Signals in the Aging Brain Contributes to Loss of Myelination
https://www.fightaging.org/archives/2024/10/dysregulation-in-eat-me-and-dont-eat-me-signals-in-the-aging-brain-contributes-to-loss-of-myelination/
The axons that connect neurons are sheathed in myelin, an insulator necessary to maintain normal electrochemical transmission through the nervous system. Demyelinating conditions such as multiple sclerosis produce profound dysfunction leading to death precisely because myelin is so fundamental to the correct operation of nerves and brain. With normal aging, a lesser degree of damage to myelin sheathing occurs, however, and this is thought to contribute to cognitive decline. As is the case for many aspects of aging, there are many possible interconnected mechanisms involved, and it isn't clear as to which are more or less important, or whether the list is complete.
Myelination is an active, ongoing process conducted by oligodendrocyte cells. Many of the possible mechanisms driving loss of myelin involve a reduced oligodendrocyte population size or activity, but in today's open access paper, researchers discuss how proteins that encourage or prevent phagocytosis, the engulfment and destruction of cells or debris in tissue by immune cells, might be involved in age-related demyelination. The researchers argue for the importance of a maladaptive increase in pro-phagocytosis decoration ("eat me" signals) near myelin structures combined with a maladaptive reduction in anti-phagocytosis decoration ("don't eat me" signals) near myelin structures and on oligodendrocytes. The result is damaged myelin and too little remyelination activity.
Dysregulated C1q and CD47 in the aging monkey brain: association with myelin damage, microglia reactivity, and cognitive decline
Although the cause of myelin pathology is not known, microglia are likely contributors as they play an important role in removing myelin debris that inhibits remyelination, a process which becomes dysregulated with age. Microglia become overburdened with degenerating myelin, and failure to clear the debris results in accumulation of damaged myelin that blocks remyelination and proper myelin maintenance. Moreover, the aging brain is characterized by chronic inflammation, which is especially elevated in white matter regions. This neuroinflammation puts microglia into a cycle of contributing to inflammation while also responding to proinflammatory signaling. Chronic neuroinflammation heightens microglia-mediated elimination of cellular components, which may become misdirected with excess pro-inflammatory signaling.
The timing and precision of microglia-mediated debris removal is regulated by immunologic proteins that either initiate or inhibit phagocytosis. Two such proteins are the "eat me" classical complement initiator, C1q, and the "don't eat me" immune-regulatory protein, CD47. Dysregulation in both C1q and CD47 have been implicated in age-related diseases such as multiple sclerosis (MS), a chronic demyelinating disease, synapse removal, and normal aging. Our previous study showed that C1q and CD47 expression are dysregulated in aging gray matter, likely contributing to age-related synapse loss.
Changes in C1q and CD47 in aging white matter may direct microglia towards chronic phagocytosis and inflammation and hinder efficient debris clearance and myelin maintenance. However, studies in white matter have mainly focused on either "eat me" or "don't eat me" proteins and not both, so the interaction between the two in white matter remains unknown even though both C1q and CD47 bind to myelin and proper balance between the two molecules is critical for phagocytosis. Since these signals have not been studied in aging white matter tracts in relation to myelin damage and related cognitive impairment, the present study aimed to assess changes in the balance of C1q and CD47 in the white matter of the aging cingulum bundle in cognitively assessed nonhuman primates.
Our findings showed significant age-related elevation in C1q localized to myelin basic protein, and this increase is associated with more severe cognitive impairment. In contrast, CD47 localization to myelin decreased in middle age and oligodendrocyte expression of CD47 RNA decreased with age. Lastly, microglia reactivity increased with age in association with the changes in C1q and CD47. Together, these results suggest disruption in the balance of "eat me" and "don't eat me" signals during normal aging, biasing microglia toward increased reactivity and phagocytosis of myelin, resulting in cognitive deficits.
A Biomarker of Aging Built from the Senescence-Associated Secretory Phenotype of Monocytes
https://www.fightaging.org/archives/2024/10/a-biomarker-of-aging-built-from-the-senescence-associated-secretory-phenotype-of-monocytes/
Modern omics technologies make it possible to generate enormous amounts of data from biological samples at low cost. All of the stages and influences on gene expression in cells, segmented by tissue and cell type, or even in single cells, are open to inspection in detail. The same is true of circulating molecules outside cells. Aging produces changes in cells and circulating molecules, some of which are individual, but many of which are much the same from person to person, and thus any sufficiently large set of biological data can be mined for signatures of aging. Machine learning has developed to the point at which this development of signatures can be accomplished as cost-effectively as the generation of the data in the first place.
In today's open access paper, researchers report on the development of signatures of aging based on senescence-associated secretory phenotype (SASP) molecules secreted by senescent monocytes. Monocytes are innate immune cells resident in the spleen, but also circulating in the bloodstream before entering tissue to transform into macrophages. Researchers first evaluated monocyte SASP in vitro to determine which molecules to look for in blood samples, and from there found signatures that correlate with mortality in large epidemiological data sets. We will probably see a lot more of this sort of segmentation of data of interest, ever finer slices, as researchers continue to explore what can be accomplished in the construction of biomarkers of aging.
A plasma proteomic signature links secretome of senescent monocytes to aging- and obesity-related clinical outcomes in humans
In recent years, senescence of immune cells, including monocytes, have been implicated as a potentially key driver of age-related pathologies. Senescence of immune cells increases with age and is thought to contribute to an age-related increase of sterile inflammation - "inflammaging" - and higher susceptibility to infectious diseases. Additionally, higher levels of senescence in the immune system drive systemic aging and propagate senescence in solid organs, such as the liver, kidney, and lung. There is emerging evidence that senescent monocytes accumulate in vivo in humans. These circulating immune cells form up to 10% of the total white blood cells and are involved in pathogen recognition via Toll-like receptors (TLRs) and regulation of inflammation. A proinflammatory phenotype of monocytes has been attributed to senescence in the elderly. Moreover, monocytes are promising sources of biomarkers due to their abundance in blood. Despite their potential involvement in inflammaging and biomarker potential, the role of monocyte senescence-associated proteins in aging and their potential as clinical biomarkers are poorly characterized.
In recent years, high-throughput proteomic studies have quantitatively profiled senescence-associated proteins in circulation and demonstrated their associations with diverse aging-related outcomes in humans, including mortality, multimorbidity, strength, and mobility. These studies leveraged human cohorts, such as InCHIANTI (Invecchiare in Chianti), BLSA (Baltimore Longitudinal Study of Aging), GESTALT (Genetic and Epigenetic Signatures of Translational Aging Laboratory Testing), Lifestyle Interventions for Elders (LIFE), and others. However, no biomarker studies to date have comprehensively characterized the monocyte-specific SASP and evaluated its clinical utility as circulating biomarkers in humans.
We identified circulating biomarkers of senescence associated with diverse clinical traits in humans to facilitate future non-invasive assessment of individual senescence burden and efficacy testing of novel senotherapeutics. Using a novel nanoparticle-based proteomic workflow, we profiled the senescence-associated secretory phenotype (SASP) in monocytes and examined these proteins in plasma samples (N = 1,060) from the BLSA. Machine learning models trained on monocyte SASP associated with several age-related phenotypes in a test cohort, including body fat composition, blood lipids, inflammation, and mobility-related traits, among others. Notably, a subset of SASP-based predictions, including a 'high impact' SASP panel that predicts age- and obesity-related clinical traits, were validated in InCHIANTI, an independent aging cohort. These results demonstrate the clinical relevance of the circulating SASP and identify relevant biomarkers of senescence that could inform future clinical studies.
An Approach to Reducing the Senescence-Associated Secretory Phenotype in Aged Tissues
https://www.fightaging.org/archives/2024/10/an-approach-to-reducing-the-senescence-associated-secretory-phenotype-in-aged-tissues/
Senescent cells accumulate with age in tissues throughout the body, an important contribution to age-related dysfunction and disease. On entering the senescent state, a cell ceases to replicate and begins to energetically secrete a pro-inflammatory mix of signals, rousing the immune system to action. In youth, cellular senescence serves useful purposes, such as coordination of regeneration from injury and removal of potentially cancerous cells. In the young, senescent cells are removed rapidly by the immune system, preventing their accumulation. With advancing age, the balance between creation and destruction shifts and a population of lingering senescent cells grows over the years. The inflammatory signals that are useful in the short term become harmful when sustained over the long term, a major contribution to the characteristic chronic inflammation of old age.
While most efforts targeting cellular senescence are focused on ways to selectively destroy these errant cells in aged tissues, a smaller faction of the research community is more interested in finding ways to reduce the secretion of inflammatory signals. In principle, the presence of senescent cells would cause comparatively little harm provided their inflammatory signaling was greatly reduced. One can look at cellular senescence in the long-lived naked mole-rats as a model for this desired goal, as senescent cells in that species do not produce anything like the same degree of inflammatory signaling. There is no way as yet to produce a similar degree of reduced inflammatory signaling in mice, but researchers continue to look for a viable approach.
Citrate metabolism controls the senescent microenvironment via the remodeling of pro-inflammatory enhancers
In response to various stimuli, senescent cells (SnCs) accumulate in aging tissues, and this occurs in parallel with chronic inflammation and age-related functional decline. SnCs are normally rare in most tissues, suggesting that the ripple effect of the senescence-associated secretory phenotype (SASP) amplifies pro-inflammatory signaling in the senescent microenvironment. Because the processes of de novo protein production and secretion consume a lot of cellular energy, unique strategies must exist to collaboratively regulate gene expression, the epigenome, and metabolism.
During the senescent transition of the cells, senescence-associated phenotypes are shaped entirely through epigenomic and metabolic coregulation. The expression of cyclin-dependent kinase inhibitor p16, one of the biomarkers for SnCs, is induced. Activation of the p16-retinoblastoma protein (RB) pathway not only causes cell-cycle arrest but also triggers metabolic reprogramming of glycolysis and mitochondrial oxidative phosphorylation (OXPHOS) by upregulating glycolytic enzymes and the pyruvate dehydrogenase phosphatase 2 that augments the active form of pyruvate dehydrogenase. Since the resulting metabolites, such as S-adenosylmethionine, α-ketoglutarate (αKG), and acetyl-coenzyme A (CoA), are used for adjusting the activities of epigenome modifiers, they further affect the epigenomic state that defines the transcriptional program of SnCs. However, molecular specificity for SASP-related pro-inflammatory gene regulation has not been convincingly established.
Citrate plays important roles in energy production, macromolecular biosynthesis, and protein modification. Within the mitochondria, citrate is generated from acetyl-CoA and oxaloacetate by the citrate synthetase and serves as a substrate in the tricarboxylic acid (TCA) cycle that produces essential metabolites for OXPHOS. In addition, citrate is exported from mitochondria to the cytoplasm and subsequently cleaved by ATP-citrate lyase (ACLY), which generates acetyl-CoA and oxaloacetate. Acetyl-CoA derived from this unique reaction, so called the non-canonical TCA cycle pathway, acts as a source for various metabolic functions, including fatty acid synthesis and the mevalonate pathway, and protein acetylation. Although recent studies have shown that ACLY inhibition improves metabolic health and physical strength in obese mice the role of the non-canonical TCA cycle pathway mediated by ACLY in SnCs remains totally unknown.
Here, we show that ACLY is essential for the pro-inflammatory SASP, independent of persistent growth arrest in senescent cells. Citrate-derived acetyl-CoA facilitates the action of SASP gene enhancers. ACLY-dependent de novo enhancers augment the recruitment of the chromatin reader BRD4, which causes SASP activation. Consistently, specific inhibitions of the ACLY-BRD4 axis suppress the STAT1-mediated interferon response, creating the pro-inflammatory microenvironment in senescent cells and tissues. Our results demonstrate that ACLY-dependent citrate metabolism represents a selective target for controlling SASP designed to promote healthy aging.
Liver Inflammation Contributes to Brain Inflammation
https://www.fightaging.org/archives/2024/10/liver-inflammation-contributes-to-brain-inflammation/
Chronic, unresolved inflammation is a feature of aging. Constant inflammatory signaling is disruptive to tissue structure and function, and contributes to the onset and progression of all of the common, ultimately fatal age-related conditions. Inflammatory signal molecules generated in one organ will circulate throughout the body to provoke inflammation in other organs. This is the one of the many ways in which any one localized point of failure or excessive amount of age-related cell and tissue damage will tend to drag down the rest of the body.
As people age, the liver is among several organs that experience chronic, low-grade inflammation, a state that keeps the immune system activated even though there is no threat. Cells that die through necroptosis burst and release substances that lead to inflammation. Using an aging mouse model, researchers demonstrated the damaging effects of necroptosis in the liver, as well as the reduction of those effects when necroptosis was blocked. They also found that activating necroptosis in the liver increased liver inflammation and, surprisingly, increased brain inflammation, which affected the ability of mice to build nests, a possible sign of cognitive impairment.
"We hypothesize that when liver necroptosis is activated, the liver secretes toxic or inflammatory molecules that enter the bloodstream and cross the blood-brain barrier, where they cause inflammation in the brain. This type of organ crosstalk is becoming very important in research. Usually, when we study a disease condition, we focus on one organ, but when we do that, we miss the systemic effect. What we have found in our mice studies so far matches what is reported for patients - that people with liver diseases have high inflammation in the liver and also have cognitive issues. Our key question is what is causing this increase in inflammation in aging? It is important that we advance our knowledge in this area because it is critical that we develop new ways to treat these diseases."
Assessing Optimal Lifestyle Choices from UK Biobank Data
https://www.fightaging.org/archives/2024/10/assessing-optimal-lifestyle-choices-from-uk-biobank-data/
Readily available epidemiological data sets have grown considerably in size over the past few decades, with the UK Biobank as an example of the type. Here, researchers use this data on correlations between lifestyle and mortality to make an assessment of the optimal choices. It is somewhat taken as read that better choices in the matter of weight, exercise, and so forth do in fact reduce mortality - that the correlation does in this case imply causation. That is the consensus, and well supported by animal studies of the effects of lifestyle factors on long term health, in which causation can be demonstrated. It is reasonable to expect that most of the lifestyle effects on mortality are similar across mammals, although one should probably also expect differences in the size of effect for any given relationship.
A prospective cohort study was conducted using data from over half a million UK Biobank participants. Two datasets were created by subjective and objective measurements of physical activity: the Subjective Physical Activity (SPA) and Objective Physical Activity (OPA) datasets. Lifestyle patterns, including diet habits, exercise levels, and sleep quality, were assessed within these datasets. Biological aging was quantified using validated methods, including Homeostatic Dysregulation, Klemera-Doubal Method Biological Age, Phenotypic Age, and Telomere Length. All-cause mortality data were obtained from the National Health Service.
The findings indicate that, in most cases, maintaining an anti-inflammatory diet, engaging in at least moderate physical activity, and ensuring healthy sleep conditions are associated with delayed physiological aging (Cohen's d ranging from 0.274 to 0.633) and significantly reduced risk of all-cause mortality (hazard ratio for SPA: 0.690; hazard ratio for OPA: 0.493). These effects are particularly pronounced in individuals under 60 years of age and in women. However, it was observed that the level of physical activity recommended by the World Health Organization (600 MET-minutes/week) does not achieve the optimal effect in delaying biological aging. The best effect in decelerating biological aging was seen in the high-level physical activity group (≥ 3000 MET-minutes/week). The study also highlights the potential of biological age acceleration and telomere length as biomarkers for predicting the risk of mortality.
Advocating for More Careful Use of the Term "Biological Age"
https://www.fightaging.org/archives/2024/10/advocating-for-more-careful-use-of-the-term-biological-age/
People age at different rates, and any give population will distribute across a range of late life health status and mortality risk. As a concept, biological age is clearly useful, a way to talk about this variance in pace of aging. The output of an attempt to measure biological age is not biological age, however. It is a measure that may or may not reflect biological age. Some researchers feel that current use of the term "biological age" is lax, often applied without qualification to the output of epigenetic clocks and other assessments.
Usage of the phrase "biological age" has picked up considerably since the advent of aging clocks and it has become commonplace to describe an aging clock's output as biological age. In contrast to this labeling, biological age is also often depicted as a more abstract concept that helps explain how individuals are aging internally, externally, and functionally. Given that the bulk of molecular aging is tissue-specific and aging itself is a remarkably complex, multifarious process, it is unsurprising that most surveyed scientists agree that aging cannot be quantified via a single metric.
We share this sentiment and argue that, just like it would not be reasonable to assume that an individual with an ideal grip strength, VO2 max, or any other aging biomarker is biologically young, we should be careful not to conflate an aging clock with whole-body biological aging.
To address this, we recommend that researchers describe the output of an aging clock based on the type of input data used or the name of the clock itself. Epigenetic aging clocks produce epigenetic age, transcriptomic aging clocks produce transcriptomic age, and so forth. If a clock has a unique name, the name of the clock can double as the output. As a compromise solution, aging biomarkers can be described as indicators of biological age. We feel that these recommendations will help scientists and the public differentiate between aging biomarkers and the much more elusive concept of biological age.
Fluid Homeostasis is Disrupted by Aging
https://www.fightaging.org/archives/2024/10/fluid-homeostasis-is-disrupted-by-aging/
The body has evolved to balance the levels of many different molecules across different tissues. Multiple systems of signaling, transport, motivation, intake, and excretion interact in order to achieve homeostasis, constantly shifting in response to deficiency or excess. Water is one of the more important molecules managed by this sort of complicated, dynamic balance. As a general rule, all complex systems in the body run awry with aging; the more complex, the more vulnerable it is to damage and dysfunction. The molecular damage of aging changes cell behavior, homeostatic systems stop working as well as they did in youth, and ultimately the failure to achieve homeostasis in the face of stresses that push the system out of normal bounds can prove fatal.
Tight control of fluid balance is essential for life. This is achieved by a physiologic system that monitors the osmolality and volume of the blood and, in response to dehydration, triggers two counterregulatory responses: water consumption, which is motivated by the sensation of thirst, and water reabsorption by the kidney, which is triggered by the hormone vasopressin (AVP). These two responses are controlled by dedicated neural circuits in the forebrain that directly sense changes in fluid balance.
Dysregulation of fluid homeostasis is a common feature of aging. For example, older adults report a reduced perception of thirst and consume less water after many thirst-evoking (dipsogenic) stimuli. In addition, the ability of the kidney to concentrate urine declines with age, leading to greater loss of fluid in older adults. As a result, aging is associated with increased prevalence of chronic dehydration, which is a significant risk factor for morbidity and mortality.
The specific alterations in the fluid homeostasis system that are caused by aging are not well understood. One challenge is that fluid balance involves multiple interacting systems, including a neuroendocrine system that controls water resorption (the AVP-kidney axis); a sensory system that monitors fluid balance and ingestion, which includes subfornical organ (SFO) glutamatergic neurons and their sensory afferents arising from the mouth, throat, and viscera; and a motivational system which drives water seeking and consumption, which includes SFO glutamatergic neurons as well as their downstream targets such as the dopamine system.
It has only recently become possible to monitor and manipulate these fluid homeostasis neurons in behaving animals. Here we have performed a comprehensive analysis of how the fluid homeostasis system is altered by aging in mice. We investigated animals of both sexes, across a range of ages from young to very old, and subjected them to batter of analyses at different levels, including: (1) physiologic measurements of fluid balance, kidney function, and AVP release and sensitivity; (2) behavioral analyses of drinking and motivation in response to diverse thirst stimuli (food, dehydration, hyperosmolality, and hypovolemia); (3) neural recordings from circuit nodes that control drinking, AVP release, and motivation, and (4) optogenetic manipulations to test the sufficiency of circuit nodes. These experiments revealed that a subset of these functions is impaired during aging, whereas others are unexpectedly enhanced.
An Aged Gut Microbiome Increases Susceptibility of Arrhythmia in a Mouse Model
https://www.fightaging.org/archives/2024/10/an-aged-gut-microbiome-increases-susceptibility-of-arrhythmia-in-a-mouse-model/
The balance of microbial populations making up the gut microbiome changes with age, in ways that negatively affect health. Pro-inflammatory microbes increase in number while populations producing beneficial metabolites decrease in size. Researchers here discuss the evidence for an aged gut microbiome to contribute to various aspects of cardiovascular disease, and show that in mice an aged gut microbiome increases risk of arrhythmia. The researchers suggest that the mechanism of interest is increased oxidative stress resulting from the activities of microbial populations, which is then disruptive to the normal metabolism of the heart. There may be other mechanisms.
The prevalence of arrhythmias and incidence of sudden cardiac death (SCD) increases markedly with age, leading to higher morbidity and mortality in the elderly. The frequency of arrhythmias, particularly atrial fibrillation (AF) and ventricular tachyarrhythmias (VT), is expected to increase with aging. Gut microbiota has been recognized as an important factor in the development of cardiovascular diseases, such as AF, heart failure (HF), ischemia, and reperfusion. It is also considered to be an endocrine organ that plays a role in the manipulation of host immunity and metabolic homeostasis. It has been shown to play both beneficial and adverse roles in AF rats and patients, which could be related to the heterogeneity of the microbiota.
Research indicates that in patients with AF, the relative abundance of Ruminococcus, Streptococcus, and Enterococcus increase, while that of Faecalibacterium, Oscillospira, and Bilophila decreases. From the perspective of intestinal content metabolism, the bacteria producing trimethylamine oxide (TMAO) in gut microbiota of AF patients increase. Moreover, local injection of TMAO in canine can activate atrial autonomic nerve plexus, shorten effective refractory period (ERP) value, and then promote arrhythmia, which because of the activation of p65/NF-κB signaling and inflammatory cytokines.
Here, we demonstrated that arrhythmia susceptibility in aged mice could be transmitted to young mice using fecal microbiota transplantation (FMT). Mechanistically, increased intestinal reactive oxygen species (ROS) in aged mice reduced ion channel protein expression and promoted arrhythmias. Gut microbiota depletion by an antibiotic cocktail reduced ROS and arrhythmia in aged mice. Interestingly, oxidative stress in heart induced by hydrogen peroxide (H2O2) increased arrhythmia. Moreover, aged gut microbiota could induce oxidative stress in young mice colon by gut microbiota metabolites transplantation. Vitexin could reduce aging and arrhythmia through OLA1-Nrf2 signaling pathway.
Overall, our study demonstrated that the gut microbiota of aged mice reduced cardiac ion channel protein expression through systemic oxidative stress, thereby increased the risk of arrhythmias.
The Two Phases of Alzheimer's Disease
https://www.fightaging.org/archives/2024/10/the-two-phases-of-alzheimers-disease/
Alzheimer's disease is characterized by a long, slow buildup of amyloid-β aggregates in the brain, and in this period symptoms are minor to non-existent. The amyloid cascade hypothesis of Alzheimer's disease suggests that this aggregation sets the stage for a later feedback loop between tau protein aggregation and chronic inflammation in the brain, which produces a more rapid, sizable increase in pathology and loss of function. Researchers here use omics technologies to produce a map of postmortem diseased brains that supports this two phase view of the development of Alzheimer's disease, adding more detail to the existing picture.
Alzheimer's disease (AD) is the leading cause of dementia in older adults. Although AD progression is characterized by stereotyped accumulation of proteinopathies, the affected cellular populations remain understudied. Here we use multiomics, spatial genomics, and reference atlases from the BRAIN Initiative to study middle temporal gyrus cell types in 84 donors with varying AD pathologies. This cohort includes 33 male donors and 51 female donors, with an average age at time of death of 88 years.
We used quantitative neuropathology to place donors along a disease pseudoprogression score. Pseudoprogression analysis revealed two disease phases: an early phase with a slow increase in pathology, presence of inflammatory microglia, reactive astrocytes, loss of somatostatin+ inhibitory neurons, and a remyelination response by oligodendrocyte precursor cells; and a later phase with exponential increase in pathology, loss of excitatory neurons and Pvalb+ and Vip+ inhibitory neuron subtypes. These findings were replicated in other major AD studies.
Regeneration of the Atrophied Thymus is a Growing Field Once Again
https://www.fightaging.org/archives/2024/10/regeneration-of-the-atrophied-thymus-is-a-growing-field-once-again/
The thymus plays host to thymocyte cells originally generated in the bone marrow, guiding their maturation into T cells of the adaptive immune system. The aged thymus steadily loses active tissue, however, and the supply of new T cells dwindles as a result. Most people in their 50s have very little thymic function, and without a supply of reinforcements the adaptive immune system becomes ever more dysfunctional over time. Back in the 2010s there was considerable academic interest in approaches to the regeneration of the thymus based on upregulation of FOXN1 expression, but that proved challenging enough for those efforts to die out (aside from one persistent academic group that may have recently found a solution). Absence of a suitable delivery system for FOXN1 gene therapy targeted to the thymus was one major issue. That FOXN1, like many transcription factors, downregulates its own expression was another. Now, however, there are a fair number of companies in the growing longevity industry working on various possible approaches to the problem.
Tolerance Bio is developing an allogeneic cell therapy platform based on induced pluripotent stem cells (iPSCs) as well as pharmacological treatments aimed at immune diseases. Thymic dysfunction is linked to various immune diseases due to age-related decline, congenital defects, or damage from medical interventions like surgery, chemotherapy, and infection. Tolerance Bio aims to reverse these effects by developing artificial thymuses from stem cells, targeting disease-specific treatments such as thymic organoids. The company also seeks to delay thymic involution with drugs to prevent both natural and accelerated thymic decline. Restoring thymic function could not only combat immune diseases but also extend healthy lifespan by improving the body's immune response.
Tolerance Bio joins a number of companies seeking to harness the power of the thymus against aging and disease, including ARPA-backed Thymmune, Vidaregen and Thymox. In 2015, Dr Greg Fahy, renowned aging researcher and CSO of Intervene Immune, commenced the first clinical trial to explore if thymus regeneration could reverse aspects of human aging, with results showing participants' epigenetic age was "significantly decreased" by the treatment.
Novel Omics Assessments of the Burden of Age-Related Inflammation Correlate with Mortality Risk
https://www.fightaging.org/archives/2024/10/novel-omics-assessments-of-the-burden-of-age-related-inflammation-correlate-with-mortality-risk/
The chronic inflammation of aging is harmful to health, the result of accumulating senescent cells, maladaptive reactions to molecular damage characteristic of aging, and other similar problems. While short-term inflammation is useful and necessary to defense against pathogens, elimination of potentially cancerous damaged cells, and regeneration from injury, unresolved, constant inflammatory signaling is disruptive to tissue structure and function. It changes cell behavior for the worse throughout the body. The immune system is complex, and so is inflammatory signaling. There are many possible ways to measure inflammation, and most have some dependency on the broader context of the state of the body, specific medical condition, and so forth. As researchers demonstrate here, it is quite possible to depart from the usual measures to produce novel and potentially better assessments of the contribution of inflammation to mortality based on omics data.
Inflammation is a critical component of chronic diseases, aging progression, and lifespan. Omics signatures may characterize inflammation status beyond blood biomarkers. We leveraged genetics (Polygenic-Risk-Score; PRS), metabolomics (Metabolomic-Risk-Score; MRS), and epigenetics (Epigenetic-Risk-Score; ERS) to build multi-omics-multi-marker risk scores for inflammation status represented by the level of circulating C-reactive protein (CRP), interleukin 6 (IL6), and tumor necrosis factor alpha (TNFa).
We found that multi-omics risk-scores generally outperformed single-omics risk scores in prediction of all-cause mortality in the Canadian Longitudinal Study on Aging. Compared with circulating inflammation biomarkers, some multi-omics risk scores had a higher hazard ratio (HR) per standard deviation (SD) increase for all cause-mortality when including both score and circulating IL6 in the same model (1-SD IL6 MRS-ERS: HR=1.77 vs. 1-SD circulating IL6 HR=1.11; 1-SD IL6 PRS-MRS: HR=1.32 vs. 1-SD circulating IL6 HR=1.31; 1-SD PRS-MRS-ERS: HR=1.62 vs. 1-SD circulating IL6: HR=1.16).
In the Nurses' Health Study (NHS), NHS II, and Health Professional Follow-up Study with available omics, 1-SD of IL6 PRS and 1-SD IL6 PRS-MRS had HR=1.13 and HR=1.13, among individuals older than 65years without mutual adjustment of the score and circulating IL6. Our study demonstrated that some multi-omics scores for inflammation markers may characterize important inflammation burden for an individual beyond those represented by blood biomarkers and improve our prediction capability for aging process and lifespan.
Mitochondrial Dysfunction in the Aging Heart
https://www.fightaging.org/archives/2024/10/mitochondrial-dysfunction-in-the-aging-heart/
Mitochondria are the powerplants of the cell, producing the chemical energy store molecule adenosine triphosphate (ATP) used to power cell activities. With age, mitochondria become less effective in this task, producing less ATP and increased amounts of oxidative byproducts, adding to cell stress. This is the result of damage to mitochondrial DNA, less well protected and repaired than the DNA in the cell nucleus, combined with maladaptive changes in the expression of genes important to mitochondrial function and quality control. A reduced supply of ATP contributes to dysfunction in tissues and organs, particularly energy-hungry tissues such as muscle and brain.
The mitochondrial electron transport chain (ETC) contributes 80%-90% of ATP in most mammalian tissues, making mitochondrial dysfunction detrimental due to reduced ATP production, indispensable for biological functions. Aging leads to alterations in ETC components, contributing to a number of age-related conditions. Hence, one of the consequences of the aging process is the drop in the efficiency of this energy production mechanism, leading to a decline in ATP production and subsequent cellular energy deficits. Dysfunctional mitochondria are increasingly associated with aged cardiovascular tissues.
Proper substrate utilization is imperative for the myocardium to fulfill its function, primarily relying on ATP (re-)synthesis through fatty acid oxidation within mitochondria. The myocyte employs additional pathways, such as glycolysis, creatine kinase, and adenylate kinase, in response to high ATP demand. During increased work, glycogen, glucose, and phosphocreatine are utilized to meet ATP demand, maintaining constant ATP levels. The efficiency of ATP production varies depending on substrate oxidation, with fatty acid oxidation producing more ATP. This metabolic plasticity diminishes in chronic pathologies like congestive heart failure, impacting myocardial oxygen efficiency and causing intracellular ATP depletion.
Spare respiratory capacity, the ability to increase ATP production during heightened demand or reduced fuel supply, is crucial for cellular function and survival. Mitochondrial plasticity involves the efficiency of mitochondrial coupling and provides increased respiratory capacity under stress conditions. This phenomenon is particularly significant in ischemic injury and situations of augmented energy demand such as sepsis, endurance exercise, trauma, or heart failure. In the heart, aging leads to a decline in mitochondrial oxidative phosphorylation function. Increased electron leakage and mitochondrial ROS production contribute to oxidative damage, particularly affecting intrafibrillar mitochondria. Deficient mitochondrial energetics, altered Ca2+ homeostasis, and excessive reactive oxygen species (ROS) generation contribute to reduced stress adaptability and augmented vulnerability to disease in the aged myocardium.
Towards Lipid-Based Senolytics
https://www.fightaging.org/archives/2024/10/towards-lipid-based-senolytics/
Senescent cells are poised for self-destruction, but held back by a range of mechanisms that are amenable to sabotage, given suitable small molecules. Much of the first wave of senolytic drug development, treatments that can selectively destroy some fraction of the harmful burden of senescent cells found in aged tissues, exploited ways to force senescent cells into apoptosis. New ways to provoke forms of programmed cell death in senescent cells are being found all the time, and it is interesting to keep an eye on this part of the field. The illustrative work noted here is only conducted in cell culture, so should be taken with a grain of salt until animal data arrives, but is novel for employing ferroptosis as the chosen path to destruction, and in the use of lipids rather than the usual small molecules.
Cellular senescence is a key driver of the aging process and contributes to tissue dysfunction and age-related pathologies. Senolytics have emerged as a promising therapeutic intervention to extend healthspan and treat age-related diseases. Through a senescent cell-based phenotypic drug screen, we identified a class of conjugated polyunsaturated fatty acids, specifically α-eleostearic acid and its methyl ester derivative, as novel senolytics that effectively killed a broad range of senescent cells, reduced tissue senescence, and extended healthspan in mice.
Importantly, these novel lipids induced senolysis through ferroptosis, rather than apoptosis or necrosis, by exploiting elevated iron, cytosolic polyunsaturated fatty acids (PUFAs) and reactive oxygen species (ROS) levels in senescent cells. Mechanistic studies and computational analyses further revealed their key targets in the ferroptosis pathway, ACSL4, LPCAT3, and ALOX15, important for lipid-induced senolysis. This new class of ferroptosis-inducing lipid senolytics provides a novel approach to slow aging and treat age-related disease, targeting senescent cells that are primed for ferroptosis.