Fight Aging! Newsletter, November 11th 2024
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- Fecal Microbiota Transplant from Old to Young Mice Produces Vascular Aging and Metabolic Dysfunction
- Improving on Fisetin as a Senolytic
- Calorie Restriction Improves Beta Cell Function and Slows Beta Cell Aging
- Muscle Strength Correlates with Mortality in the Oldest People
- Infectious Agents in the Gut Can Accelerate Neurodegeneration
- F-actin in the Brain Inhibits Autophagy to Promote Neurodegeneration
- Mifepristone Triggers Some of the Same Benefits as Rapamycin
- Changes in Microglia in the Aged Brain: Cause or Consequence of Neurodegeneration?
- Amount of Central Fat Predicts Mortality Risk in Non-Obese Individuals
- Tricarboxylic Acid Cycle Genes are Downregulated with Age
- Developmental Reversal May Be More Common than Thought in Lower Animals
- The NIH on Research into the Biology of Aging
- A Glance at the Work of Calico Labs on the Integrated Stress Response
- Obstructive Sleep Apnea Correlates with a Raised Risk of Later Dementia
- Investigating the Relationship Between Circadian Rhythm and Longevity in Mammals
Fecal Microbiota Transplant from Old to Young Mice Produces Vascular Aging and Metabolic Dysfunction
https://www.fightaging.org/archives/2024/11/fecal-microbiota-transplant-from-old-to-young-mice-produces-vascular-aging-and-metabolic-dysfunction/
Here are two interesting points about the gut microbiome that have become clear in recent years: (a) the composition of the gut microbiome, the relative sizes of microbial populations, changes with age in ways that contribute to inflammation and tissue dysfunction throughout the body; and (b) it is possible to produce lasting change in the composition of the gut microbiome through either engineering of an immune response against target microbes or the procedure of fecal microbiota transplantation from a donor with a very different microbiome.
A simple example of the immune engineering approach is to inject small amounts of flagellin, the protein making up bacterial flagellae, to rouse the immune system into greater efforts to destroy anything it can find equipped with a flagellum. In the gut, most such bacteria are undesirable. Like fecal microbiota transplantation from a younger donor, the effects are unknowable in advance, generally in the direction of producing benefit, but these are not precision approaches to therapy. One can't yet engineer the exact gut microbiome one desires. Unfortunately strategies involving oral probiotics, which seem the most obvious path towards obtaining more of the specific microbes desired in the gut, have yet to advance to the point at which they are capable of producing lasting change; their effects are very transient.
As today's open access paper illustrates, the aged gut microbiome is clearly harmful. It is harmful in ways that even a young body and immune system cannot escape from. Just as fecal microbiota transplantation from young to old animals produces a lasting change to a young-looking microbiome in an old body and consequent benefits to health, the reverse produces a lasting change to an old-looking microbiome in a young body and consequent damage and dysfunction to tissues throughout the body. This is a good argument for replacement of the microbiome to be the primary thrust of development when it comes to finding ways to remove this aspect of aging. It seems unlikely that rousing the aged immune system is going to solve enough of the problem if a young immune system cannot wrestle an aged gut microbiome into shape.
Aged Gut Microbiome Induces Metabolic Impairment and Hallmarks of Vascular and Intestinal Aging in Young Mice
The aging vasculature is associated with endothelial dysfunction, arterial stiffness, increased oxidative stress and chronic inflammation, contributory to higher risks of cardiovascular diseases, such as heart failure and coronary artery disease. 'Dysbiosis' is considered as a new integrative hallmark of aging. During aging, the microbial composition in intestine varies that the homeostatic relationship between the host and gut microbiome deteriorates, contributory to altered immune and inflammatory responses in the elderly. Age-associated dysbiosis also increases the risks of various diseases, particularly cancers, cardiovascular diseases (CVDs), and diabetes, potentially through shift in intestinal microbial composition from providing benefits to causing chronic inflammation, and through alterations in the production of gut-derived substances to influence host nutrient-sensing pathways. However, the comprehensive mechanism of how age-related dysbiosis promotes other recognized hallmarks of aging remains elusive.
Of note, the vasculature serves as the first-line barrier vulnerable to the changes in gut microbiome due to close proximity between the intestine and blood circulation. Besides, the increased intestinal permeability, known as 'leaky gut', during aging further aggravates the vulnerability of vasculature towards dysbiosis. However, whether age-associated dysbiosis promotes host premature aging remains unclear. Previous studies showed that gut microbiome suppression by antibiotics ameliorates endothelial dysfunction in aged mice, and age-associated hyperproduction of harmful gut-derived metabolite (e.g., trimethylamine-N-oxide) drives endothelial dysfunction. It is therefore reasonable to hypothesize that age-associated dysbiosis shall promote vascular aging by triggering aging hallmarks in the vasculature, such as telomere attrition, endothelial dysfunction, and vascular inflammation and oxidative stress.
In this study, we performed fecal microbiome transfer (FMT) from aged to young mice to (i) study whether age-associated dysbiosis causes premature vascular and intestinal dysfunction; (ii) unveil whether such transfer changes the metabolic profiles; (iii) uncover microbiome alterations and underlying mechanism that are potentially critical; and (iv) identify potential interventions that might partially reverse age-related harmful effects. We demonstrated that age-associated dysbiosis, achieved by aged-to-young FMT, caused endothelial dysfunction, telomere dysfunction, inflammation, and oxidative stress in vascular tissues, partially reflective of premature vascular aging. Moreover, aged-to-young FMT also caused metabolic impairment and altered gut microbial profiles in young mice, along with disrupted intestinal integrity. Interestingly, aged-to-young FMT caused telomere dysfunction in both intestinal and aortic tissues. These findings highlight the harmful effects of aged microbiome on intestine and vasculature, providing important insight that gut-vascular connection represents a potential intervention target against age-related cardiometabolic complications.
Improving on Fisetin as a Senolytic
https://www.fightaging.org/archives/2024/11/improving-on-fisetin-as-a-senolytic/
The enormous cost of medical regulation ensures that natural compounds that may be useful receive little rigorous attention in the form of clinical trials and correspondingly little adoption in the mainstream medical community. Since the use of these compounds cannot be patented in a way that prevents competition, companies focused on these compounds cannot become valuable enough to raise the funding needed to conduct extensive development and formal clinical trials. Thus little tends to be known in certain about even quite widely used natural compounds, far less than is known about the average small molecule drug.
We can see these incentives at work in the case of the senolytic flavonoid fisetin; despite the existence of animal data suggesting it to be as good at clearing senescent cells from aged tissues as the combination of dasatinib and quercetin, we still don't know if it works in the same way in humans, what the optimal dose might be, how delivery is best improved given its low bioavailability, and so forth. No-one is putting significant funds into answering any of those questions, and it is unlikely that anyone ever will. What does tend to happen, as illustrated by today's open access research, is that groups attempt the slow process of producing patentable variants of the molecule in question and move ahead with those into the regulatory system.
Development of novel flavonoid senolytics through phenotypic drug screening and drug design
Accumulation of senescent cells drives aging and age-related diseases. Senolytics, which selectively kill senescent cells, offer a promising approach for treating many age-related diseases. Using a senescent cell-based phenotypic drug discovery approach that combines drug screening and drug design, we developed two novel flavonoid senolytics, SR29384 and SR31133, derived from the senolytic fisetin. These compounds demonstrated enhanced senolytic activities, effectively eliminating multiple senescent cell types, reducing tissue senescence in vivo, and extending healthspan in a mouse model of accelerated aging.
Mechanistic studies utilizing RNA-Seq, machine learning, network pharmacology, and computational simulation suggest that these novel flavonoid senolytics target PARP1, BCL-xL, and CDK2 to induce selective senescent cell death. This phenotype-based discovery of novel flavonoid senolytics, coupled with mechanistic insights, represents a key advancement in developing next-generation senolyticss with potential clinical applications in treating aging and age-related diseases.
Calorie Restriction Improves Beta Cell Function and Slows Beta Cell Aging
https://www.fightaging.org/archives/2024/11/calorie-restriction-improves-beta-cell-function-and-slows-beta-cell-aging/
The practice of calorie restriction alters near all aspects of cellular biochemistry throughout the body. The result is improved function and modestly slowed aging, an evolved response to low nutrient levels that serves to increase the odds of surviving a famine to reproduce once plenty returns. Seasonal famine is the most common such circumstance, and while the calorie restriction response appears to be near universal across all forms of life, short-lived species exhibit a much greater extension of life span as a result than is the case for long-lived species. A season is a sizable fraction of a mouse life span, but not of a human life span. So mice can live up to 40% longer on a low calorie diet, while humans likely gain only a few years.
Since calorie restriction changes just about everything for the better in the aging body, one can find any number of papers examining one very specific aspect of the calorie restriction response. Today's open access paper, for example, is focused on how beta cells are improved, and their functional decline with aging is slowed, in calorie restricted mice. Beta cells reside in the pancreas, produce insulin, and are thus of central importance in insulin metabolism and glucose metabolism. This portion of overall metabolism affects the pace of aging, as illustrated by the accelerated aging exhibited by diabetic patients.
Calorie restriction increases insulin sensitivity to promote beta cell homeostasis and longevity in mice
Beta cells secrete insulin in response to increases in blood glucose levels to sustain normal glucose homeostasis for an entire lifetime. Several studies have investigated the impact of aging on beta cells and established that aging beta cells have compromised expression of transcription factors (TFs) and re-organization of gene regulatory networks (GRNs) that maintain beta cell identity, accumulation of islet fibrosis, inflammation, and ER stress, reduced KATP channel conductance, loss of coordinated beta cell calcium dynamics, impaired beta cell autophagy and accumulation of beta cell DNA damage, and/or beta cell senescence. When combined with an unhealthy lifestyle during old age, these aging signatures could pre-dispose beta cells to failure and lead to type 2 diabetes (T2D) onset.
Caloric restriction (CR) and CR-mimicking approaches (e.g., time-restricted feeding (TRF)) can prolong organismal longevity and delay aging from yeast to non-human primates. These beneficial effects are associated with improved glucose homeostasis due to prolonged fasting and enhanced peripheral insulin sensitivity, enhanced insulin signaling, lower adiposity, enhanced mitochondrial homeostasis and lower ATP generation, increased autophagy, enhanced protein homeostasis and reduced ER stress and inflammation. In the pancreas, 20-40% CR or CR achieved via TRF are linked to lower islet cell mass in lean mice, whereas in pre-diabetic mice, CR restores normal beta cell secretory function, identity, and preserves beta cell mass in a process dependent on activation of beta cell autophagy via Beclin-2. In patients with a recent T2D diagnosis, the efficacy of extreme CR (average of 835 kcal/day or greater than 50% CR based on a 2000 kcal/day diet) to reverse T2D depends on the capacity of beta cells to recover from previous exposure to a T2D metabolic state. However, how beta cells adapt during CR, and whether CR can delay the hallmarks of beta cell aging remains largely unknown.
We investigated these questions by exposing adult male mice to mild CR (i.e., 20% restriction) for up to 12 months and applied comprehensive in vivo and in vitro metabolic phenotyping of beta cell function followed by single-cell multiomics and multi-modal high-resolution microscopy pipelines. Our data reveals that CR reduces the demand for beta cell insulin release necessary to sustain euglycemia by increasing peripheral insulin sensitivity. Ad-libitum (AL) consumption of a diet with reduced caloric intake failed to trigger a similar phenotype, thus indicating that CR and CR-associated fasting periods are required for this adaptive metabolic response. During CR, the transcriptional architecture of beta cells is re-organized to promote a largely post-mitotic and long-lived phenotype with enhanced cell homeostasis and mitochondrial structure-function. This is associated with reduced onset and/or expression of beta cell aging and senescence signatures. When exposed to a high-fat diet (HFD), CR beta cells upregulate insulin release, however they have a compromised adaptive response due to limited cell proliferation resulting in reduced beta cell mass. Therefore, our results provide a molecular footprint of how CR modulates adult beta cell function and insulin sensitivity to promote beta cell longevity and delay aging in mice.
Muscle Strength Correlates with Mortality in the Oldest People
https://www.fightaging.org/archives/2024/11/muscle-strength-correlates-with-mortality-in-the-oldest-people/
Loss of muscle mass and strength is universal across the aging population. A perhaps surprising amount of this loss is the result of lifestyle choice, however. We live in an age of comfort, in which people conduct lesser degrees of physical activity than was normally the case in past centuries. Compare the average modern first world individual with the average modern hunter-gatherer, and the hunter-gatherer is in better shape, better maintaining muscle function into later life. Given than people age at different rates, and people undertake different degrees of physical activity, one might expect to see variations in muscle mass and strength in later life, and indeed this is the case.
In today's open access paper, researchers examine the correlation between measures of strength and mortality in a population over 90 years of age. The more muscle, the lower the mortality risk. It is worth bearing in mind other studies that have shown programs of resistance exercise, which builds muscle and strength, to lower mortality risk in older individuals. A fair degree of the state of muscle in later life is under our control. Muscle is a metabolically active tissue, producing a comparatively poorly understood set of myokine signals that are generally beneficial to the operation of metabolism throughout the body. So having more muscle, and better quality muscle tissue, isn't just a matter of avoiding frailty, it is also beneficial in other ways.
Association of Muscle Strength With All-Cause Mortality in the Oldest Old: Prospective Cohort Study From 28 Countries
Ageing is associated with a gradual loss of muscle strength, which in the end may have consequences for survival. Whether muscle strength and mortality risk associate in a gradual or threshold-specific manner remains unclear. This study investigates the prospective association of muscle strength with all-cause mortality in the oldest old. We included 1890 adults aged ≥ 90 years (61.6% women, mean age 91.0 ± 1.5 years) from 27 European countries and Israel participating in the Survey of Health, Ageing and Retirement in Europe (SHARE) study. Muscle strength was assessed using handgrip dynamometry. We determined the prospective association of muscle strength with mortality, controlling for age, sex, smoking, BMI, marital status, education, geographical region, and self-perceived health.
Over a mean follow-up of 4.2 ± 2.4 years, more than half of the participants died (n = 971, 51.4%). The mean handgrip strength was 20.4 ± 8.0 kg for all participants, with men (26.7 ± 7.5 kg) showing significantly higher strength than women (16.4 ± 5.4 kg). Using the median level of muscle strength as reference (18 kg), lower and higher levels were associated in a gradual and curvilinear fashion with higher and lower mortality risk, respectively. The 10th percentile of muscle strength (10 kg) showed a hazard ratio (HR) of 1.27. The 90th percentile (31 kg) showed an HR of 0.69. Stratified for sex, the median levels of muscle strength were 26 kg for men and 16 kg for women. The 10th percentile of muscle strength showed HRs of 1.33 at 15 kg for men and 1.19 at 10 kg for women. The 90th percentile of muscle strength showed HRs of 0.75 at 35 kg for men and 0.75 at 23 kg for women. Sensitivity analyses, which excluded individuals who died within the first 2 years of follow-up, confirmed the main findings.
Rather than a specific threshold, muscle strength is gradually and inversely associated with mortality risk in the oldest old. As muscle strength at all ages is highly adaptive to resistance training, these findings highlight the importance of improving muscle strength in both men and women among the oldest old.
Infectious Agents in the Gut Can Accelerate Neurodegeneration
https://www.fightaging.org/archives/2024/11/infectious-agents-in-the-gut-can-accelerate-neurodegeneration/
A growing weight of evidence indicates that changes in the gut microbiome taking place over the course of aging contribute to the onset and progression of neurodegenerative conditions. Species producing beneficial metabolites, such as butyrate to upregulate expression of BDNF to encourage neurogenesis, decline in number. Species that are harmful because they contribute to the constant, unresolved inflammation that is characteristic of old age increase in number. It is thought that the decline of immune function plays a role in this shift, as the immune system becomes ever less capable of gardening the gut microbiome to remove problematic microbes. Other factors are likely in play, such as barrier dysfunction, both in the intestine and brain, allowing microbes and unwanted, pro-inflammatory metabolites to pass into tissue in increasing numbers.
The aging of the gut microbiome is longer-term process of change, taking place over decades and leading to a distinctly dysfunctional gut microbiome in patients with neurodegenerative conditions. But in the short term, the presence of infectious agents in the aged gut microbiome can accelerate neurodegenerative processes via the same inflammatory mechanisms. In today's open access paper, researchers illustrate this point using a mouse model of Alzheimer's disease infected with a common species of bacteria that causes pneumonia. Infection clearly worsens the neurodegenerative pathology in these mice, as one might expect for any significant cause of inflammation.
An Enteric Bacterial Infection Triggers Neuroinflammation and Neurobehavioral Impairment in 3xTg-AD Transgenic Mice
Klebsiella pneumoniae is infamous for hospital-acquired infections and sepsis, which have also been linked to Alzheimer disease (AD)-related neuroinflammatory and neurodegenerative impairment. However, its causative and mechanistic role in AD pathology remains unstudied. Thus a preclinical model of K. pneumoniae enteric infection and colonization is developed in an AD model (3xTg-AD mice) to investigate whether and how K. pneumoniae pathogenesis exacerbates neuropathogenesis via the gut-blood-brain axis.
K. pneumoniae, particularly under antibiotic-induced dysbiosis, was able to translocate from the gut to the bloodstream by penetrating the gut epithelial barrier. Subsequently, K. pneumoniae infiltrated the brain by breaching the blood-brain barrier. Significant neuroinflammatory phenotype was observed in mice with K. pneumoniae brain infection. K. pneumoniae-infected mice also exhibited impaired neurobehavioral function and elevated total tau levels in the brain. Metagenomic analyses revealed an inverse correlation of K. pneumoniae with gut biome diversity and commensal bacteria, highlighting how antibiotic-induced dysbiosis triggers an enteroseptic "pathobiome" signature implicated in gut-brain perturbations.
The findings demonstrate how infectious agents following hospital-acquired infections and consequent antibiotic regimen may induce gut dysbiosis and pathobiome and increase the risk of sepsis, thereby increasing the predisposition to neuroinflammatory and neurobehavioral impairments via breaching the gut-blood-brain barrier.
F-actin in the Brain Inhibits Autophagy to Promote Neurodegeneration
https://www.fightaging.org/archives/2024/11/f-actin-in-the-brain-inhibits-autophagy-to-promote-neurodegeneration/
Researchers here report on an interesting mechanism by which the cell maintenance processes of autophagy are inhibited in the aging brain, in flies at least. Changes in the maintenance of the actin cytoskeleton inside a cell cause this reduction in autophagy, but can be blocked via small molecules in order to restore a more youthful function in brain tissue. In general, approaches to improve autophagy in aging tissue have been shown to produce a slowing of aging and improved function of aged tissues in short-lived species. From what we know of interventions such as exercise and calorie restriction, both of which improve autophagy, the effects on life span are not as large in long-lived species such as our own, even if some of the short term benefits are similar.
The actin cytoskeleton is a key determinant of cell structure and homeostasis. However, possible tissue-specific changes to actin dynamics during aging, notably brain aging, are not understood. Actin can be found in two forms: monomeric (G-actin) and filamentous (F-actin). Assembly and disassembly of actin filaments are regulated by a large number of actin-interacting proteins, making maintenance of the actin cytoskeleton highly susceptible to disruption caused by aging. Here, we show that there is an age-related increase in filamentous actin (F-actin) in Drosophila brains, which is counteracted by prolongevity interventions.
Critically, decreasing F-actin levels in aging neurons prevents age-onset cognitive decline and extends organismal healthspan. Mechanistically, we show that autophagy, a recycling process required for neuronal homeostasis, is disabled upon actin dysregulation in the aged brain. Remarkably, disrupting actin polymerization in aged animals with cytoskeletal drugs restores brain autophagy to youthful levels and reverses cellular hallmarks of brain aging. Finally, reducing F-actin levels in aging neurons slows brain aging and promotes healthspan in an autophagy-dependent manner. Our data identify excess actin polymerization as a hallmark of brain aging, which can be targeted to reverse brain aging phenotypes and prolong healthspan.
Mifepristone Triggers Some of the Same Benefits as Rapamycin
https://www.fightaging.org/archives/2024/11/mifepristone-triggers-some-of-the-same-benefits-as-rapamycin/
Mifepristone is known to slow aging in flies. While mifepristone is not a drug that one should take to slow aging, as it has complex, sizeable effects on hormone levels that would tend to outweigh any benefits obtained, it is interesting to see that it has some of the same effects as rapamycin on life span and aspects of autophagy. Autophagy recycles damaged cell structures, and improved autophagy is a feature of many of the interventions known to slow aging in short-lived laboratory species, such as the flies used in this study. The researchers focused on measuring autophagy targeting mitochondria, known as mitophagy. Given the importance of mitochondrial dysfunction to aging, that is a reasonable choice. Nonetheless, it is hard to imagine much in the way of further research emerging based on the use of mifepristone or other near analog small molecules because of the effects on hormonal metabolism.
The drugs mifepristone and rapamycin were compared for their relative ability to increase the life span of mated female Drosophila melanogaster. Titration of rapamycin indicated an optimal concentration of approximately 50 μM, which increased median life span here by average +81%. Meta-analysis of previous mifepristone titrations indicated an optimal concentration of approximately 466 μM, which increased median life span here by average +114%. Combining mifepristone with various concentrations of rapamycin did not produce further increases in life span, and instead reduced life span relative to either drug alone.
Assay of maximum midgut diameter indicated that rapamycin was equally efficacious as mifepristone in reducing mating-induced midgut hypertrophy. The mito-QC mitophagy reporter is a previously described green fluorescent protein (GFP)-mCherry fusion protein targeted to the outer mitochondrial membrane. Inhibition of GFP fluorescence by the acidic environment of the autophagolysosome yields an increased red/green fluorescence ratio indicative of increased mitophagy. Creation of a multi-copy mito-QC reporter strain facilitated assay in live adult flies, as well as in dissected midgut tissue. Mifepristone was equally efficacious as rapamycin in activating the mito-QC mitophagy reporter in the adult female fat-body and midgut. The data suggest that mifepristone and rapamycin act through a common pathway to increase mated female Drosophila life span, and implicate increased mitophagy and decreased midgut hypertrophy in that pathway.
Changes in Microglia in the Aged Brain: Cause or Consequence of Neurodegeneration?
https://www.fightaging.org/archives/2024/11/changes-in-microglia-in-the-aged-brain-cause-or-consequence-of-neurodegeneration/
Researchers can measure a great many facets of aging in the brain and elsewhere in the body, ranging across structural changes, gene expression changes, cell behavior changes, and so forth ad infinitum. The challenge lies in establishing cause and effect, and the relative importance of different possible mechanisms of damage and dysfunction. So, as researchers point out here, there is a compelling picture to be painted of the way in which the innate immune cells called microglia change in biochemistry and behavior in the aging brain, but no concrete certainty that these changes are the major contribution to neurodegenerative conditions that many researchers argue them to be. Inflammatory microglia may well be an important proximate cause of dysfunction in the brain, and a range of animal studies strongly suggest this to be the case, but as ever solid proof lags somewhat behind inference.
Microglia signatures refer to specific profiles of microglia activity or gene expression. Through a comprehensive analysis of gene and protein expression profiles, we can identify specific genes and proteins that characterize different states of microglial activation, including those associated with pro-inflammatory and anti-inflammatory states. This approach contributes to the knowledge base regarding the dynamics of microglial activation in both physiological and pathological conditions. The question of whether these signatures are a cause or a consequence of microglia-related brain disorders is highly relevant since understanding whether alterations in microglia are a primary cause of brain pathologies (e.g., neurodegenerative diseases such as Alzheimer's disease) or whether they are a secondary response to such pathologies can significantly influence therapeutic strategies.
Microglia can become hyperactive or dysfunctional, releasing inflammatory cytokines and neurotoxic factors that can damage neurons and the extracellular matrix. This may contribute to the pathogenesis of diseases such as Alzheimer's disease and Parkinson's disease. Microglia can have a proactive role in shaping the neuronal environment. If altered, they can negatively affect synaptogenesis, synaptic plasticity, and clearance of cellular debris, leading to brain dysfunction. Microglia interact closely with neurons, astrocytes, and other cell types in the brain. Alterations in these interactions caused by primary diseases may lead to changes in microglia signatures as an adaptive response, which could exacerbate the disease. Microglia may be activated in response to brain damage or other pathologies. In this scenario, alterations in their signatures could be a consequence of the presence of pathogens, abnormal protein deposits, or neuronal damage. In neurodegenerative disorders, neuroinflammation may be a secondary response to primary pathological processes. For example, in Alzheimer's disease, microglia may be activated by amyloid-β deposits.
The relationship between microglia signatures and brain disorders is likely to be bidirectional and dynamic. In some conditions, dysfunctional microglia may actively contribute to disease onset and progression (cause), while in other situations, they may represent an adaptive or maladaptive response to pre-existing damage or pathology (consequence). Understanding this complex interaction requires further research, including longitudinal studies and experimental models that can isolate the various factors involved. Unraveling these dynamics may lead to new and more effective therapeutic strategies for microglia-related brain diseases.
Amount of Central Fat Predicts Mortality Risk in Non-Obese Individuals
https://www.fightaging.org/archives/2024/11/amount-of-central-fat-predicts-mortality-risk-in-non-obese-individuals/
The more visceral fat you have, and the longer you have it for, the worse off you are. Visceral fat contributes to chronic inflammation and metabolic dysfunction, accelerating the onset and progression of age-related conditions. This is well understood in the case of obesity, but even lesser degrees of being overweight are harmful to long-term health, as the data here illustrates.
Visceral fat tissue, interspersed with resident immune cells, when activated, increases local or systemic inflammation, leading to the production of cytokines and other immune and pro-inflammatory mediators, promoting insulin resistance, oxidative stress, and altered cell metabolism. Abdominal fat accumulation is associated with changes in glucose metabolism and lipid metabolism, primarily due to insulin resistance, resulting in hyperlipidemia, hypertension, glucose intolerance, and mitochondrial abnormalities in skeletal muscle.
An individual's leanness or corpulence is commonly assessed using the Body Mass Index (BMI), but this measure does not account for fat distribution or differentiate between fat and muscle mass. Therefore, clinicians have explored alternative anthropometric measurements that better reflect body composition and mortality risk, such as waist circumference (WC) and waist-to-hip and waist-to-height ratios. Most of these measures fail to reflect body composition effectively or are easily affected by variations in other body measurements. A new body shape index (A Body Shape Index, ABSI) has been introduced as an anthropometric measure unrelated to BMI, based on waist circumference adjusted for weight and height. ABSI offers a better explanation of how central abdominal adiposity is strongly associated with mortality than other anthropometric measurements, and it captures additional harmful effects not captured by BMI.
This prospective cohort study included 159 volunteers (94 women, aged 60-80 years), recruited in the frame of the "Physical Activity and Nutrition for Great Ageing" (PANGeA) Cross-border Cooperation Program Slovenia-Italy 2007-2013, and followed for 10 years. During the 10-year follow-up, 10 deaths (6.7%) were recorded. ABSI (adjusted for age, smoking, comorbidities, and therapy) was an independent predictor of mortality (hazard ratio = 4.65). Higher ABSI scores were linked to reduced VO2max (r = -0.190) and increased systolic blood pressure (r = 0.262). An ABSI-based predictive model showed strong discriminatory power, and thus ABSI is a reliable predictor of 10-year mortality in active, non-obese elderly individuals and may improve risk stratification in clinical practice.
Tricarboxylic Acid Cycle Genes are Downregulated with Age
https://www.fightaging.org/archives/2024/11/tricarboxylic-acid-cycle-genes-are-downregulated-with-age/
The tricarboxylic acid (TCA) cycle is an important part of the process by which mitochondria generate chemical energy store molecules to power the cells. With age, mitochondrial function diminishes throughout the body. This produces disruption to cell and tissue function, particularly in energy-hungry tissues such as the brain and muscles. This loss of mitochondrial function is thought to be the consequence of some combination of damage to mitochondrial DNA and maladaptive changes in the expression of relevant genes, such as those coding for proteins necessary to mitochondrial energy production. For example, researchers here point out the reduced production of TCA cycle proteins in aged tissues, and note it as as a contribution to age-related mitochondrial dysfunction.
Aging is associated with a decline in physiological functions and an increased risk of metabolic disorders. The liver, a key organ in metabolism, undergoes significant changes during aging that can contribute to systemic metabolic dysfunction. This study investigates the expression of genes involved in the tricarboxylic acid (TCA) cycle, a critical pathway for energy production, in the aging liver. We analyzed RNA sequencing data from the Genotype-Tissue Expression (GTEx) project to assess age-related changes in gene expression in the human liver. To validate our findings, we conducted complementary studies in young and old mice, examining the expression of key TCA cycle genes using quantitative real-time PCR.
Our analysis of the GTEx dataset revealed a significant reduction in the expression of many genes that are critical for metabolism, including fat mass and obesity associated (FTO) and adiponectin receptor 1 (ADIPOR1). The most overrepresented pathway among the statistically enriched ones was the TCA cycle, with multiple genes exhibiting downregulation in older humans. This reduction was consistent with findings in aging mice, which also showed decreased expression of several TCA cycle genes. These results suggest a conserved pattern of age-related downregulation of TCA cycle, potentially leading to diminished mitochondrial function and energy production in the liver. The reduced expression of TCA cycle genes in the aging liver may contribute to metabolic dysfunction and increased susceptibility to age-related diseases. Understanding the molecular basis of these changes provides new insights into the aging process and highlights potential targets for interventions aimed at promoting healthy aging and preventing metabolic disorders.
Developmental Reversal May Be More Common than Thought in Lower Animals
https://www.fightaging.org/archives/2024/11/developmental-reversal-may-be-more-common-than-thought-in-lower-animals/
Lower animals that are essentially tiny blobs of stem cells are in principle capable of immortality, as illustrated by hydra and the jellyfish Turritopsis dohrnii that cycles from immaturity to adulthood and back again. Even if not actually immortal, their potential life spans absent predation are too long to be experimentally confirmed in any practical way. These species are so very different from higher animals with complex nervous systems that store data that it is quite possible there is little of practical use to medicine to be learned here. A blob of stem cells can continually regrow and replace all of its component parts, or change its shape and state of maturity as needed, whereas a vertebrate is more vulnerable, more locked in to its structure and the state of that structure. We might think that aging has the look of an inevitable consequence of having a nervous system that stores data, coming to rely on the structural state of that tissue, no longer being able to easily discard cells and replace them.
To date, the capacity of one life cycle stage to transform back to the preceding stage by morphological reorganization has been regarded as a distinctive and unparallelled feature of cnidarians. This ability for reverse development known for a few cnidarian species was first reported over a century ago and gained wide renown with the discovery of the peculiar life cycle of the so-called immortal jellyfish, Turritopsis dohrnii. This hydrozoan is currently considered the only animal able to repeatedly rejuvenate after sexual reproduction, challenging our understanding of aging and suggesting a potential for biological immortality.
Ctenophores (or comb jellies) are one of the oldest extant animal lineages. Accumulated evidence supporting their phylogenetic position as the sister group to all other animals place them as a pivotal model to study unique evolutionary innovations potentially rooted within the deepest branches of the animal tree of life. Here, we demonstrate that the ctenophore Mnemiopsis leidyi is capable of reversal from mature lobate to early cydippid when fed following a period of stress. Our findings illuminate central aspects of ctenophore development, ecology, and evolution and show the high potential of M. leidyi as a unique model system to study reverse development and rejuvenation.
The NIH on Research into the Biology of Aging
https://www.fightaging.org/archives/2024/11/the-nih-on-research-into-the-biology-of-aging/
This article from the National Institutes of Health (NIH) takes a look at some of the mainstream research efforts aimed at measuring and better understanding the processes of biological aging. Where intervention arises from this part of the field, efforts tend to focus on altering the operation of metabolism to modestly slow aging, such as via the use of autophagy-promoting drugs like rapamycin and other mTOR inhibitors. The alternative, much better approach of identifying and repairing specific forms of cell and tissue damage in order to produce rejuvenation, continues to receive less attention, despite the compelling data produced by senolytic drugs that clear senescent cells.
With advancing age comes an increased risk of disease and disability. As people live longer, they are more likely to develop at least one age-related disease. Aging in people results from the gradual accumulation of defects and damage to the molecules and cells that make up our bodies. Unlike a car, our bodies have built-in mechanisms for repairing this damage. But even these repair mechanisms wear out over time. Eventually, enough damage accumulates to affect the function of whole organs and systems. NIH-funded researchers have been working to better understand aging at the molecular level. They're studying ways to measure differences in how people age before health problems appear. They're also exploring possible ways to slow, or even reverse, aging at the molecular level. This could lead to better approaches to prevent or treat age-related disease and disability.
Before you can tell if a treatment could slow or even reverse aging, you need to know how fast someone is aging in the first place. It's no secret that people age at different rates. Some people remain healthy and disease-free well into their ninth or even tenth decade of life. Others develop age-related diseases, such as cancer, heart disease, and dementia, much earlier. The concept of "biological age" is often used to describe these differences. Biological age reflects the molecular damage that accumulates over the years and eventually leads to disease and disability. Differences in biological age can develop years before age-related diseases appear. So a treatment to slow aging would also need to start well before such diseases appear. Then, to find out if a treatment worked or not, you'd have to track people for the rest of their lives. That's why researchers have been working to develop "aging clocks" to measure a person's biological age.
Age-reversing therapies like these are still some way in the future. Still, there are hints of lifestyle interventions that may have potential to lengthen life and delay aging. One that's been particularly well-studied is calorie restriction (CR). This is where you reduce the total number of calories you consume, but still get enough of the essential nutrients. To find out whether CR might have benefits in humans, too, NIH funded the Comprehensive Assessment of Long-Term Effects of Reducing Intake of Energy (CALERIE) study. More than 200 healthy, middle-aged volunteers were randomly assigned to two groups. Participants in one group were challenged to reduce their daily caloric intake by 25% for two years and given dietary and behavioral strategies for doing so. Those in the other group continued to eat their normal diets. Researchers examined the pace of biological aging in CALERIE participants. Those in the CR group had a much slower pace of aging as measured by clinical blood biomarkers. They also had a small but significant decrease in DunedinPACE, a rate of aging clock, while participants in the other group did not.
A Glance at the Work of Calico Labs on the Integrated Stress Response
https://www.fightaging.org/archives/2024/11/a-glance-at-the-work-of-calico-labs-on-the-integrated-stress-response/
The work conducted at Calico Labs is representative of the broad faction of the aging research community that aims to alter metabolism in order to modestly slow the progression of aging. The damaged and dysfunctional environment of aged tissues and cell structures produces cell stress via many different mechanisms. Cells respond to that stress in a smaller set of ways, and some of those responses are maladaptive, making the situation worse. The best way forward would be to repair the damage that causes cell stress; the approach taken here is to instead alter the behavior of cells in order to selectively sabotage some of the maladaptive response to cell stress.
The Integrated Stress Response (ISR) is a conserved signaling pathway across species and an important area of focus for Calico because of its possible link to many age-related diseases and its potential as a target for new drug development. Calico is currently developing an ISR inhibitor, Fosigotifator (ABBV-CLS-7262), which is being tested in the clinic as a potential treatment for two neurodegenerative diseases. To gain a deeper understanding of how the ISR controls cell states, the Calico team used a highly specific and tunable cellular model to disentangle the effects of the ISR from other processes that are engaged when cells encounter stress or damage that disrupts them.
A key discovery was the suppression of a process known as the tricarboxylic acid (TCA) cycle which is a series of reactions that are essential for creating energy via cellular respiration. The researchers found that when the ISR is turned on even at low levels, carbon is redirected from mitochondria to make amino acids and glutathione, a key antioxidant that protects cells. This shows how the ISR may help cells adapt to mitochondrial dysfunction or starvation, two common triggers of the pathway, by rewiring their metabolism. Using a synthetic tool researchers also showed that activation of the ISR can lead to the formation of droplets that store fats, also known as lipids. This is interesting because lipid droplets have been linked to neurodegenerative diseases.
Obstructive Sleep Apnea Correlates with a Raised Risk of Later Dementia
https://www.fightaging.org/archives/2024/11/obstructive-sleep-apnea-correlates-with-a-raised-risk-of-later-dementia/
Researchers here correlate obstructive sleep apnea in older individuals with a greater risk of the later development of dementia. In the present environment of widespread excess body weight, and the harms caused by excess visceral fat tissue, we might reasonably anticipate that correlations between obstructive sleep apnea and dementia risk are the result of excess weight contributing independently to both outcomes. The Stop-BANG screening questionnaire used to define the presence of obstructive sleep apnea in a patient includes a weight threshold as a factor, but it nonetheless seems an oversight to not also control for the weight of study participants.
This study included 18,815 women and men age 50+ years (dementia-free at baseline) who participated in the Health and Retirement Study (HRS), a nationally representative cohort of US adults. Presence of obstructive sleep apnea (OSA) was defined by self-reported diagnosis or key HRS items that correspond to elements of a validated OSA screening tool (STOP-Bang). Incident dementia cases were identified using a validated, HRS-based algorithm derived from objective cognitive assessments. Survey-weighted regression models based on pseudo-values were utilized to estimate sex- and age-specific differences in cumulative incidence of dementia by OSA status.
Data from 18,815 adults were analyzed, of which 9% of women and 8% of men (weighted proportions) met criteria for incident dementia. Known/suspected OSA was more prevalent in men than in women (weighted proportions 68% vs. 31%). Unadjusted sex-stratified analyses showed that known/suspected OSA was associated with higher cumulative incidence of dementia across ages 60-84 years for women and men. By age 80, relative to adults without known/suspected OSA, the cumulative incidence of dementia was 4.7% higher for women with known/suspected OSA, and 2.5% for men with known/suspected OSA, respectively. Adjusted associations between age-specific OSA and cumulative incidence of dementia attenuated for both women and men but remained statistically significant.
Investigating the Relationship Between Circadian Rhythm and Longevity in Mammals
https://www.fightaging.org/archives/2024/11/investigating-the-relationship-between-circadian-rhythm-and-longevity-in-mammals/
A range of interesting research delves into the relevance of circadian rhythm to aging, from both (a) the perspective of how the regulation of circadian rhythm becomes dysfunctional with age, and (b) the evolutionary perspective of how differences in circadian rhythm may be relevant to differences in species life span. The research noted here falls into the second camp, looking at the evolution of genes that regulate circadian rhythm. The data is suggestive of the importance of circadian rhythm to the evolution of longevity in a species, but strangely, this importance is not universal across the varieties of mammal.
The relationship between genomic characteristics and species traits is of paramount importance for biology. We proposed a novel technique that allows one to determine the relationship between any genomic characteristic and species traits, such as maximal reported lifespan, the body weight of an adult animal, and the related longevity quotient. This technique is exemplified in the physiologically significant genes involved in regulating circadian rhythms, which change quite rapidly during evolution.
Regardless of devising this technique, the study of the genes that are critical for circadian rhythms is of interest on its own. For instance, we thoroughly examined the paralogous genes Fbxl21 and Fbxl3, which are involved in the regulation of circadian rhythms. We found out that the above-mentioned characteristic of the Fbxl21 gene correlates with the maximal reported lifespan and body weight only in two superorders of placental mammals, Euarchontoglires (the clades Euarchonta, Lagomorpha, and Rodentia) and Afrotheria. On the contrary, such a correlation is not observed in other superorders, such as Laurasiatheria and Xenarthra. The presence or absence of the correlation is confirmed statistically with a very high accuracy.
Thus for certain genes (such as Fbxl21), the accumulation of amino acid substitutions up to pseudogenization or gene loss, as well as the preference for certain amino acids in the encoded protein, is an effective way to achieve a significant phylogenetic change. The Fbxl21 gene and the species-specific maximal reported lifespan, together with body weight, are examples of such a phylogenetic change in Euarchontoglires and Afrotheria, which is also observed in relatively small taxonomic groups, as, for example, in anthropoid apes and the Cercopithecidae.