Fight Aging! Newsletter, September 16th 2024

Aging is a complex biological process characterized by obesity and immunosenescence throughout the organism. Immunosenescence involves a decline in immune function and the increase in chronic-low grade inflammation, called inflammaging. Adipose tissue expansion, particularly that of visceral adipose tissue (VAT), is associated with an increase in pro-inflammatory macrophages that play an important role in modulating immune responses and producing inflammatory cytokines. The leukotriene B4 receptor 1 (BLT1) is a regulator of obesity-induced inflammation. Its ligand, LTB4, acts as a chemoattractant for immune cells and induces inflammation. Studies have shown that BLT1 is crucial for cytokine production during lipopolysaccharide (LPS) endotoxemia challenge in younger organisms. However, the expression patterns and function of BLT1 in older organisms remains unknown.

In this study, we investigated BLT1 expression in immune cell subsets within the VAT of aged male and female mice. Moreover, we examined how antagonizing BLT1 signaling could alter the inflammatory response to LPS in aged mice. Our results demonstrate that aged mice exhibit increased adiposity and inflammation, characterized by elevated frequencies of B cells and T cells, along with pro-inflammatory macrophages in VAT. BLT1 expression is the highest in VAT macrophages. LPS and LTB4 treatment result in increased BLT1 in young and aged bone marrow-derived macrophages (BMDMs). However, LTB4 treatment resulted in amplified Il6 from aged, but not young BMDMs. Treatment of aged mice with the BLT1 antagonist, U75302, followed by LPS-induced endotoxemia resulted in an increase in anti-inflammatory macrophages, reduced phosphorylated NFκB and reduced Il6.

In conclusion, this study provides valuable insights into the age- and sex- specific changes in BLT1 expression on immune cell subsets within VAT. This study offers support for the potential of BLT1 in modulating inflammation in aging.

Cellular senescence (CS), as a hallmark feature of aging, plays a crucial role in various aging-related diseases, including central nervous system (CNS) disorders. Research findings from cellular or animal disease models, along with detection data from human components, such as cerebrospinal fluid and brain tissue, provide compelling evidence supporting the close correlation between CS and CNS diseases. The transition of critical cellular components in the brain, such as microglia, astrocytes, and brain vascular endothelial cells, toward the senescent phenotype often triggers inflammatory cascades, disrupts the integrity of the blood-brain barrier, impairs neuroregeneration, and contributes to various pathological processes. This exacerbates neural damage, hampers tissue repair, and adversely affects prognosis.

Senescent cells (SCs), besides exhibiting a decline in normal structure and function, are intricately linked to the aberrant generation and accumulation of pathogenic substances, such as β-amyloid (Aβ), Tau protein, and α-Synuclein (α-Syn) in the brain, which contribute to prolonged and complicated conditions. Moreover, SCs can disrupt the balance of the local microenvironment through paracrine mechanisms, amplifying senescent effects and harming surrounding healthy cells. Notably, the development of CNS diseases involves molecular mechanisms that can induce CS. This process exacerbates neurotoxicity in SCs, creating a vicious cycle. Therefore, CS is a promising target for therapeutic intervention in CNS diseases, as disrupting the vicious cycle mediated by SCs in the brain has prospects for preventing and managing such conditions.

Recently, CS has become a prominent area of research in CNS diseases, especially neurodegenerative disorders. Clinical trials on senolytics in CNS disorders are limited. This is primarily because CS-based targeted therapy represents a relatively novel approach, and the diverse complexity of CNS diseases poses challenges in implementing and designing these methods. Further complicating matters is the unique structure of the blood-brain barrier, which limits the entry of many drugs into the brain to exert their effects while avoiding severe adverse effects. Only one study on Alzheimer's disease (AD) (NCT04063124) has published preliminary results. The trial recruited five patients with early AD symptoms for a 12-week intermittent anti-CS treatment (dasatinib and quercetin, D+Q). According to published data, both senolytic components D and Q levels are elevated in the blood. D was detected in the cerebrospinal fluid of four patients, while Q was not in any patient's cerebrospinal fluid. Notably, the team observed an increase in the expression of inflammatory cytokines in the participants' fluid. They speculated that this could be related to a transient trigger of inflammation when SCs are cleared or that it could serve as a marker of SC death.

While this early clinical study established that senolytic therapy is safe, feasible, and well tolerated in AD patients, effectively clearing amyloid-like proteins and reducing blood inflammation, a larger sample size and a placebo control group are required in future studies for further scientific validation. Trials NCT04685590 and NCT04785300 are advancing in this direction. These pioneering efforts to leverage senolytics for treating CNS diseases are highly anticipated.

Polyamines, including putrescine, spermidine, and spermine, as well as their precursors and regulatory enzymes, are highly conserved across species. Our previous work has highlighted the multifaceted consequences of spermidine supplementation, which exerts cardioprotective and neuroprotective effects, stimulates autophagy and mitochondrial function, and extends lifespan in a variety of laboratory models. These findings are particularly salient given that polyamine metabolism, predominantly regulated by the pacemaker enzyme ODC1 (ornithine decarboxylase 1), is a critical driver of cellular growth. The concordant activity of polyamines, stimulation of cell growth and induction of autophagy, differs from the discordant action of MTOR (mechanistic target of rapamycin kinase), which stimulates cell growth but represses autophagy.

Rapamycin, a potent and selective inhibitor of MTOR, has long been recognized for its ability to extend longevity across species, including yeast and worms. Our recent data demonstrate that rapamycin treatment in yeast is accompanied by a concomitant increase in endogenous spermidine levels. Notably, the inhibition of endogenous spermidine synthesis significantly attenuates the autophagy-inducing and longevity-promoting effects of rapamycin in yeast, human cell lines, and worms, underscoring the essential role of polyamine metabolism in these processes. Accordingly, our study provides further compelling evidence that the pro-autophagic and lifespan-extending effects of dietary restriction and intermittent fasting - physiological triggers that shut down TOR signaling - are largely dependent on functional endogenous polyamine metabolism.

Acute fasting is associated with an increase in polyamine levels across multiple species and tissues, supporting our hypothesis that this rise in polyamines is necessary to trigger the autophagic cascade. Moreover, genetic perturbation of MTOR activity in transgenic mice further corroborates our findings, as changes in spermidine levels align with expected autophagic outcomes. Notably, our previous work has shown that spermidine can effectively counteract the downstream effects of hyperactive insulin-IGF1 signaling during cardiac aging in mice. These findings indicate that spermidine is not only a "caloric restriction mimetic" in the sense that its supplementation mimics the beneficial effects of nutrient deprivation on organismal health but that it is also an obligatory downstream effector of the antiaging effects of fasting and rapamycin.

A total of 115 participants were included in this study, of whom 40 received 5 mg/week of rapamycin, 36 received 10 mg/week of rapamycin, and 39 received placebo. At baseline, all participant groups were comparable across measures of age, sex, height, weight, BMI, and blood safety markers, with the exception of the mean HbA1C, which was lower in the 5 mg group than placebo. Overall, participants were in exceptionally good health at baseline, as evaluated by self-reports of health.

No significant differences in markers of metabolic health, liver, and kidney function, or moderate to severe adverse events in the rapamycin treatment groups were reported compared to placebo after 48 weeks. This is consistent with previous reports that healthy individuals are not likely to experience serious side effects from low dose rapamycin, and suggests that concerns over negative effects of rapamycin stemming from studies of high-dose, daily usage in chronically ill individuals may have limited applicability in the context of rapamycin use for healthy aging. Indeed, we observed more instances of individuals reporting improvements in chronic ailments in the rapamycin treatment groups than in placebo, and more instances reported of worsening ailments in the placebo group compared to treatment groups after 48 weeks. This effect will be important to investigate further in longitudinal follow-up with PEARL participants.

Over the 48 weeks of the study, weekly rapamycin use demonstrated dose-dependent and sex-specific improvements in multiple functional healthspan metrics compared to placebo, including lean tissue mass, bone mineral content, pain (SF-36, WOMAC), social functioning (SF-36), overall quality of life (SF-36), and overall osteoarthritis (WOMAC) score. All statistically significant benefits were observed in participants taking 10 mg rapamycin per week and consistent with preclinical reports of a female-benefit bias in mice, female participants demonstrated significant benefits across all the outcome measures except bone mineral content. Findings from this study that male participants in the 10 mg rapamycin group gained an average of 1.4% bone mineral content (BMC) over 48 weeks and female participants in the 10 mg group gained an average lean tissue mass of 4.5% hold significant promise for rapamycin in reducing risks of age-related disease and mortality.

While this trial extended notably longer than other human trials of rapamycin use for healthy longevity to date, it is likely that even greater effects would be observed with an increased observation period, a broader (specifically higher) range of doses, as well as a larger study cohort. Across all measures in this study, a remarkable level of variability in response was observed for all rapamycin users, regardless of dose. Given our recent work on the variability of rapamycin bioavailability in individuals, we expect that it played a meaningful role in the results observed here, though this trial concluded prior to our findings on bioavailability. Further, we have discovered since the conclusion of this trial that compounded rapamycin is approximately 3.5x less bioavailable than commercially available formulations, suggesting that the 5mg and 10mg rapamycin groups received an average equivalent of 1.4mg and 2.9mg respectively. Although both doses are relatively low, making the observation of benefits in the treatment group more striking, the 10mg rapamycin cohort in this study was more firmly in the range of what is thought to be an optimal longevity dose range for rapamycin.

Using the NHANES database, a large GWAS database, and Mendelian randomization (MR) analyses, this study investigated the complex relationship between periodontitis, cardiovascular disease (CVD), and biological aging. The results indicated that periodontitis was a risk factor for CVD and that aging plays a mediating role in this association. Gene-level predictive analysis further confirmed the causal effect of periodontitis on small-vessel stroke and revealed the causal effect of biological aging on periodontitis and specific CVD. Simultaneously, the study found that CVD may exacerbate the progression of biological aging.

We observed that an increase in the degree of periodontitis was associated with an increased risk of CVD. Additionally, MR analysis revealed the potential causal effect of periodontitis on small vessel stroke. A number of epidemiologic studies have suggested a significant positive association between periodontitis and CVD, such as CHD and stroke. The possible mechanisms for this association include the systemic inflammation caused by periodontitis. Patients with periodontitis often have elevated levels of inflammatory markers in the blood, such as c-reactive protein and white blood cell count. These biomarkers play a key role in the pathophysiological mechanism of CVD. On the other hand, pathophysiological studies have revealed the potential role of oral bacteria in the formation of atherosclerosis. In addition, further supporting the pathological link between periodontitis and CVD is the observation of pathological changes similar to CVD, such as the formation of atherosclerotic plaques, in animal experimental models following the induction of periodontitis.

We investigated the relationship between periodontitis, CVD, and aging markers. The results indicated that the progression of periodontitis is significantly associated with biological aging. This suggests that periodontitis may not only affect oral health but accelerate the systemic aging process. The presence of periodontitis may aggravate the aging of organisms and even increase all-cause mortality. These findings provide strong evidence for the important role of periodontitis in the mechanism of systemic aging. Furthermore, biological aging was found to be linked to a higher risk of CVD, which aligned with previous research. Our findings also suggest a potential causal relationship between biological aging and periodontitis, as well as a reciprocal causal effect between aging and CVD. In other words, aging contributes to the development of periodontitis and CVD and can also be a potential consequence of CVD. These results underscore the intricate interplay between periodontitis, CVD, and biological aging.

Aging-related biochemical changes in nerve cells lead to dysfunctional synapses and disrupted neuronal circuits, ultimately affecting vital processes such as brain plasticity, learning, and memory. The imbalance between excitation and inhibition in synaptic function during aging contributes to cognitive impairment, emphasizing the importance of compensatory mechanisms. Fear conditioning-related plasticity of the somatosensory barrel cortex, relying on the proper functioning and extensive up regulation of the GABAergic system, in particular interneurons containing somatostatin, is compromised in aging (one-year-old) mice.

The present research explores two potential interventions, taurine supplementation, and environmental enrichment, revealing their effectiveness in supporting learning-induced plasticity in the aging mouse brain. They do not act through a mechanism normalizing the Glutamate/GABA balance that is disrupted in aging. Still, they allow for increased somatostatin levels, an effect observed in young animals after learning. These findings highlight the potential of lifestyle interventions and diet supplementation to mitigate age-related cognitive decline by promoting experience-dependent plasticity.

As individuals age, there is a concomitant decline in the number of muscle fibres and the cross-sectional area of muscle. The decline in mass and function of skeletal muscle in older adults often results in falls, disability and even death. Hydrogen sulfide (H2S) is a gasotransmitter that is produced endogenously in mammals, primarily through enzymatic pathways. H2S directly reacts with oxygen, hydrogen peroxide, and peroxynitrite, thereby reducing cellular oxidative damage. Additionally, it can modify proteins post-translationally through S-sulfhydration, which affects their functionality. Studies have demonstrated that human skeletal muscle expresses a considerable number of H2S-producing enzymes.

H2S has been shown to effectively alleviate muscle atrophy caused by diabetes and obesity. The precise mechanism by which this occurs is not yet fully understood. However, scientists have postulated that it may be related to H2S antioxidant stress, the regulation of mitochondrial energy metabolism, the reduction of apoptosis, and the up-regulation of autophagy. The objective of this study was to investigate whether H2S can enhance the expression and S-sulfhydration of USP5, thereby facilitating the deubiquitination of AMPKα1. Which, in turn, would result in the up-regulation of autophagy, which would contribute to the alleviation of skeletal muscle ageing. We find this to be the case.

Aggregation of alpha-Synuclein (αSyn) has been connected to several neurodegenerative diseases, such as Parkinson's disease (PD), dementia with Lewy Bodies (DLB), and multiple system atrophy (MSA), that are collected under the umbrella term synucleinopathies. The membrane binding abilities of αSyn to negatively charged phospholipids have been well described and are connected to putative physiological functions of αSyn. Consequently, αSyn-related neurodegeneration has been increasingly connected to changes in lipid metabolism and membrane lipid composition.

Indeed, αSyn aggregation has been shown to be triggered by the presence of membranes in vitro, and some genetic risk factors for PD and DLB are associated with genes coding for proteins directly involved in lipid metabolism. At the same time, αSyn aggregation itself can cause alterations of cellular lipid composition and brain samples of patients also show altered lipid compositions. Thus, it is likely that there is a reciprocal influence between cellular lipid composition and αSyn aggregation, which can be further affected by environmental or genetic factors and ageing.

Little is known about lipid changes during physiological ageing and regional differences of the lipid composition of the aged brain. In this review, we aim to summarise our current understanding of lipid changes in connection to αSyn and discuss open questions that need to be answered to further our knowledge of αSyn related neurodegeneration.

The human gastrointestinal (GI) tract contains trillions of microorganisms that exist symbiotically with the host due to a tolerant, regulatory cell- rich intestinal immune system. The microbiota-gut-brain axis (MGBA) refers to the interaction between host microbiome, the central nervous system (CNS), and the gastrointestinal tract. Barriers extending beyond the gut epithelial barrier, spanning the MGBA, are emerging as novel pathways facilitating communication between the gut microbiome and the brain. Disruption of the barrier integrity contributes a variety of gastrointestinal and neurological diseases. For decades, our understanding of barriers has shifted from perceiving them as rigidly impermeable cellular structures to dynamic and finely regulated communication interfaces with varying levels of permeability.

In this review, we explore barrier structure and function across the MGBA and examine the modulation of barrier function upon gut microbiota alteration. Additionally, we provide a summary of current knowledge concerning the lymphatic vasculature in the GI tract and CNS, highlighting its role in linking the reciprocal relationship between the lymphatic system and the microbiota, which collectively contributes to whole-body homeostasis. For decades, blood vessels and nerves were thought to be the primary pathways by which metabolites and toxins affect distant organs. It now appears that intestinal lymphatics constitute an additional pathway in the gut-organ axis. Numerous diseases are associated with deranged blood vessel endothelial barrier function, increased permeability, and extravasation into the microenvironment surrounding lymphatic vessels. It is conceivable that the microbiota might exert its effect on the initiation or progression of CNS disease through the lymphatic network in a direct or indirect manner.

Heterochronic parabiosis, the parabiotic pairing of two animals of different ages, qualities, or conditions, has been used to provide an experimental system to test the systemic effects of aging, development of age-related diseases, or other age-related parameters. Therefore, we hypothesized that certain systemic factors contribute to the robust regeneration of skin tissues in young animals and inhibit regeneration in old animals. To avoid animal discomfort and mortality owing to parabiosis, the procedure was performed carefully following a precise protocol approved by our animal care committee. To measure changes in the levels of plasma proteins of each parabiont, broad-scale proteomic analysis was performed.

In this study, we demonstrated for the first time that hyaluronan and proteoglycan link protein 1 (HAPLN1, previously known as link protein), whose level of expression decreases in mouse sera with age, played a previously unrecognized function: it restored the amounts of collagen and hyaluronic acid (HA), which progressively declined with skin age. HAPLN1 is a structural protein that links HA and proteoglycans, thus promoting the formation of stable water-rich aggregates in the pericellular matrix (PCM). Our studies suggest that HAPLN1 is a key player that reduces or eliminates cellular damage accumulated in aging skin owing to its involvement in multiple regeneration mechanisms, such as anti-oxidation, anti-senescence, and possibly anti-inflammation. Hence, HAPLN1 substitution therapy could be a promising rejuvenating strategy for preventing or restoring aged skin.

FOXO transcription factors modulate aging-related pathways and influence longevity in multiple species, but the transcriptional targets that mediate these effects remain largely unknown. Here, we identify an evolutionarily conserved FOXO target gene, Oxidative stress-responsive serine-rich protein 1 (OSER1), whose overexpression extends lifespan in silkworms, nematodes, and flies, while its depletion correspondingly shortens lifespan.

In flies, overexpression of OSER1 increases resistance to oxidative stress, starvation, and heat shock, while OSER1-depleted flies are more vulnerable to these stressors. In silkworms, hydrogen peroxide both induces and is scavenged by OSER1 in vitro and in vivo. Knockdown of OSER1 in Caenorhabditis elegans leads to increased ROS production and shorter lifespan, mitochondrial fragmentation, decreased mitochondrial ATP production, and altered transcription of mitochondrial genes.

Human proteomic analysis suggests that OSER1 plays roles in oxidative stress response, cellular senescence, and reproduction, which is consistent with the data and suggests that OSER1 could play a role in fertility in silkworms and nematodes. Human studies demonstrate that polymorphic variants in OSER1 are associated with human longevity. In summary, OSER1 is an evolutionarily conserved FOXO-regulated protein that improves resistance to oxidative stress, maintains mitochondrial functional integrity, and increases lifespan in multiple species. Additional studies will clarify the role of OSER1 as a critical effector of healthy aging.

Astrocytes are the most abundant cell type in the mammalian brain and provide structural and metabolic support to neurons, regulate synapses and become reactive after injury and disease. However, a small subset of astrocytes settles in specialized areas of the adult brain where these astrocytes instead actively generate differentiated neuronal and glial progeny and are therefore referred to as neural stem cells. Common parenchymal astrocytes and quiescent neural stem cells share similar transcriptomes despite their very distinct functions. Thus, how stem cell activity is molecularly encoded remains unknown.

Here we examine the transcriptome, chromatin accessibility, and methylome of neural stem cells and their progeny, and of astrocytes from the striatum and cortex in the healthy and ischaemic adult mouse brain. We identify distinct methylation profiles associated with either astrocyte or stem cell function. Stem cell function is mediated by methylation of astrocyte genes and demethylation of stem cell genes that are expressed later. Ischaemic injury to the brain induces gain of stemness in striatal astrocytes. We show that this response involves reprogramming the astrocyte methylome to a stem cell methylome and is absent if the de novo methyltransferase DNMT3A is missing. Overall, targeting DNA methylation to gain stemness or astrocyte features offers a potential therapeutic avenue to repair the diseased nervous system or fight cancer.

Previous studies have shown that glial and neuronal changes may trigger synaptic dysfunction in Alzheimer's disease (AD). However, the link between glial and neuronal markers and synaptic abnormalities in the living brain is poorly understood. Here, we investigated the association between biomarkers of astrocyte and microglial reactivity and synaptic dysfunction in 478 individuals across the aging and AD spectrum from two cohorts with available cerebrospinal fluid (CSF) measures of amyloid-β (Aβ), phosphorylated tau(pTau181), astrocyte reactivity (GFAP), microglial activation (sTREM2), and synaptic biomarkers (GAP43 and neurogranin).

Elevated CSF GFAP levels were linked to presynaptic and postsynaptic dysfunction, regardless of cognitive status or Aβ presence. CSF sTREM2 levels were associated with presynaptic biomarkers in cognitively unimpaired and impaired Aβ+ individuals and postsynaptic biomarkers in cognitively impaired Aβ+ individuals. Notably, CSF pTau181 levels mediated all associations between GFAP or sTREM2 levels and synaptic dysfunction biomarkers. These results suggest that neuronal-related synaptic biomarkers could be used in clinical trials targeting glial reactivity in AD.

In conclusion, our findings support a link between glial reactivity and synaptic dysfunction in living humans, which appears to be explained by pathological phosphorylation of tau. While astrocyte reactivity seems to be a partially independent phenomenon leading to synaptic dysfunction in aging and AD, the effects of microglial activation on synaptic function are determined by the emergence of Aβ pathology. These results suggest that synaptic biomarkers hold potential as secondary endpoints for clinical trials targeting glial reactivity in aging and AD.

Parkinson's disease (PD) has been consistently linked to alterations within the gut microbiome. Metagenomic sequencing was used to characterize taxonomic and functional changes to the PD microbiome and to explore their relation to bacterial metabolites and disease progression. Motor and non-motor symptoms were tracked using Movement Disorder Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS) and levodopa equivalent dose across ≤5 yearly study visits.

PD-derived stool samples had reduced intermicrobial connectivity and seven differentially abundant species compared to controls. A suite of bacterial functions differed between PD and controls, including depletion of carbohydrate degradation pathways and enrichment of ribosomal genes. Faecalibacterium prausnitzii-specific reads contributed significantly to more than half of all differentially abundant functional terms. A subset of disease-associated functional terms correlated with faster progression of MDS-UPDRS part IV and separated those with slow and fast progression with moderate accuracy. Most PD-associated microbial trends were stronger in those with symmetric motor symptoms.

In conclusion, we provide further evidence that the PD microbiome is characterized by reduced intermicrobial communication and a shift to proteolytic metabolism in lieu of short-chain fatty acid production, and suggest that these microbial alterations may be relevant to disease progression.

The intersection of aging and cancer is a multifaceted issue arising from the interplay between aging processes and cancer development. In fact, aging is linked to a higher frequency of genetic mutations and genomic instability, all of which can predispose cells to malignant transformation. Additionally, the efficiency of DNA repair mechanisms and immune surveillance declines with age, further increasing cancer risk. Chronic inflammation, characteristic of both aging and cancer, creates an environment conducive to cancer initiation, growth, and progression. Addressing the complex relationship between cancer and aging requires a deep understanding of the underlying molecular and cellular processes and a personalized approach to cancer prevention, detection, and treatment.

Recent research has highlighted the significant impact of chronic inflammation on immune aging, showing a strong correlation between inflammation and telomere biology in various major health conditions, including cancer. New evidence suggests that aging is driven by chronic inflammation, which depletes stem cells, disrupts cellular communication, and leads to telomere loss - telomeres being protective "caps" at chromosome ends. To maintain telomere length and protect chromosomes from damage, highly proliferative cell types, such as hematopoietic progenitors and effector leukocytes, use the enzyme telomerase. Telomerase activity is influenced by leukocyte proliferation, persistent inflammation, and the production of reactive oxygen species (ROS). This review focuses on potential interactions between inflammation and telomere biology in cancer development. Understanding the immune system's interplay with telomerase activity could reveal new therapeutic targets for treating cancer and other age-related disorders.