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- Senescent Cells Contribute to the Harms Caused by Aged Blood
- Evidence for Parkinson's Disease to Have a Bacterial Origin
- Mitochondrially Targeted Lipid Nanoparticles as a Delivery System
- Initial STOMP-AD Trial Results Published, Not Yet Enough Data for Firm Conclusions to be Drawn
- A High Fat Diet Accelerates Atherosclerosis Less Directly than One Might Suspect
- How to Construct Measures of Biological Age
- A Long-Term Comparison of Metformin in Diabetics with Non-Diabetic Controls
- In Search of Distinctive Features of the Gut Microbiome in Long-Lived Individuals
- Greater Fitness in Humans Implies a Younger Epigenome and Transcriptome
- Intestinal Barrier Dysfunction as a Feature of Aging in Many Species
- NAFLD as an Age-Related Condition
- Towards Sensory Hair Cell Regeneration in the Inner Ear
- Raised Levels of PLGF are Associated with Vascular Dementia
- Extracellular Chaperones to Remove Damaged Proteins Outside the Cell
- Categorizing the Landscape of Companies and Approaches in the Longevity Industry
Senescent Cells Contribute to the Harms Caused by Aged Blood
The present state of parabiosis studies demonstrates that diluting blood in old animals produces improved health, whether this is achieved using saline or young blood. Thus we expect there to be few beneficial factors in young blood, and many harmful factors in old blood. So far there has been mixed or little benefit noted in studies in which young plasma is transfused into old recipients, but dilution appears more promising.
As noted here, the growing burden of senescent cells in aged tissue is a significant source of those harmful factors. Senescent cells are very active, generating a mix of factors known as the senescence-associated secretory phenotype (SASP). Much of this is inflammatory signaling, which when sustained for the long term causes a broad range of disarray in the immune system and tissue function. That includes encouraging more cells to become senescent, a feedback loop of damage and signaling, like much of aging.
An Oil Change is Not a Gasket Change: Insights from the Interaction of "Old Blood" and Senolytic Therapy
Does aging damage drive the pro-aging signaling environment in old plasma? Or does old plasma cause the aging damage? Researchers chose to look at the interplay between circulating factors and senescent cells, because each of them is known to worsen the other. Could "pro-aging" factors in blood from a biologically aged organism drive aging damage in a young animal? The answer: Yes. When they bathed cells from the deep layers of mouse skin in old mouse blood, the cells began to exhibit signs of senescence.
In living, breathing mice, even a single round of old blood transfusion was enough to push a substantial number of the cells in young mice into senescence. The effect emerged within the first two days, and even more senescent cells crept into the young animals' tissues over the following two weeks. And the corrosive spread of senescent cell markers was accompanied by a surge of circulating SASP factors in the young animals' blood. Between the eruption of senescent cells in their tissues and the tainting of their blood with "pro-aging" factors, the young mice became afflicted with many of the infirmities of old age. The aged blood sapped them of strength and endurance, fat infiltrated their muscles, they suffered minor kidney damage, and their liver function declined as the organ became somewhat fibrotic.
Why does an animal's blood become fouled with these baleful proteins with age? All of this deranged "pro-aging" signaling is the agonized biochemical crying-out of a body riddled with aging damage. As cells and essential biomolecules become damaged, they increasingly function abnormally, including in the production and reception of signaling molecules.
Researchers set out to purge the tissues of aged mice of a significant number of their senescent cells using either of two different drug regimens that destroy senescent cells: Navitoclax or the cocktail dasatinib plus quercetin (D+Q). Then they would see if having removed some of that damage from the old animals' tissues would make their blood less "pro-aging." And that's exactly what happened. Pretreating an old mouse with either senolytic approach before transferring its blood into a young mouse greatly reduced the "pro-aging" effects of its blood on the young animal, driving fewer of the young mouse's cells into senescence and causing less organ dysfunction
Evidence for Parkinson's Disease to Have a Bacterial Origin
The most visible symptoms of Parkinson's disease, the tremors and loss of motor control, result from the death of a small but vital population of dopamine-generating neurons in the brain. These neurons happen to be more sensitive than others to the underlying harmful biochemistry of the condition. Parkinson's disease begins with the misfolding of α-synuclein, one of the few proteins in the body that can become altered in a way that encourages other molecules of the same protein to alter in the same way, joining together to form solid aggregates. These α-synuclein aggregates are disruptive to cell function and ultimately toxic, causing cell death.
In recent years it has become clear that a sizable fraction of Parkinson's disease begins in the intestines. The initial α-synuclein misfolding occurs there, and then slowly spreads through the nervous system to the brain. In today's open access paper, researchers provide evidence for a specific bacterial species found in the gut to be responsible for producing this initial misfolded α-synuclein. It remains to be seen as to whether further human gut microbiome studies will replicate the results here and further support a role for bacteria in the origination of Parkinson's disease, or whether it is only a smaller fraction of the overall incidence of Parkinson's disease that has a bacterial origin.
To the extent that bacteria are capable of producing a sizable amount of misfolded α-synuclein in comparison to natural misfolding in human cells, one might expect to find it responsible for a majority of the incidence of Parkinson's disease. While this discovery may lead to the prevention of much of Parkinson's disease in the best case scenario, it doesn't much help those people who already have misfolded α-synuclein present in the central nervous system; at that point it is too late and other strategies will be needed.
Desulfovibrio bacteria enhance alpha-synuclein aggregation in a Caenorhabditis elegans model of Parkinson's disease
The aggregation of the neuronal protein alpha-synuclein (alpha-syn) is a key feature in the pathology of Parkinson's disease (PD). Alpha-syn aggregation has been suggested to be induced in the gut cells by pathogenic gut microbes such as Desulfovibrio bacteria, which has been shown to be associated with PD. This study aimed to investigate whether Desulfovibrio bacteria induce alpha-syn aggregation.
Fecal samples of ten PD patients and their healthy spouses were collected for molecular detection of Desulfovibrio species, followed by bacterial isolation. Isolated Desulfovibrio strains were used as diets to feed Caenorhabditis elegans nematodes which overexpress human alpha-syn fused with yellow fluorescence protein. Curli-producing Escherichia coli MC4100, which has been shown to facilitate alpha-syn aggregation in animal models, was used as a control bacterial strain, and E. coli LSR11, incapable of producing curli, was used as another control strain. The head sections of the worms were imaged using confocal microscopy. We also performed survival assay to determine the effect of Desulfovibrio bacteria on the survival of the nematodes.
Statistical analysis revealed that worms fed Desulfovibrio bacteria from PD patients harbored significantly more and larger alpha-syn aggregates than worms fed Desulfovibrio bacteria from healthy individuals or worms fed E. coli strains. In addition, during similar follow-up time, worms fed Desulfovibrio strains from PD patients died in significantly higher quantities than worms fed E. coli LSR11 bacteria. These results suggest that Desulfovibrio bacteria contribute to PD development by inducing alpha-syn aggregation.
Mitochondrially Targeted Lipid Nanoparticles as a Delivery System
Mitochondrial function declines with age, and one of the effects of this decline is an increased production of oxidizing molecules. Delivering antioxidants specifically to mitochondria has shown some ability to modestly slow aging in animal models, and has demonstrated its worth in the treatment of a few conditions characterized by excessive oxidative stress.
Efforts to develop mitochondrially targeted antioxidants to date have largely involved small molecules, and a limited number of classes of such molecules, those capable of localizing themselves to the mitochondria, have been established to date. Given a delivery system like lipid nanoparticles (LNPs) capable of targeting mitochondria, however, one can consider many different payloads. A broader selection of antioxidants, for a start, but there are many forms of protein therapy and gene therapy that one might want to send to mitochondria, given the means to do so.
Today's open access paper is focused on the liver as a target for LNP-delivered antioxidant therapy, as LNPs tend to end up in the liver, like most injected compounds or therapies. It is, however, possible to build LNPs that have very different biodistribution characteristics, either more broadly distributed throughout the body, or much more localized to specific tissues other than the liver. We should expect to see steady innovation on this front given initial demonstrations of the ability to target the delivery of LNP payloads to the mitochondria.
A system that delivers an antioxidant to mitochondria for the treatment of drug-induced liver injury
Mitochondria function as hubs for the integration and control of metabolic and immune systems by communicating with other organelles to maintain their individual functions and provide energy and signals. This organelle produces reactive oxygen species (ROS) in the electron transport chain that produces adenosine triphosphate (ATP). ROS production is regulated by oxidoreductases and antioxidant pathways, and moderate levels of ROS that play a role in signal transmission, cell survival, apoptosis, differentiation, and the activation of the immune system.
However, when mitochondria are unable to maintain homeostasis due to external stimulation, they generate excessive levels of ROS, thus inducing oxidative damage. Increased oxidative stress leads to mitochondrial dysfunction, resulting in premature ageing and the development of various diseases. On this point, the delivery of antioxidant molecules to mitochondria would be a useful type of therapeutic strategy.
Delivering a drug or other molecule to mitochondria needs to reach the target organ, be taken up by cells and then transferred to an organelle. The use of lipid nanoparticles (LNPs) for lipid-based drug delivery have the potential to overcome these challenges. Coenzyme Q10 (CoQ10) is a well-known antioxidant molecule and also acts as an essential coenzyme for ATP production in mitochondria. We previously reported on a method for preparing a CoQ10-MITO-Porter, a mitochondria-targeted LNP encapsulating CoQ10, using a microfluidic device. The procedure had a high degree of reproducibility and could be scaled up.
This study reports on an attempt to establish a system for delivering an antioxidant molecule CoQ10 to mitochondria and the validation of its therapeutic efficacy in a model of acetaminophen liver injury caused by oxidative stress in mitochondria. A CoQ10-MITO-Porter, a mitochondrial targeting lipid nanoparticle (LNP) containing encapsulated CoQ10, was prepared using a microfluidic device. It was essential to include polyethylene glycol (PEG) in the lipid composition of this LNP to ensure stability of the CoQ10, since it is relatively insoluble in water.
Based on transmission electron microscope observations and small angle X-ray scattering measurements, the CoQ10-MITO-Porter was estimated to be a 50nm spherical particle without a regular layer structure. The use of the CoQ10-MITO-Porter improved liver function and reduced tissue injury, suggesting that it exerted a therapeutic effect on APAP liver injury.
Initial STOMP-AD Trial Results Published, Not Yet Enough Data for Firm Conclusions to be Drawn
The initial results from the first five patients enrolled in the STOMP-AD trial were recently published as a preprint paper. This clinical trial assesses the outcome of a (possibly too low) dose of the senolytic combination of dasatinib and quercetin in Alzheimer's patients. The hypothesis to be tested is that the age-related increase in the burden of senescent cells in the brain is important in the onset and progression of neurodegeneration. Animal models of inflammatory neurodegeneration have shown considerable improvement following clearance of senescent cells, and a range of evidence implicates senescent cells in aspect of brain aging.
Because only a few patients have completed the trial so far, there isn't too much that one can say about the results, but they do confirm that the treatment passes the blood-brain barrier as expected, and is relatively safe. The researchers observed changes in inflammatory markers consistent with a reduction in harmful senescent cell signaling, but not in a statistically robust way given the low number of patients. They did not observe any useful outcome in measures of cognitive function, which is unfortunate.
There is some thought in the community that the doses used in the Mayo Clinic sponsored trials of dasatinib and quercetin are too low (e.g. 100mg or 125mg of dastinib and 1000mg or 1250mg of quercetin). The Betterhumans clinical trial conducted a few years ago used higher doses; unfortunately nothing has yet been published on this, I believe. Nonetheless, one would have hoped to see some improvement in cognitive function in these patients if cellular senescence is a major mechanism in Alzheimer's disease and other forms of neurodegeneration. We will have to see how the rest of the trial data looks as it emerges over the next few years. These trials are not moving rapidly, and there is definitely room for independent efforts to test these senolytics in other conditions and many more patients.
Senolytic therapy to modulate the progression of Alzheimer's Disease (SToMP-AD) - Outcomes from the first clinical trial of senolytic therapy for Alzheimer's disease
Cellular senescence has been identified as a pathological mechanism linked to tau and amyloid beta (Aβ) accumulation in mouse models of Alzheimer's disease (AD). Clearance of senescent cells using the senolytic compounds dasatinib (D) and quercetin (Q) reduced neuropathological burden and improved clinically relevant outcomes in the mice. Herein, we conducted a vanguard open-label clinical trial of senolytic therapy for AD with the primary aim of evaluating central nervous system (CNS) penetrance, as well as exploratory data collection relevant to safety, feasibility, and efficacy.
Participants with early-stage symptomatic AD were enrolled in an open-label, 12-week pilot study of intermittent orally-delivered D+Q. CNS penetrance was assessed by evaluating drug levels in cerebrospinal fluid (CSF) using high performance liquid chromatography with tandem mass spectrometry. Safety was continuously monitored with adverse event reporting, vitals, and laboratory work. Cognition, neuroimaging, and plasma and CSF biomarkers were assessed at baseline and post-treatment. Five participants (mean age: 76±5 years; 40% female) completed the trial. Treatment was well-tolerated with no early discontinuation and six mild to moderate adverse events occurring across the study.
Our study was not powered to examine target engagement, but instead designed to collect exploratory data on baseline to post-treatment changes in markers of cellular senescence and senescence-associated secretory phenotype (SASP) both in CSF and blood. Change in IL-6 was a prespecified secondary outcome. The analyses revealed a statistically significant elevation of IL-6 in CSF after treatment. Plasma levels modestly increased, but did not reach statistical significance. The treatment-induced changes in IL-6 may reflect senescent cell apoptosis whereby IL-6 was directly released from senescent cells upon their lysis; alternatively, apoptosis may have initiated an immune response to clear the cellular debris.
Recognizing that IL-6 is a pleiotropic cytokine, we simultaneously performed a broader evaluation of cytokines and chemokines to better infer the treatment effect. CSF analyses indicated baseline to post-treatment decreases in adaptive immunity markers, TARC, IL-17A, I-TAC, Eotaxin and Eotaxin-2; and chemokine, MIP-1α. A similar pattern was observed in plasma whereby treatment was associated with a decrease in adaptive immunity markers IL-23, IL-21, IL-17, IL-31, and VEGF54; and chemokines, MIP-1α and MIP-1β. Given that senescent cells secrete these molecules as SASP factors, the observed reduction support a decrease in senescent cell burden post-treatment.
In CSF, we observed a significant increase in GFAP levels from baseline to post-treatment. CSF GFAP levels are presumed to reflect reactive astrogliosis and demonstrate elevations early in the neurodegenerative disease process. In our study, it is unclear if increases in GFAP reflect or an acute response to treatment. Coupled with the elevated CSF IL-6 data, it is tempting to speculate that the concomitant increase in GFAP may reflect apoptosis of senescent astrocytes. Supporting evidence for this would require additional blood and CSF collections, weeks or months after the end of treatment, to determine if increased GFAP and IL-6 were transient or sustained responses to senolytic treatment.
A High Fat Diet Accelerates Atherosclerosis Less Directly than One Might Suspect
High blood cholesterol accelerates the onset of atherosclerosis, making it easier to reach the tipping point at which localized excesses of cholesterol form in blood vessel walls. The majority of cholesterol is generated in the liver, not obtained from the diet - and yet high fat diets are well proven to accelerate atherosclerosis. Researchers here provide evidence for the mechanism to be less direct than might be expected, involving the gut microbiome and its relationship with tissues and the immune system. Certain components of dietary fat lead to a cascade of events that provoke an inflammatory response, and the more fat, the greater the chronic inflammation.
Anything that induces a lasting state of unresolved inflammatory signaling will accelerate the development of atherosclerosis. This is again a matter of shifting the tipping point at which the innate immune cells called macrophages, responsible for clearing excess cholesterol from blood vessel walls, become overwhelmed by circumstances. Inflammatory signaling shifts macrophages into a state more appropriate for defense against pathogens than for clearing up metabolic debris. Fewer macrophages clearing cholesterol means a greater deposition of cholesterol.
High-fat diet 'turns up the thermostat' on atherosclerosis
Obesity and a high-cholesterol, high-fat diet are both well-established risk factors for atherosclerosis. In fact, obese individuals are two and a half times more likely to develop heart disease. However, the mechanistic link between obesity and atherosclerosis eludes scientists. The researchers behind this new study believe the link may be in how specific derivatives of natural emulsifiers in a Western diet alter the way that cells that line the intestines interact with gut-resident bacteria. "We study natural emulsifiers in the diet called phospholipids. For example, if you look at salad dressing and shake it up, it is the phospholipids, or emulsifiers, that keeps the oil in globules. Those emulsifiers can get modified by specific enzymes in the intestinal cells into very potent pro-inflammatory molecules in the body."
Using a mouse model, researchers found that on a high-fat high-cholesterol diet, the cells that line the small intestine churn out reactive phospholipids that makes the intestinal lining more susceptible to invasion by the bacteria that live in the gut. "The normal defenses for intestinal lining cells to keep bacteria in the lumen of the intestine are reduced when they take up large amounts of cholesterol and fat. This also results in bacteria being able to come in direct contact with the cells lining your intestines called enterocytes. Without those defenses, this results in more bacterial products, like bacterial cell membranes that contain a toxin called endotoxin, getting into the bloodstream to cause inflammation."
"People who are obese and people eating high-fat, high-cholesterol diets have higher levels of endotoxin in their blood. It's not at the level of causing sepsis, but it causes a low level of inflammation. When the cholesterol and fat come into the mix, the endotoxin kind of turns up the thermostat on inflammation and that accelerates atherosclerosis and leads to increased heart attacks and strokes."
Role of enterocyte Enpp2 and autotaxin in regulating lipopolysaccharide levels, systemic inflammation, and atherosclerosis
Conversion of lysophosphatidylcholine to lysophosphatidic acid (LPA) by autotaxin, a secreted phospholipase D, is a major pathway for producing LPA. We previously reported that feeding Ldlr-/- mice standard mouse chow supplemented with unsaturated LPA or lysophosphatidylcholine qualitatively mimicked the dyslipidemia and atherosclerosis induced by feeding a Western diet. Here, we report that adding unsaturated LPA to standard mouse chow also increased the content of reactive oxygen species and oxidized phospholipids (OxPLs) in intestinal mucus.
We conclude that the Western diet increases the formation of intestinal OxPL, which i) induce enterocyte autotaxin resulting in higher enterocyte LPA levels; that ii) contribute to the formation of reactive oxygen species that help to maintain the high OxPL levels; iii) decrease intestinal antimicrobial activity; and iv) raise plasma lipopolysaccharide levels that promote systemic inflammation and enhance atherosclerosis.
How to Construct Measures of Biological Age
This paper provides an introduction to the several different methodological approaches that can be used to assemble a measure of biological age from data sets that exhibit changes with age. In recent years, many varied aging clocks have been produced and tested. Where such clocks are derived from epigenetic, transcriptomic, proteomic, and similar data, it remains unclear as to which processes of aging they reflect, and to what level of sensitivity. Clocks that use very few data points can produce good measures in a naturally aging population, but are unlikely to be useful when assessing the outcome of a potential rejuvenation therapy that targets only one or a few specific mechanisms of aging.
Aging is accompanied by a progressive decline in physiological functions and an accumulation of damage to the body, leading to an increased risk of morbidity and mortality. Based on birth date, chronological age (CA) is the traditional criterion for assessing aging. However, the degree of aging may vary significantly between individuals with the same CA. Therefore, CA is not the best indicator for evaluating the degree of aging in human individuals.
To seek a better index to assess the degree of aging of individuals, biological age (BA) are used as alternatives to CA to estimate aging status. BA is the most popularly used model. Aging markers are the basis for constructing biological age, and in this article we summarize the markers used in constructing biological age.
There are many ways to classify markers of aging, e.g., the aging markers can classify into two categories: histology-based data (DNA methylation, metabolomics, proteomics, etc.), and clinical biomarkers obtained from blood chemistry, hematology, anthropometry, and organ function test measurements. The "aging clock" developed from omics data is another form of biological age, multiple omics data can be combined to build the clock.
Until now, omics data have rarely been used in the construction of BA because of the high cost of its application in large-scale populations. Previously built BA models commonly choose aging biomarkers in multiple organs/systems, such as blood biomarkers, genetic indicators, and physical activity data. Biomarkers from diverse organs are more reflective of the overall body state. To build the BA model, these biomarkers can be applied to different model building methods like multiple linear regression (MLR), principal component analysis (PCA), Klemera and Doubal's method (KDM), deep learning, and other methods.
A Long-Term Comparison of Metformin in Diabetics with Non-Diabetic Controls
The study that started present interest in metformin as a potential approach to modestly slow aging was problematic in a number of ways, as examined in a lengthy series of posts at the SENS Research Foundation. It appeared to show that type 2 diabetics on metformin enjoyed a small survival advantage over non-diabetics not taking metformin. Here, researchers look at survival over twenty years, and find an apparent short-term gain in life expectancy over non-diabetics that vanishes after a few years. The hypothesis is that the effects of type 2 diabetes overwhelm the benefits of metformin given time. It remains unclear as to whether metformin can have any meaningful small benefit for non-diabetics; finding out is the goal of the proposed TAME trial.
We examined longevity in type 2 diabetes (T2D) patients treated with metformin therapy and compared them to matched controls and T2D patients treated with sulphonylurea therapy. Looking at individuals over a period of up to twenty years we showed that T2D patients had shorter survival times after first treatment than matched controls. When the study period was artificially truncated, we found a statistically significant benefit of metformin therapy for longevity over matched non-diabetic controls within the first three years. However, this benefit disappeared when we looked over longer periods of time (after five years).
This suggests that benefits of metformin may be short-term only and/or the longer-term benefits of metformin are negated by the life-shortening effects of T2D and associated comorbidities. An alternative explanation is that T2D patients experience better short-term survival outcomes following treatment due to lifestyle adjustment, as recommended by doctors. However, we did not see a benefit to longevity in the short-term for sulphonylurea therapy patients who would presumably be motivated to improve their lifestyle in the same way.
Metformin has been linked to lower mortality due to cancer, and to reduced cardiovascular disease (CVD) risk. Compared to the sulphonylurea therapy group, we did see significantly lower lifetime prevalence of cancer, and lower rates of cardiovascular disease. Excluding individuals with history of cancer and CVD prior to first treatment, these differences were even larger. This finding is supportive of the protective effects of metformin for cancer and CVD compared to other diabetes treatments. However, as we used non-diabetic controls who were matched on cancer and CVD status to the diabetic cases, we are unable to distinguish if there is a benefit of this treatment.
In Search of Distinctive Features of the Gut Microbiome in Long-Lived Individuals
Given the lack of compelling results to date in the search for genetic variants associated with longevity, I don't hold out a great deal of hope for the discovery of specific differences in gut microbial populations associated with longevity. A lot of small effect sizes will likely be discovered in a range of studies, but these results will not replicate between study populations. Equally, it seems clear that the gut microbiome as a whole does have a sizable effect on long-term health, and changes significantly with age in harmful ways. Rejuvenation of the gut microbiome does appear to be a viable strategy for improved health in later life, based on animal studies and very limited human data, and clinical trials should be undertaken to prove this point sooner rather than later.
Gut microbiota associated with longevity plays an important role in the adaptation to damaging stimuli accumulated during the aging process. The mechanism by which the longevity-associated microbiota protects the senescent host remains unclear, while the metabolites of the gut bacteria are of particular interest. Here, an integrated analysis of untargeted metabolomics and 16S rRNA gene sequencing was used to characterize the metabolite and microbiota profiles of long-lived individuals (aged ≥90 years) in comparison to old-elderly (aged 75-89 years), young-elderly (aged 60-74 years), and young to middle-aged (aged ≤59 years) individuals.
This novel study constructed both metabolite and microbiota trajectories across aging in populations from Jiaoling county (the seventh longevity town of the world) in China. We found that the long-lived group exhibited remarkably differential metabolomic signatures, highlighting the existence of metabolic heterogeneity with aging. Importantly, we also discovered that long-lived individuals from the familial longevity cohort harbored a microbiome distinguished from that of the general population.
Specifically, we identified that the levels of a candidate metabolite, pinane thromboxane A2 (PTA2), which is positively associated with aging, were consistently higher in individuals with familial longevity and their younger descendants than in those of the general population. Furtherly, functional analysis revealed that PTA2 potentiated the efficiency of microglial phagocytosis of β-amyloid 40 and enhanced an anti-inflammatory phenotype, indicating a protective role of PTA2 toward host health. Collectively, our results improve the understanding of the role of the gut microbiome in longevity and may facilitate the development of strategies for healthy aging.
Greater Fitness in Humans Implies a Younger Epigenome and Transcriptome
Exercise improves health and life expectancy in humans, so it shouldn't be all that surprising to find studies in which assessments of the epigenome and transcriptome show signs of greater youth in people with greater aerobic fitness. It is in fact somewhat surprising that early epigenetic clocks were insensitive to the state of physical fitness. In the study noted here, the researchers do not use any of the existing epigenetic or transcriptomic clocks, and instead build their own assessment of the youthfulness of epigenetic and transcriptomic profiles as compared to chronological age. The findings are interesting, but specific to muscle tissue rather than the body as a whole.
Exercise training prevents age-related decline in muscle function. Targeting epigenetic aging is a promising actionable mechanism and late-life exercise mitigates epigenetic aging in rodent muscle. Whether exercise training can decelerate, or reverse epigenetic aging in humans is unknown. Here, we performed a powerful meta-analysis of the methylome and transcriptome of an unprecedented number of human skeletal muscle samples (n = 3,176).
We show that: (1) individuals with higher baseline aerobic fitness have younger epigenetic and transcriptomic profiles, (2) exercise training leads to significant shifts of epigenetic and transcriptomic patterns toward a younger profile, and (3) muscle disuse "ages" the transcriptome. Higher fitness levels were associated with attenuated differential methylation and transcription during aging. Furthermore, both epigenetic and transcriptomic profiles shifted toward a younger state after exercise training interventions, while the transcriptome shifted toward an older state after forced muscle disuse.
We demonstrate that exercise training targets many of the age-related transcripts and DNA methylation loci to maintain younger methylome and transcriptome profiles, specifically in genes related to muscle structure, metabolism, and mitochondrial function. Our comprehensive analysis will inform future studies aiming to identify the best combination of therapeutics and exercise regimes to optimize longevity.
Intestinal Barrier Dysfunction as a Feature of Aging in Many Species
One of the more noteworthy aspect of fly aging is the degree to which it is centered around intestinal dysfunction. Increasing leakage of the intestinal barrier is a feature of aging in many species, however, as noted here. When the intestinal barrier is compromised, the result is an invasion of tissues by gut microbes, provoking chronic inflammation throughout the body and further consequent dysfunction.
A major challenge in the biology of aging is to understand how specific age-onset pathologies relate to the overall health of the organism. The integrity of the intestinal epithelium is essential for the wellbeing of the organism throughout life. In recent years, intestinal barrier dysfunction has emerged as an evolutionarily conserved feature of aged organisms, as reported in worms, flies, fish, rodents, and primates. Moreover, age-onset intestinal barrier dysfunction has been linked to microbial alterations, elevated immune responses, metabolic alterations, systemic health decline, and mortality.
Here, we provide an overview of these findings. We discuss early work in the Drosophila model that sets the stage for examining the relationship between intestinal barrier integrity and systemic aging, then delve into research in other organisms. An emerging concept, supported by studies in both Drosophila and mice, is that directly targeting intestinal barrier integrity is sufficient to promote longevity. A better understanding of the causes and consequences of age-onset intestinal barrier dysfunction has significant relevance to the development of interventions to promote healthy aging.
NAFLD as an Age-Related Condition
Non-alcoholic fatty liver disease (NAFLD) is an excess of lipids in the liver, disruptive of liver function. In our modern society of cheap calories and machineries of comfort the most common way to achieve an excess of lipids in the liver is obesity. That perhaps obscures the point that aspects of aging, such as growing mitochondrial dysfunction, change liver metabolism, and metabolism in general, to increase the risk of suffering NAFLD at a given weight in later life. We might not tend to think of NAFLD as an age-related condition per se, but it is certainly influenced by aging.
Due to the decline in the regenerative ability of the liver and dysfunctions in the immune response, older people are more likely to suffer from non-alcoholic fatty liver disease (NAFLD), acute and chronic liver injury, liver fibrosis, and other diseases. Studies have reported that the prevalence of NAFLD increases in the elderly, with a prevalence of less than 30% in people under 40 years of age and more than 50% in people over 60 years of age.
Currently, it is believed that the mechanism of development of NAFLD includes increased production of fat, increased dietary free fatty acid (FFA) levels, β-oxidative damage, and dysfunction in very low density lipoprotein synthesis. However, reduced activity and changes in diet structure lead to a continuous increase in body fat in the elderly. These factors lead to the accumulation of triglycerides (TGs) in the liver and eventually cause age-related NAFLD.
Studies have reported that the accumulation of TG droplets in hepatocytes is not a harmful process in itself. On the contrary, it is considered an adaptive response to excessive lipid uptake or the production of fat, and this imbalance in TG synthesis and breakdown causes fatty degeneration of the liver. In addition, the structural and functional changes in the mitochondria have been shown to be related to the pathogenesis of NAFLD. Ultramicroscopic analyses have demonstrated a disordered morphology of hepatocyte mitochondria in elderly patients with NAFLD, and the damage to the structure and function led to fatty degeneration of the liver and other injuries.
The changes in mitosis and fusion of mitochondria during ageing lead to the inhibition of mitochondrial phagocytosis. Cell function can be affected further if the damaged mitochondria are not cleared in time. The structural and functional changes in the mitochondria have been proven to be related to the pathogenesis of NAFLD, the loss of mitochondrial DNA (mtDNA) in hepatocytes affects function, leading to hepatic steatosis and other injuries. The present study reviewed the manifestations, role and mechanism of mitochondrial dysfunction in the progression of NAFLD in the elderly. In addition, the study discusses the treatment strategies for NAFLD based on the understanding of mitochondrial dysfunction and abnormal lipid metabolism to provide new ideas for the development of innovative drugs for the prevention and treatment of NAFLD.
Towards Sensory Hair Cell Regeneration in the Inner Ear
Numerous forms of deafness, including age-related hearing loss, involve either loss of hair cells in the inner ear or loss of their axonal connections to the brain. These cells do not normally regenerate in mammals, and there is some interest in finding a way to bypass the suppression mechanisms that allow growth of hair cells during development but prevent regrowth during adult life. Approaches that show promise in animal studies include stem cell transplants, gene therapies, and small molecules targeting regulatory pathways. Here, researchers report on the ability of a mix of small molecules and siRNAs to produce regeneration of hair cells; an interesting option, but clearly still at a very early stage of development.
Strategies to overcome irreversible cochlear hair cell (HC) damage and loss in mammals are of vital importance to hearing recovery in patients with permanent hearing loss. In mature mammalian cochlea, co-activation of Myc and Notch1 reprograms supporting cells (SC) and promotes HC regeneration. Understanding of the underlying mechanisms may aid the development of a clinically relevant approach to achieve HC regeneration in the non-transgenic mature cochlea. By single-cell RNAseq, we show that MYC/NICD "rejuvenates" the adult mouse cochlea by activating multiple pathways including Wnt and cyclase activator of cyclic AMP (cAMP), whose blockade suppresses HC-like cell regeneration despite Myc/Notch activation.
We screened and identified a combination (the cocktail) of drug-like molecules composing of small molecules and small interfering RNAs to activate the pathways of Myc, Notch1, Wnt and cAMP. We show that the cocktail effectively replaces Myc and Notch1 transgenes and reprograms fully mature wild-type (WT) SCs for HC-like cells regeneration in vitro. Finally, we demonstrate the cocktail is capable of reprogramming adult cochlea for HC-like cells regeneration in WT mice with HC loss in vivo. Our study identifies a strategy by a clinically relevant approach to reprogram mature inner ear for HC-like cells regeneration, laying the foundation for hearing restoration by HC regeneration.
Raised Levels of PLGF are Associated with Vascular Dementia
Angiogenesis, the growth of new blood vessels, is a complex process of successive stages, in which numerous cell types and signal molecules play changing roles as budding and growth of the new vessel progresses. Angiogensis becomes less effective with age, for reasons that remain unclear. Here, researchers note that increased levels of PLGF, a companion signal molecule to VEGF in regulating angiogenesis, are associated with poor outcomes in cerebral small vessel disease, a dysfunction of the smaller blood vessels in the brain. They hypothesize that an increased effort to conduct angiogenesis, likely unsuccessful given the noted decline in capillary density with age, is a reaction to the damage found in these aged, inflamed blood vessels.
Cerebral small vessel disease, a common disease marked by damage to the cells lining the blood vessels in the brain, is a major driver of cognitive problems and dementia in older adults. However, it can be difficult for doctors to determine whether a patient's cognitive impairments stem predominately from Alzheimer's disease or vascular problems, the two most common causes of dementia. In new research, scientists found that patients with higher levels of placental growth factor (PLGF) - a key molecule involved in the formation of new blood vessels, or angiogenesis - were more likely to have cognitive impairment or evidence of brain injury.
Researchers identified signaling involved in angiogenesis as potential biomarkers, theorizing that the body may respond to damaged small blood vessels in the brain with intensified efforts to grow more. For this study, researchers focused on just one of those signals, PLGF, which has previously been associated with cerebral blood flow regulation. Data had also suggested this may be a useful biomarker for identifying patients with cognitive impairment and dementia due to vascular brain injury.
335 patients underwent brain imaging, cognitive testing and blood collection. Researchers found those in the top quartile for PLGF measurement were three times as likely to have cognitive impairment or dementia compared to those in the bottom quartile. Every unit increase in total PLGF in the bloodstream was also associated with a 22% increase in the likelihood of having cognitive impairment and a 16% increase in the likelihood of having neuroimaging evidence of cerebral small vessel disease.
Extracellular Chaperones to Remove Damaged Proteins Outside the Cell
While the operation of chaperone proteins inside the cell is fairly well understood, how chaperones operate on proteins outside the cell is less well researched. Damaged and misfolded proteins exist outside the cell just as they exist inside the cell; consider amyloid-β aggregates in the context of Alzheimer's disease, for example. A greater understanding of extracellular chaperone proteins may enable novel strategies to target damaged and misfolded proteins characteristic of aging and disease, particularly in the brain.
A set of unique proteins - molecular chaperones - play an essential role in proteostasis: they target and interact with misfolded proteins, maintain their solubility, and designate them for refolding or degradation. And, while intracellular proteostasis is well understood, extracellular conditions are harsher. Mediating proteostasis in this environment requires specific extracellular molecular chaperones, and the specifics of extracellular proteostasis are yet to be fully understood. Take, for example, an extracellular chaperone, alpha 2-macroglobulin (ɑ2M), an abundant plasma protein. ɑ2M targets defective proteins and is speculated to facilitate the clearance of defective proteins. However, the exact mechanism of how this happens is unknown.
Now researchers have identified the substrates that ɑ2M targets for degradation. They also developed a novel assay that detects how ɑ2M mediates the lysosomal degradation of targeted proteins. The group also compared the substrate specificities of α2M and clusterin, another extracellular chaperone. Clusterin also plays a part in the extracellular degradation of proteins like amyloid-beta, the extracellular aggregation of which has been implicated in Alzheimer's disease. The group found that while α2M and clusterin had overlapping functions, their pathways were not redundant. α2M was seen to recognize the defective proteins more prone to aggregation. According to the researchers, this finding lends credence to the theory that an array of extracellular chaperones cooperates to protect us from the spectrum of misfolded proteins likely to be found in the body.
In the future, elucidating the molecular mechanism of protein degradation by extracellular chaperones may prove useful in treating related diseases, like Alzheimer's disease. By degrading and removing abnormal proteins that accumulate outside cells, extracellular chaperones have the potential to be a valuable therapeutic tool.
Categorizing the Landscape of Companies and Approaches in the Longevity Industry
Here I'll note an interesting effort to produce a taxonomy of companies and approaches to treatment in the longevity industry. There is a growing diversity of efforts to find ways to target various mechanisms and manifestations of aging, and since the industry is still small it remains possible for one person to walk through a list of the participants and understand what each is doing in a reasonable amount of time.
This post aims to provide a survey of all different scientific approaches in longevity biotech. Although comprehensive databases like Longevity List and AgingBiotech offer valuable information on various companies, it is still challenging to see the big picture and identify established or unexplored paths. Beginning with a broad overview of the entire landscape, we will delve deeper into each approach and scope out under-explored areas with promising potential.
There are four paradigms for longevity biotech therapeutics. (1) Reset and Repair: This paradigm focuses on targeting specific, known age-related pathways, factors, or damages identified in hallmarks of aging (with some modifications). (2) Replace: Falling within the domain of regenerative medicine, this paradigm includes the replacement of aged cells, tissues, organs, or even the whole body with younger counterparts or endogenous regeneration. (3) Reprogram: This paradigm is inspired by the natural rejuvenation process that occurs during early embryonic development, which enables the production of youthful offspring from old gametes. It aims to activate a similar embryonic-like program within aged cells, without altering their cell identity, through a process known as partial reprogramming. (4) Discover: This paradigm focuses on identifying novel targets or interventions for aging by analyzing extensive datasets using advanced machine learning techniques.
Compared to other biotech sectors such as oncology, longevity biotech is still in its infancy, both in terms of funding and the number of companies involved, despite the potential it holds to tackle the leading cause of death - aging. There is still an abundance of untapped opportunities in each paradigm, leaving several avenues for commercial development. In creating this landscape, my aim is to provide a structured approach to identify and address the lesser-known approaches within this field. As a starting point, consider which paradigm you'd like to see expanded, and go deeper there to find new opportunities for company formation or investment.